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Sample records for b-raf mutational status

  1. TAp73 is one of the genes responsible for the lack of response to chemotherapy depending on B-Raf mutational status

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    Cavia-Saiz Mónica

    2010-02-01

    Full Text Available Abstract Background Although there have been many studies on the p73 gene, some of its functions still remain unclear. There is little research on the relationship between p73 gene transcription and its protein expression and the response to certain drugs such as oxaliplatin and cetuximab, which are drugs currently used in colorectal cancer. The purpose of this study was to evaluate the impact of TAp73 expression on oxaliplatin and cetuximab-based chemotherapy in colorectal cancer cell lines with different K-Ras and B-Raf mutational status. Methods TAp73 was analyzed in three colorectal tumor cell lines HT-29, SW-480 and Caco-2. mRNA TAp73 was determined using Real time PCR; TAp73 protein by immunoblotting and cell viability was analyzed by the MTT method. Results We found that mRNA and TAp73 protein were decreased in cells treated with oxaliplatin (in monotherapy or combined with cetuximab when B-Raf is mutated. This was statistically significant and was also associated with higher cell viability after the treatment. Conclusions Here, for the first time we report, that there is a signaling loop between B-Raf activation and p73 function. Low expression of TAp73 in colorectal cancer cell lines with mutated B-Raf may be involved in the lack of response to oxaliplatin in monotherapy or combined with cetuximab.

  2. B-Raf mutation: a key player in molecular biology of cancer.

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    Rahman, M A; Salajegheh, A; Smith, R A; Lam, A K-Y

    2013-12-01

    B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common.

  3. The B-Raf status of tumor cells may be a significant determinant of both antitumor and anti-angiogenic effects of pazopanib in xenograft tumor models.

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    Brunilde Gril

    Full Text Available Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis.

  4. ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics

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    Levidou Georgia

    2012-02-01

    Full Text Available Abstract Background Colorectal (CRC carcinogenesis through various morphological stages has been linked to several genetic and epigenetic changes. The Raf/MEK/ERK (MAPK signal transduction cascade is an important mediator of a number of cellular fates. Methods In this study, we investigated the presence of B-raf and K-ras mutations in 94 consecutive cases of primary colon adenocarcinoma in correlation with the immunohistochemical expression of total and activated ERK and the expression of mismatch repair proteins (MMR hMLH1 and hMSH2 as well as their correlations with standard clinicopathological parameters. Results The immunostaining pattern for total and activated ERK was nuclear and cytoplasmic. hMLH1 and hMSH2 proteins were preserved in 45/63 (71.43% cases and 35/53 (66.04% cases respectively. Total ERK nuclear expression, was positively correlated with tumor stage (p = 0.049, whereas nuclear pERK expression was positively correlated with histological grade (p = 0.0113 and tumor stage (p = 0.0952, although the latter relationship was of marginal significance. DNA sequencing showed that 12 samples (12.7% had a mutation in B-RAF Exon 15 and none in Exon 11, whereas 22 (23.4% had a K-ras mutation. Disruption of the MAP kinase pathway-either through K-ras or B-raf mutation-was detected in 37% of all the examined cases, although the overexpression of total and activated ERK1/2 was not correlated with the mutational status of K-ras or B-raf genes. Finally, the preservation of hMLH1 or hMSH2 immunoexpression was not correlated with the presence of B-raf and/or K-ras mutations. Conclusions In this study, we present evidence that ERK activation occurs in a K-ras or B-raf -independent manner in the majority of primary colon cancer cases. Moreover, B-raf mutations are not associated with mismatch-repair deficiency through loss of hMLH1 or hMSH2 expression. Activated ERK could possibly be implicated in tumor invasiveness as well as in the acquisition of

  5. Preponderance of the oncogenic V599E and V599K mutations in B-raf kinase domain is enhanced in melanoma cutaneous/subcutaneous metastases

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    Downstream of Ras, the serine/threonine kinase B-raf has been reported to be mutated, among other carcinomas, in a substantial subset of primary melanomas with a preponderance of mutations within the kinase domain including the activating V599E and V599K transitions. We here investigated a representative series of 60 resection specimens of cutaneous and subcutaneous melanoma metastases for the presence of mutations within the activation segment (exon 15) of the B-raf kinase domain by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) gel electrophoresis. Sequencing of cloned PCR-SSCP amplicons resulted in 24 (40%) samples harbouring somatic mutations which is not exceeding the mutation frequency in recently investigated primary melanomas. The activating mutation T1796A was present in 24/60 (40%) resection specimens, followed in frequency by the oncogenic g1795A mutation in 8/60 (13%) cases. As to the B-raf protein sequence, the acidic amino acid transitions V599E and V599K were predicted in 19/60 (32%) and 6/60 (10%) cases, resepectively, but were not associated with enhanced risk for subsequent metastasis in patients' follow up. In comparison to the primary melanomas that we recently investigated, the spectrum of predicted B-raf protein mutations narrowed significantly in the cutaneous/subcutaneous metastases. Unexpectedly, V599 and V599E mutations were absent in cutaneous/subcutaneous metastases derived from acrolentiginous melanomas as preceding primary tumours. During transition from primary melanomas towards cutaneous/subcutaneous metastases, the spectrum of predicted B-raf mutations narrows significantly. Focusing on the V599E and V599K, these oncogenic mutations are likely to affect melanocyte-specific pathways controlling proliferation and differentiation

  6. Detection of up to 65% of Precancerous Lesions of the Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1

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    Schneider, Mandy; Scholtka, Bettina, E-mail: scholtka@uni-potsdam.de [Chair of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur- Scheunert-Allee 114-116, 14558 Nuthetal (Germany); Gottschalk, Uwe [Maria Heimsuchung Caritas-Klinik Pankow, Breite Straße 46/47, 13187 Berlin (Germany); Faiss, Siegbert [III. Medizinische Abteilung - Gastroenterologie und Hepatologie, Asklepios Klinik Barmbek, Rubenkamp 220, 22291 Hamburg (Germany); Schatz, Daniela; Berghof-Jäger, Kornelia [BIOTECON Diagnostics GmbH, Hermannswerder Haus 17, 14473 Potsdam (Germany); Steinberg, Pablo, E-mail: scholtka@uni-potsdam.de [Chair of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur- Scheunert-Allee 114-116, 14558 Nuthetal (Germany); Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover (Germany)

    2010-12-29

    In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous lesions carrying at least one of the four above-mentioned genes in a mutated form. CTNNB1 and B-Raf were screened by PCR-single-strand conformation polymorphism analysis, K-Ras by restriction fragment length polymorphism analysis and the APC gene mutation cluster region (codons 1243–1567) by direct DNA sequencing. APC mutations were only detected in 10% of the serrated lesions but in 34% of the adenomas. Twenty percent of the serrated lesions and 14% of the adenomas carried a mutated K-Ras. B-Raf was found to be mutated in 50% of the serrated lesions and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in serrated lesions. By using the above gene marker panel it could be shown that 65% of the serrated lesions and 61% of the adenomas carried at least one of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (in this study) and neoplastic lesions (in a previous study) of the human colon and rectum, this primer combination might also be suited to efficiently and non-invasively detect genetic alterations in stool DNA of patients with early colorectal cancer.

  7. Detection of up to 65% of Precancerous Lesions of the Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1

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    Daniela Schatz

    2010-12-01

    Full Text Available In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous lesions carrying at least one of the four above-mentioned genes in a mutated form. CTNNB1 and B-Raf were screened by PCR-single-strand conformation polymorphism analysis, K-Ras by restriction fragment length polymorphism analysis and the APC gene mutation cluster region (codons 1243–1567 by direct DNA sequencing. APC mutations were only detected in 10% of the serrated lesions but in 34% of the adenomas. Twenty percent of the serrated lesions and 14% of the adenomas carried a mutated K-Ras. B-Raf was found to be mutated in 50% of the serrated lesions and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in serrated lesions. By using the above gene marker panel it could be shown that 65% of the serrated lesions and 61% of the adenomas carried at least one of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (in this study and neoplastic lesions (in a previous study of the human colon and rectum, this primer combination might also be suited to efficiently and non-invasively detect genetic alterations in stool DNA of patients with early colorectal cancer.

  8. Detection of up to 65% of Precancerous Lesions of the Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1

    International Nuclear Information System (INIS)

    In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous lesions carrying at least one of the four above-mentioned genes in a mutated form. CTNNB1 and B-Raf were screened by PCR-single-strand conformation polymorphism analysis, K-Ras by restriction fragment length polymorphism analysis and the APC gene mutation cluster region (codons 1243–1567) by direct DNA sequencing. APC mutations were only detected in 10% of the serrated lesions but in 34% of the adenomas. Twenty percent of the serrated lesions and 14% of the adenomas carried a mutated K-Ras. B-Raf was found to be mutated in 50% of the serrated lesions and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in serrated lesions. By using the above gene marker panel it could be shown that 65% of the serrated lesions and 61% of the adenomas carried at least one of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (in this study) and neoplastic lesions (in a previous study) of the human colon and rectum, this primer combination might also be suited to efficiently and non-invasively detect genetic alterations in stool DNA of patients with early colorectal cancer

  9. 食管鳞癌K-ras、EGFR和B-raf突变的初步研究%A preliminary study on K-ras, EGFR, and B-raf mutations of esophageal squamous cell carcinoma

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    Huili Ma; Yongfei Xue; Changsheng Li; Jingwei Zhang; Zhonghai Ren

    2011-01-01

    Objective:Molecular targeted drugs have been widely used in clinical application which has successfully prolonged some patients'life.Meanwhile,molecular targeted drug therapy for esophageal cancer are attracting more and more attention from doctors and experts.However,little study has been done towards the effect of this approach for treating esophageal squamous cell carcinoma.This paper,therefore,intends to explore the possibilities of applying EGFR-TKI inhibitors or anti-EGFR monoclonal antibody in esophageal squamous cell carcinoma by studying the mutations of EGFR,K-ras and B-raf in the esophageal squamous cell carcinoma tissues.Methods:Thirty-five cases of resected specimens of diagnosed esophageal squamous cell carcinoma with complete clinical and pathological data from January to April 2009 were collected.Pyrophosphate was used for observing the mutations of EGFR,K-ras and B-raf in the esophageal squamous cell carcinoma tissues.Results:Examinations were undertaken respectively to the codon segment 746-754 of exon 19 in EGFR genes,codon 12 and 13 in K-ras genes as well as condon 600 in B-raf genes.No mutation was found in EGFR and B-raf genes with mutation rate 0% (0/35),all of codon 12 in K-ras genes were wild-type without any mutation,while 2 specimens of codon 13 had mutations with mutation rate of 5.71% (2/35).Conclusion:In treating esophageal squamous cell carcinoma patients,all K-ras genes are expressed as wild type due to low mutation rate; cetuximab is effective due to low mutation rate of B-raf while EGFR-TKI inhibitor will not be effective enough because of low mutation rate of EGFR genes.

  10. B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells.

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    Herr, Ricarda; Köhler, Martin; Andrlová, Hana; Weinberg, Florian; Möller, Yvonne; Halbach, Sebastian; Lutz, Lisa; Mastroianni, Justin; Klose, Martin; Bittermann, Nicola; Kowar, Silke; Zeiser, Robert; Olayioye, Monilola A; Lassmann, Silke; Busch, Hauke; Boerries, Melanie; Brummer, Tilman

    2015-01-01

    BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf(V600E) oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf(V600E) decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf(V600E) in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells. PMID:25381152

  11. Ras-mutant cancer cells display B-Raf binding to Ras that activates extracellular signal-regulated kinase and is inhibited by protein kinase A phosphorylation.

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    Li, Yanping; Takahashi, Maho; Stork, Philip J S

    2013-09-20

    The small G protein Ras regulates proliferation through activation of the mitogen-activated protein (MAP) kinase (ERK) cascade. The first step of Ras-dependent activation of ERK signaling is Ras binding to members of the Raf family of MAP kinase kinase kinases, C-Raf and B-Raf. Recently, it has been reported that in melanoma cells harboring oncogenic Ras mutations, B-Raf does not bind to Ras and does not contribute to basal ERK activation. For other types of Ras-mutant tumors, the relative contributions of C-Raf and B-Raf are not known. We examined non-melanoma cancer cell lines containing oncogenic Ras mutations and express both C-Raf and B-Raf isoforms, including the lung cancer cell line H1299 cells. Both B-Raf and C-Raf were constitutively bound to oncogenic Ras and contributed to Ras-dependent ERK activation. Ras binding to B-Raf and C-Raf were both subject to inhibition by the cAMP-dependent protein kinase PKA. cAMP inhibited the growth of H1299 cells and Ras-dependent ERK activation via PKA. PKA inhibited the binding of Ras to both C-Raf and B-Raf through phosphorylations of C-Raf at Ser-259 and B-Raf at Ser-365, respectively. These studies demonstrate that in non-melanocytic Ras-mutant cancer cells, Ras signaling to B-Raf is a significant contributor to ERK activation and that the B-Raf pathway, like that of C-Raf, is a target for inhibition by PKA. We suggest that cAMP and hormones coupled to cAMP may prove useful in dampening the effects of oncogenic Ras in non-melanocytic cancer cells through PKA-dependent actions on B-Raf as well as C-Raf.

  12. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease.

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    Takeshi Satoh

    Full Text Available BACKGROUND: Langerhans cell histiocytosis (LCH features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600EB-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients. METHODS AND RESULTS: Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600EB-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLATB-RAF insertion mimicked the structural and functional consequences of the (V600EB-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLATB-RAF and (V600EB-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599AB-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599AB-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation. CONCLUSIONS: Our data confirmed presence of the (V600EB-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600EB-RAF and (600DLATB-RAF mutations are somatic mutants enriched in LCH CD1a(+ cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599AB-RAF allele.

  13. B-RAF Mutant Alleles Associated with Langerhans Cell Histiocytosis, a Granulomatous Pediatric Disease

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    Lu, Hui-chun; Mian, Sophie; Trouillet, Celine; Mufti, Ghulam; Emile, Jean-Francois; Fraternali, Franca; Donadieu, Jean; Geissmann, Frederic

    2012-01-01

    Background Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or ‘LCH cells’. Badalian-Very et al. recently reported the presence of a canonical V600EB-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients. Methods and Results Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using ‘next generation’ pyrosequencing. In 9 cases the mutation identified was V600EB-RAF. In 2 cases novel polymorphisms were identified. A somatic 600DLATB-RAF insertion mimicked the structural and functional consequences of the V600EB-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The 600DLATB-RAF and V600EB-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%–2% relative mutation abundance. A novel germ line T599AB-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, T599AB-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation. Conclusions Our data confirmed presence of the V600EB-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that V600EB-RAF and 600DLATB-RAF mutations are somatic mutants enriched in LCH CD1a+ cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line T599AB-RAF allele. PMID:22506009

  14. Identification of aurora kinase B and Wee1-like protein kinase as downstream targets of (V600E)B-RAF in melanoma.

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    Sharma, Arati; Madhunapantula, SubbaRao V; Gowda, Raghavendra; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

    2013-04-01

    BRAF is the most mutated gene in melanoma, with approximately 50% of patients containing V600E mutant protein. (V600E)B-RAF can be targeted using pharmacological agents, but resistance develops in patients by activating other proteins in the signaling pathway. Identifying downstream members in this signaling cascade is important to design strategies to avoid the development of resistance. Unfortunately, downstream proteins remain to be identified and therapeutic potential requires validation. A kinase screen was undertaken to identify downstream targets in the (V600E)B-RAF signaling cascade. Involvement of aurora kinase B (AURKB) and Wee1-like protein kinase (WEE1) as downstream proteins in the (V600E)B-RAF pathway was validated in xenografted tumors, and mechanisms of action were characterized in size- and time-matched tumors. Levels of only AURKB and WEE1 decreased in melanoma cells, when (V600E)B-RAF, mitogen-activated protein kinase 1/2, or extracellular signal-regulated kinase 1/2 protein levels were reduced using siRNA compared with other identified kinases. AURKB and WEE1 were expressed in tumors of patients with melanoma at higher levels than observed in normal human melanocytes. Targeting these proteins reduced tumor development by approximately 70%, similar to that observed when inhibiting (V600E)B-RAF. Furthermore, protein or activity levels of AURKB and WEE1 decreased in melanoma cells when pharmacological agents targeting upstream (V600E)B-RAF or mitogen-activated protein kinase were used to inhibit the (V600E)B-RAF pathway. Thus, AURKB and WEE1 are targets and biomarkers of therapeutic efficacy, lying downstream of (V600E)B-RAF in melanomas.

  15. Low incidence of minor BRAF V600 mutation-positive subclones in primary and metastatic melanoma determined by sensitive and quantitative real-time PCR

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    Kielsgaard Kristensen, Thomas; Clemmensen, Ole; Hoejberg, Lise

    2013-01-01

    BRAF V600 mutation is an important biological marker for therapeutic guidance in melanoma, where mutation-positive cases are candidates for therapy targeting mutant B-Raf. Recent studies showing intratumor variation in BRAF mutation status have caused concern that sensitive mutation analysis can ...

  16. The phosphorylation specificity of B-RAF(WT), B-RAF(D594V), B-RAF(V600E) and B-RAF(K601E) kinases: An in silico study

    DEFF Research Database (Denmark)

    Fratev, Filip Filipov; Jonsdottir, Svava Osk

    2010-01-01

    dynamics (MD) simulations and GRID molecular interaction field analysis. According to our analysis, Thr599 and Ser602 were the only residues in the activation segment in B-RAF(WT) that were well exposed to ATP binding, which is in agreement with the experimental results, and provide a molecular basis...... of the observed phosphorylation. The phosphorylation specificity was altered significantly for each of the three different mutants studied due to the large conformational changes and subsequent alterations in the electrostatic forces between several residues for each of these mutants. Thus the analysis revealed...

  17. An in silico study of the molecular basis of B-RAF activation and conformational stability

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    Fratev, Filip Filipov; Jonsdottir, Svava Osk

    2009-01-01

    B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood. RESULTS: In this study we suggest a novel molecular basis of B-RAF activation...... the A-loop and the alphaC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAFD594V mutant that has impaired kinase activity, and in B-RAFWT these interactions were strong and stabilized the kinase inactive...

  18. Mutant B-Raf(V600E) Promotes Melanoma Paracellular Transmigration by Inducing Thrombin-mediated Endothelial Junction Breakdown.

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    Zhang, Pu; Feng, Shan; Liu, Gentao; Wang, Heyong; Zhu, Huifeng; Ren, Qiao; Bai, Huiyuan; Fu, Changliang; Dong, Cheng

    2016-01-29

    Tumor invasiveness depends on the ability of tumor cells to breach endothelial barriers. In this study, we investigated the mechanism by which the adhesion of melanoma cells to endothelium regulates adherens junction integrity and modulates tumor transendothelial migration (TEM) by initiating thrombin generation. We found that the B-Raf(V600E) mutation in metastatic melanoma cells up-regulated tissue factor (TF) expression on cell membranes and promoted thrombin production. Co-culture of endothelial monolayers with metastatic melanoma cells mediated the opening of inter-endothelial spaces near melanoma cell contact sites in the presence of platelet-free plasma (PFP). By using small interfering RNA (siRNA), we demonstrated that B-Raf(V600E) and TF silencing attenuated the focal disassembly of adherens junction induced by tumor contact. Vascular endothelial-cadherin (VE-cadherin) disassembly was dependent on phosphorylation of p120-catenin on Ser-879 and VE-cadherin on Tyr-658, Tyr-685, and Tyr-731, which can be prevented by treatment with the thrombin inhibitor, hirudin, or by silencing the thrombin receptor, protease-activated receptor-1, in endothelial cells. We also provided strong evidence that tumor-derived thrombin enhanced melanoma TEM by inducing ubiquitination-coupled VE-cadherin internalization, focal adhesion formation, and actin assembly in endothelium. Confocal microscopic analysis of tumor TEM revealed that junctions transiently opened and resealed as tumor cells accomplished TEM. In addition, in the presence of PFP, tumor cells preferentially transmigrated via paracellular routes. PFP supported melanoma transmigration under shear conditions via a B-Raf(V600E)-thrombin-dependent mechanism. We concluded that the activation of thrombin generation by cancer cells in plasma is an important process regulating melanoma extravasation by disrupting endothelial junction integrity. PMID:26504080

  19. The role of autophagy in cytotoxicity induced by new oncogenic B-Raf inhibitor UI-152 in v-Ha-ras transformed fibroblasts

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    Ahn, Jun-Ho [Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon 406-772 (Korea, Republic of); Ahn, Soon Kil [Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon 406-772 (Korea, Republic of); YOUAI Co., Ltd., Suwon-Si, Gyeonggi-Do 443-766 (Korea, Republic of); Lee, Michael, E-mail: mikelee@incheon.ac.kr [Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon 406-772 (Korea, Republic of)

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer We recently discovered a potent and selective B-Raf inhibitor, UI-152. Black-Right-Pointing-Pointer UI-152 displayed a selective cytotoxicity toward v-Ha-ras transformed cells. Black-Right-Pointing-Pointer UI-152-induced growth inhibition was largely meditated by autophagy. Black-Right-Pointing-Pointer UI-152 induced paradoxical activation of Raf-1. -- Abstract: In human cancers, B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade, making it an important therapeutic target. We recently discovered a potent and selective B-Raf inhibitor, UI-152, by using a structure-based drug design strategy. In this study, we examined whether B-Raf inhibition by UI-152 may be an effective therapeutic strategy for eliminating cancer cells transformed with v-Ha-ras (Ras-NIH 3T3). UI-152 displayed selective cytotoxicity toward Ras-NIH 3T3 cells while having little to no effect on non-transformed NIH 3T3 cells. We found that treatment with UI-152 markedly increased autophagy and, to a lesser extent, apoptosis. However, inhibition of autophagy by addition of 3-MA failed to reverse the cytotoxic effects of UI-152 on Ras-NIH 3T3 cells, demonstrating that apoptosis and autophagy can act as cooperative partners to induce growth inhibition in Ras-NIH 3T3 cells treated with UI-152. Most interestingly, cell responses to UI-152 appear to be paradoxical. Here, we showed that although UI-152 inhibited ERK, it induced B-Raf binding to Raf-1 as well as Raf-1 activation. This paradoxical activation of Raf-1 by UI-152 is likely to be coupled with the inhibition of the mTOR pathway, an intracellular signaling pathway involved in autophagy. We also showed for the first time that, in multi-drug resistant cells, the combination of UI-152 with verapamil significantly decreased cell proliferation and increased autophagy. Thus, our findings suggest that the inhibition of autophagy, in combination with UI-152, offers a more effective

  20. The role of autophagy in cytotoxicity induced by new oncogenic B-Raf inhibitor UI-152 in v-Ha-ras transformed fibroblasts

    International Nuclear Information System (INIS)

    Highlights: ► We recently discovered a potent and selective B-Raf inhibitor, UI-152. ► UI-152 displayed a selective cytotoxicity toward v-Ha-ras transformed cells. ► UI-152-induced growth inhibition was largely meditated by autophagy. ► UI-152 induced paradoxical activation of Raf-1. -- Abstract: In human cancers, B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade, making it an important therapeutic target. We recently discovered a potent and selective B-Raf inhibitor, UI-152, by using a structure-based drug design strategy. In this study, we examined whether B-Raf inhibition by UI-152 may be an effective therapeutic strategy for eliminating cancer cells transformed with v-Ha-ras (Ras-NIH 3T3). UI-152 displayed selective cytotoxicity toward Ras-NIH 3T3 cells while having little to no effect on non-transformed NIH 3T3 cells. We found that treatment with UI-152 markedly increased autophagy and, to a lesser extent, apoptosis. However, inhibition of autophagy by addition of 3-MA failed to reverse the cytotoxic effects of UI-152 on Ras-NIH 3T3 cells, demonstrating that apoptosis and autophagy can act as cooperative partners to induce growth inhibition in Ras-NIH 3T3 cells treated with UI-152. Most interestingly, cell responses to UI-152 appear to be paradoxical. Here, we showed that although UI-152 inhibited ERK, it induced B-Raf binding to Raf-1 as well as Raf-1 activation. This paradoxical activation of Raf-1 by UI-152 is likely to be coupled with the inhibition of the mTOR pathway, an intracellular signaling pathway involved in autophagy. We also showed for the first time that, in multi-drug resistant cells, the combination of UI-152 with verapamil significantly decreased cell proliferation and increased autophagy. Thus, our findings suggest that the inhibition of autophagy, in combination with UI-152, offers a more effective therapeutic strategy for v-Ha-ras-transformed cells harboring wild-type B-Raf.

  1. RKIP regulates MAP kinase signaling in cells with defective B-Raf activity.

    Science.gov (United States)

    Zeng, Lingchun; Ehrenreiter, Karin; Menon, Jyotsana; Menard, Ray; Kern, Florian; Nakazawa, Yoko; Bevilacqua, Elena; Imamoto, Akira; Baccarini, Manuela; Rosner, Marsha Rich

    2013-05-01

    MAP kinase (MAPK) signaling results from activation of Raf kinases in response to external or internal stimuli. Here, we demonstrate that Raf kinase inhibitory protein (RKIP) regulates the activation of MAPK when B-Raf signaling is defective. We used multiple models including mouse embryonic fibroblasts (MEFs) and primary keratinocytes from RKIP- or Raf-deficient mice as well as allografts in mice to investigate the mechanism. Loss of B-Raf protein or activity significantly reduces MAPK activation in these cells. We show that RKIP depletion can rescue the compromised ERK activation and promote proliferation, and this rescue occurs through a Raf-1 dependent mechanism. These results provide formal evidence that RKIP is a bona fide regulator of Raf-1. We propose a new model in which RKIP plays a key role in regulating the ability of cells to signal through Raf-1 to ERK in B-Raf compromised cells.

  2. Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein.

    Science.gov (United States)

    Ohtsuka, T; Shimizu, K; Yamamori, B; Kuroda, S; Takai, Y

    1996-01-19

    Rap1 small GTP-binding protein has the same amino acid sequence at its effector domain as that of Ras. Rap1 has been shown to antagonize the Ras functions, such as the Ras-induced transformation of NIH 3T3 cells and the Ras-induced activation of the c-Raf-1 protein kinase-dependent mitogen-activated protein (MAP) kinase cascade in Rat-1 cells, whereas we have shown that Rap1 as well as Ras stimulates DNA synthesis in Swiss 3T3 cells. We have established a cell-free assay system in which Ras activates bovine brain B-Raf protein kinase. Here we have used this assay system and examined the effect of Rap1 on the B-Raf activity to phosphorylate recombinant MAP kinase kinase (MEK). Recombinant Rap1B stimulated the activity of B-Raf, which was partially purified from bovine brain and immunoprecipitated by an anti-B-Raf antibody. The GTP-bound form was active, but the GDP-bound form was inactive. The fully post-translationally lipid-modified form was active, but the unmodified form was nearly inactive. The maximum B-Raf activity stimulated by Rap1B was nearly the same as that stimulated by Ki-Ras. Rap1B enhanced the Ki-Ras-stimulated B-Raf activity in an additive manner. These results indicate that not only Ras but also Rap1 is involved in the activation of the B-Raf-dependent MAP kinase cascade.

  3. Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Berger, Dan M.; Torres, Nancy; Dutia, Minu; Powell, Dennis; Ciszewski, Greg; Gopalsamy, Ariamala; Levin, Jeremy I.; Kim, Kyung-Hee; Xu, Weixin; Wilhelm, James; Hu, YongBo; Collins, Karen; Feldberg, Larry; Kim, Steven; Frommer, Eileen; Wojciechowicz, Donald; Mallon, Robert; (Wyeth)

    2010-11-19

    As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.

  4. Genetic mutations associated with status epilepticus.

    Science.gov (United States)

    Bhatnagar, M; Shorvon, S

    2015-08-01

    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  5. Genetic mutations associated with status epilepticus.

    Science.gov (United States)

    Bhatnagar, M; Shorvon, S

    2015-08-01

    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  6. Requirement of B-Raf, C-Raf, and A-Raf for the growth and survival of mouse embryonic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Wenjing; Hao, Baixia; Wang, Qian; Lu, Yingying; Yue, Jianbo, E-mail: jbyue@me.com

    2013-11-01

    Extracellular signal-regulated kinases (ERKs) have been implicated to be dispensable for self-renewal of mouse embryonic stem (ES) cells, and simultaneous inhibition of both ERK signaling and glycogen synthase kinase 3 (GSK3) not only allows mouse ES cells to self-renew independent of extracellular stimuli but also enables more efficient derivation of naïve ES cells from mouse and rat strains. Interestingly, some ERKs stay active in mouse ES cells which are maintained in regular medium containing leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP). Yet, the upstream signaling for ERK activation and their roles in mouse ES cells, other than promoting or priming differentiation, have not been determined. Here we found that mouse ES cells express three forms of Raf kinases, A-Raf, B-Raf, and C-Raf. Knocking-down each single Raf member failed to affect the sustained ERK activity, neither did A-Raf and B-Raf double knockdown or B-Raf and C-Raf double knockdown change it in ES cells. Interestingly, B-Raf and C-Raf double knockdown, not A-Raf and B-Raf knockdown, inhibited the maximal ERK activation induced by LIF, concomitant with the slower growth of ES cells. On the other hand, A-Raf, B-Raf, and C-Raf triple knockdown markedly inhibited both the maximal and sustained ERK activity in ES cells. Moreover, Raf triple knockdown, similar to the treatment of U-0126, an MEK inhibitor, significantly inhibited the survival and proliferation of ES cells, thereby compromising the colony propagation of mouse ES cells. In summary, our data demonstrate that all three Raf members are required for ERK activation in mouse ES cells and are involved in growth and survival of mouse ES cells. - Highlights: ●Mouse ES (mES) cells express all three Raf members, A-Raf, B-Raf, and C-Raf. ●Leukemia inhibitory factor (LIF) temporally activates ERKs in mES cells. ●B-Raf and C-Raf are required for LIF-induced maximal ERKs activity in mES cells. ●All Raf members are

  7. No evidence of oncogenic KRAS mutations in squamous cell carcinomas of the anogenital tract and head and neck region independent of human papillomavirus and p16(INK4a) status.

    Science.gov (United States)

    Prigge, Elena-Sophie; Urban, Katharina; Stiegler, Sandrine; Müller, Meike; Kloor, Matthias; Mai, Sabine; Ottstadt, Martine; Lohr, Frank; Wenz, Frederik; Wagner, Steffen; Wittekindt, Claus; Klussmann, Jens Peter; Hampl, Monika; von Knebel Doeberitz, Magnus; Reuschenbach, Miriam

    2014-11-01

    Carcinogenesis of squamous cell carcinomas (SCCs) in the anogenital tract and head and neck region is heterogeneous. A substantial proportion of SCC in the vulva, anus, and head and neck follows a human papillomavirus (HPV)-induced carcinogenic pathway. However, the molecular pathways of carcinogenesis in the HPV-independent lesions are not completely understood. We hypothesized that oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations might represent a carcinogenic mechanism in a proportion of those HPV-negative cancers. Considering the repeated observation of KRAS-associated p16(INK4a) overexpression in human tumors, it was assumed that KRAS mutations might be particularly present in the group of HPV-negative, p16(INK4a)-positive cancers. To test this hypothesis, we analyzed 66 anal, vulvar, and head and neck SCC with known immunohistochemical p16(INK4a) and HPV DNA status for KRAS mutations in exon 2 (codons 12, 13, and 15). We enriched the tumor collection with HPV DNA-negative, p16(INK4a)-positive cancers. A subset of 37 cancers was also analyzed for mutations in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene. None of the 66 tumors harbored mutations in KRAS exon 2, thus excluding KRAS mutations as a common event in SCC of the anogenital and head and neck region and as a cause of p16(INK4a) expression in these tumors. In addition, no BRAF mutations were detected in the 37 analyzed tumors. Further studies are required to determine the molecular events underlying HPV-negative anal, vulvar, and head and neck carcinogenesis. Considering HPV-independent p16(INK4a) overexpression in some of these tumors, particular focus should be placed on alternative upstream activators and potential downstream disruption of the p16(INK4a) pathway.

  8. Oncostatin M-induced cardiomyocyte dedifferentiation regulates the progression of diabetic cardiomyopathy through B-Raf/Mek/Erk signaling pathway.

    Science.gov (United States)

    Zhang, Xiaotian; Ma, Sai; Zhang, Ran; Li, Shuang; Zhu, Di; Han, Dong; Li, Xiujuan; Li, Congye; Yan, Wei; Sun, Dongdong; Xu, Bin; Wang, Yabin; Cao, Feng

    2016-03-01

    It has been reported that oncostatin M (OSM) could initiate cardiomyocyte dedifferentiation both in vivo and in vitro. OSM-induced cardiomyocyte dedifferentiation might be a new target for the treatment of diabetic cardiomyopathy (DCM). This study was designed to determine the role of OSM in cardiomyocyte dedifferentiation and the progression of DCM. A mouse DCM model was established to evaluate the effects of OSM in vivo. Echocardiography was applied to determine cardiac function. Sirius red staining was used to detect fibrosis area. Transmission electron microscopy was used to evaluate mitochondria impairment. Real-time polymerase chain reaction and western blot analysis were performed to detect relative mRNA expressions and cardiomyocyte dedifferentiation-related protein expressions, respectively. OSM treatment induced similar impaired cardiac function and cardiac ultrastructure impairment to those detected in DCM mice. The expressions of dedifferentiation markers of cardiomyocyte (Runx1, and α-SM-actin) were up-regulated in the OSM-treated mice compared with those in the control group. To further demonstrate the important role of OSM, OSM receptor knockout (Oβ(ko)) mice were used. In Oβ(ko) mice, cardiomyocytes dedifferentiation markers of c-kit, Runx1, and atrial natriuretic peptide were down-regulated, with attenuated DCM injury and abrogated OSM/B-Raf/Mek/Erk signaling pathway. In conclusion, OSM-induced cardiomyocyte dedifferentiation plays a crucial role in the progression of DCM. The mechanism of OSM-induced cardiomyocyte dedifferentiation is associated with B-Raf/Mek/Erk signaling pathway through the OSM receptor Oβ. PMID:26837420

  9. Cassava Mutation Breeding: Current Status and Trends

    International Nuclear Information System (INIS)

    Cassava (Manihot esculenta Crantz) is an important energy source in the diets of millions of people in the tropical and subtropical regions of the world, especially the poor. Also its industrial uses are steadily growing for starch, animal feed and bio-ethanol. Although it has high economic and social relevance, few major scientific efforts have been made to improve the crop until the 1970s. With the goals and objectives of cassava improvement through breeding, different strategies have been developed during the last several decades, such as evaluation and selection of the local landraces, introduced germplasm (as clones or segregating F1 population), hybridization (including inbreeding by both recurrent back-cross schemes and double haploids (DH)), interspecific hybridization, polyploidy breeding, genetic transformation, use of molecular markers and mutation breeding. Induced mutation breeding on cassava has been explored in the last several decades with few published papers. Yet, the production of novel genotypes, such as high amylose and small granule mutants and mutants with tolerance to post harvest physiological deterioration (PPD), has been reported. These results suggest that mutagenesis could be an effective alternative for cassava breeding. However, many drawbacks still exist in cassava mutation breeding, such as the occurrence of chimeras. Validated and developing protocols for different biotechnologies, such as TILLING protocol, cassava genome sequencing and cassava somatic embryogenesis, will significantly ameliorate the drawbacks to traditional mutation breeding, and consequently aid the routine application of induced mutation in both cassava improvement and in gene discovery and elucidation. (author)

  10. Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay.

    Science.gov (United States)

    Li, Yisu; Guo, Binbin; Xu, Zhijian; Li, Bo; Cai, Tingting; Zhang, Xinben; Yu, Yuqi; Wang, Heyao; Shi, Jiye; Zhu, Weiliang

    2016-01-01

    Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 μM and 1.90 μM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 μM), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures. PMID:27501852

  11. HFE gene mutations and iron status of Brazilian blood donors

    Directory of Open Access Journals (Sweden)

    P.C.J.L. Santos

    2010-01-01

    Full Text Available Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542 were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018 and a 83.65% decrease (P = 0.007 in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001 and the HFE 63HD plus DD genotype (55.84%, P = 0.021. In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

  12. B- and C-RAF display essential differences in their binding to Ras: the isotype-specific N terminus of B-RAF facilitates Ras binding.

    Science.gov (United States)

    Fischer, Andreas; Hekman, Mirko; Kuhlmann, Jürgen; Rubio, Ignacio; Wiese, Stefan; Rapp, Ulf R

    2007-09-01

    Recruitment of RAF kinases to the plasma membrane was initially proposed to be mediated by Ras proteins via interaction with the RAF Ras binding domain (RBD). Data reporting that RAF kinases possess high affinities for particular membrane lipids support a new model in which Ras-RAF interactions may be spatially restricted to the plane of the membrane. Although the coupling features of Ras binding to the isolated RAF RBD were investigated in great detail, little is known about the interactions of the processed Ras with the functional and full-length RAF kinases. Here we present a quantitative analysis of the binding properties of farnesylated and nonfarnesylated H-Ras to both full-length B- and C-RAF in the presence and absence of lipid environment. Although isolated RBD fragments associate with high affinity to both farnesylated and nonfarnesylated H-Ras, the full-length RAF kinases revealed fundamental differences with respect to Ras binding. In contrast to C-RAF that requires farnesylated H-Ras, cytosolic B-RAF associates effectively and with significantly higher affinity with both farnesylated and nonfarnesylated H-Ras. To investigate the potential farnesyl binding site(s) we prepared several N-terminal fragments of C-RAF and found that in the presence of cysteine-rich domain only the farnesylated form of H-Ras binds with high association rates. The extreme N terminus of B-RAF turned out to be responsible for the facilitation of lipid independent Ras binding to B-RAF, since truncation of this region resulted in a protein that changed its kinase properties and resembles C-RAF. In vivo studies using PC12 and COS7 cells support in vitro results. Co-localization measurements using labeled Ras and RAF documented essential differences between B- and C-RAF with respect to association with Ras. Taken together, these data suggest that the activation of B-RAF, in contrast to C-RAF, may take place both at the plasma membrane and in the cytosolic environment.

  13. Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF.

    Science.gov (United States)

    Baljuls, Angela; Dobrzyński, Maciej; Rauch, Jens; Rauch, Nora; Kolch, Walter

    2016-10-01

    RAF family kinases are central components of the Ras-RAF-MEK-ERK cascade. Dimerization is a key mechanism of RAF activation in response to physiological, pathological and pharmacological signals. It is mediated by a dimer interface region in the RAF kinase domain that is also conserved in KSR, a scaffolding protein that binds RAF, MEK and ERK. The regulation of RAF dimerization is incompletely understood. Especially little is known about the molecular mechanism involved in the selection of the dimerization partner. Previously, we reported that Ras-dependent binding of the tumour suppressor DiRas3 to C-RAF inhibits the C-RAF:B-RAF heterodimerization. Here we show that DiRas3 binds to KSR1 independently of its interaction with activated Ras and RAF. Our data also suggest that depending on the local stoichiometry between DiRas3 and oncogenic Ras, DiRas3 can either enhance homodimerization of KSR1 or recruit KSR1 to the Ras:C-RAF complex and thereby reduce the availability of C-RAF for binding to B-RAF. This mechanism, which is shared between A-RAF and C-RAF, may be involved in the regulation of Ras12V-induced cell transformation by DiRas3. PMID:27368419

  14. Licochalcone A, a Polyphenol Present in Licorice, Suppresses UV-Induced COX-2 Expression by Targeting PI3K, MEK1, and B-Raf

    Directory of Open Access Journals (Sweden)

    Nu Ry Song

    2015-02-01

    Full Text Available Licorice is a traditional botanical medicine, and has historically been commonly prescribed in Asia to treat various diseases. Glycyrrhizin (Gc, a triterpene compound, is the most abundant phytochemical constituent of licorice. However, high intake or long-term consumption of Gc has been associated with a number of side effects, including hypertension. However, the presence of alternative bioactive compounds in licorice with anti-carcinogenic effects has long been suspected. Licochalcone A (LicoA is a prominent member of the chalcone family and can be isolated from licorice root. To date, there have been no reported studies on the suppressive effect of LicoA against solar ultraviolet (sUV-induced cyclooxygenase (COX-2 expression and the potential molecular mechanisms involved. Here, we show that LicoA, a major chalcone compound of licorice, effectively inhibits sUV-induced COX-2 expression and prostaglandin E2 PGE2 generation through the inhibition of activator protein 1 AP-1 transcriptional activity, with an effect that is notably more potent than Gc. Western blotting analysis shows that LicoA suppresses sUV-induced phosphorylation of Akt/ mammalian target of rapamycin (mTOR and extracellular signal-regulated kinases (ERK1/2/p90 ribosomal protein S6 kinase (RSK in HaCaT cells. Moreover, LicoA directly suppresses the activity of phosphoinositide 3-kinase (PI3K, mitogen-activated protein kinase kinase (MEK1, and B-Raf, but not Raf-1 in cell-free assays, indicating that PI3K, MEK1, and B-Raf are direct molecular targets of LicoA. We also found that LicoA binds to PI3K and B-Raf in an ATP-competitive manner, although LicoA does not appear to compete with ATP for binding with MEK1. Collectively, these results provide insight into the biological action of LicoA, which may have potential for development as a skin cancer chemopreventive agent.

  15. Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status?

    OpenAIRE

    Liu, Guo-Yan; Zhang, Wei

    2012-01-01

    In Western countries, the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer, especially for women of the Ashkenazi Jewish ethnicity. Recent studies in the Cancer Genome Atlas project have demonstrated that BRCA2 mutation carriers are more responsive to platinum-based chemotherapy among high-grade serous ovarian cancer patients. Thus, in Western countries, the mutation status of BRCA1 ...

  16. Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas.

    Science.gov (United States)

    Routhier, Caitlin Ann; Mochel, Mark C; Lynch, Kerry; Dias-Santagata, Dora; Louis, David N; Hoang, Mai P

    2013-11-01

    BRAF mutation is seen in a variety of human neoplasms including cutaneous malignant melanoma, papillary thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, pleomorphic xanthoastrocytoma, and others. Currently, there are 2 commercially available monoclonal antibodies for the detection of BRAF V600E mutation; however, a full and practical comparison of their performance in various tumor types on an automated staining platform has not been done. We investigated their sensitivity and specificity in detecting the BRAF V600E mutation in a series of 152 tumors including 31 malignant melanomas, 25 lung carcinomas, 32 gastrointestinal carcinomas, 23 thyroid carcinomas, 35 gliomas, and 6 other malignancies. In this series, the concordance rate between immunohistochemistry (IHC) and mutational analyses was 97% (148/152) for VE1 and 88% (131/149) for anti-B-Raf. The sensitivity and specificity were 98% (60/61) and 97% (88/91) for monoclonal VE1 and 95% (58/61) and 83% (73/88) for anti-B-Raf, respectively. There were 4 cases with discordant IHC and mutational results for monoclonal VE1 in contrast to 18 cases for anti-B-Raf. Our studies showed that IHC with monoclonal VE1 has a better performance compared with anti-B-Raf in an automated staining platform and confirmed that clone VE1 provides excellent sensitivity and specificity for detecting the BRAF V600E mutation in a variety of tumor types in a clinical setting.

  17. EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients

    Directory of Open Access Journals (Sweden)

    Li SHAN

    2013-02-01

    Full Text Available Background and objective Epidermal growth factor receptor (EGFR, a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2% of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2% of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7% of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.001. Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2% is significantly lower than that in Han lung adenocarcinoma patients (45.7%.

  18. Distinct Clinicopathological Patterns of Mismatch Repair Status in Colorectal Cancer Stratified by KRAS Mutations.

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    Wenbin Li

    Full Text Available In sporadic colorectal cancer (CRC, the BRAFV600E mutation is associated with deficient mismatch repair (MMR status and inversely associated with to KRAS mutations. In contrast to deficient MMR (dMMR CRC, data on the presence of KRAS oncogenic mutations in proficient MMR (pMMR CRC and their relationship with tumor progression are scarce. We therefore examined the MMR status in combination with KRAS mutations in 913 Chinese patients and correlated the findings obtained with clinical and pathological features. The MMR status was determined based on detection of MLH1, MSH2, MSH6 and PMS2 expression. KRAS mutation and dMMR status were detected in 36.9% and 7.5% of cases, respectively. Four subtypes were determined by MMR and KRAS mutation status: KRAS (+/pMMR (34.0%, KRAS (+/dMMR (2.9%, KRAS (-/pMMR (58.5% and KRAS (-/dMMR (4.6%. A higher percentage of pMMR tumors with KRAS mutation were most likely to be female (49.0%, proximal located (45.5%, a mucinous histology (38.4%, and to have increased lymph node metastasis (60.3%, compared with pMMR tumors without BRAFV600E and KRAS mutations (36.0%, 29.3%, 29.4% and 50.7%, respectively; all P < 0.01. To the contrary, compared with those with KRAS(-/dMMR tumors, patients with KRAS(+/dMMR tumors demonstrated no statistically significant differences in gender, tumor location, pT depth of invasion, lymph node metastasis, pTNM stage, and histologic grade. This study revealed that specific epidemiologic and clinicopathologic characteristics are associated with MMR status stratified by KRAS mutation. Knowledge of MMR and KRAS mutation status may enhance molecular pathologic staging of CRC patients and metastatic progression in CRC can be estimated based on the combination of these biomarkers.

  19. BRAF V600E mutation detection by immunohistochemistry in colorectal carcinoma.

    Science.gov (United States)

    Affolter, Kajsa; Samowitz, Wade; Tripp, Sheryl; Bronner, Mary P

    2013-08-01

    The serine/threonine-protein kinase B-raf (BRAF) is an oncogene mutated in various neoplasms, including 5-15% of colorectal carcinomas. The T1799A point mutation, responsible for a large majority of these alterations, results in an amino acid substitution (V600E) causing the constitutive activation of a protein kinase cascade. BRAF V600E in MLH1 deficient tumors implicates somatic tumor-only methylation of the MLH1 promoter region instead of a germline MLH1 mutation. BRAF V600E also predicts poor prognosis in microsatellite stable colorectal cancers and may be a marker of resistance to anti-EGFR therapy in metastatic disease. Currently, only molecular methods are available for assessing BRAF mutational status. An immunohistochemical approach is evaluated here. Colon cancers from 2008 to 2012 tested by pyrosequencing for BRAF V600E mutation were selected. A total of 31 tumors with (n = 14) and without (n = 17) the BRAF V600E mutation were analyzed by immunohistochemistry using a commercially available antibody specific to the V600E-mutated protein. All 14 colorectal carcinomas with the BRAF V600E mutation demonstrated cytoplasmic positivity in tumor cells with the anti-BRAF antibody. In a minority of cases, staining intensity for the mutated tumor samples was weak (n = 2) or heterogeneous (n = 4); however, the majority of cases showed diffuse, strong cytoplasmic positivity (8 of 14 cases). None of the 17 BRAF wild-type colorectal cancers showed immunoreactivity to the antibody. The overall sensitivity and specificity of the immunohistochemical BRAF V600E assay was 100%. Detection of the BRAF V600E mutation in colorectal cancer by immunohistochemistry is a viable alternative to molecular methods.

  20. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara;

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy...... mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL....

  1. Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma

    OpenAIRE

    Carrillo, JA; Lai, A; Nghiemphu, PL; Kim, HJ; Phillips, HS; Kharbanda, S; Moftakhar, P; Lalaezari, S; YONG, W; Ellingson, BM; Cloughesy, TF; Pope, WB

    2012-01-01

    BACKGROUND AND PURPOSE: Both IDH1 mutation and MGMT promoter methylation are associated with longer survival. We investigated the ability of imaging correlates to serve as noninvasive biomarkers for these molecularly defined GBM subtypes. MATERIALS AND METHODS: MR imaging from 202 patients with GBM was retrospectively assessed for nonenhancing tumor and edema among other imaging features. IDH1 mutational and MGMT promoter methylation status were determined by DNA sequencing and methylation-sp...

  2. EGFR gene-mutation status correlated with therapeutic decision making in lung adenocarcinoma

    OpenAIRE

    Ren YY; Yao YB; Ma Q; Zhong DS

    2015-01-01

    Yaoyao Ren, Yibing Yao, Qing Ma, Diansheng Zhong Oncology Department, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China Abstract: The purpose of this study was to investigate the correlation between EGFR-mutation status and treatment efficacy for advanced lung adenocarcinoma patients. A total of 47 patients receiving erlotinib as first-line therapy were divided into two groups: the EGFR gene mutation group included 19 patients with known EGFR-sensiti...

  3. Involvement of Krüppel-like factor 6 (KLF6) mutation in the development of nonpolypoid colorectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To examine Krüppel-like factor 6 (KLF6) mutations in nonpolypoid-type tumors and alterations of K-ras, p53,and B-raf in relation between mutation and morphologic type, particularly nonpolypoid-type colorectal carcinomas.METHODS: Fifty-five early nonpolypoid colorectal carcinomas were analyzed. Loss of heterozygosity (LOH) of KLF6 and p53 was determined by microsatellite assay.Mutations of KLF6, K-ras, and B-raf were examined by polymerase chain reaction-single-strand conformation polymorphism followed by direct sequencing. In LOH-positive and/or mutation-positive tumors, multiple (4-7) samples in each tumor were microdissected and examined for genetic alterations, p53 expression was evaluated by immunohistochemistry.RESULTS: LOH of KLF6 and p53 was found in 14 of 29 (48.3%) and 14 of 31 (45.2%) tumors, respectively. In 10 of the 14 (71.4%) KLF6 LOH-positive tumors and 9 of the 14 (64.3%) p53 LOH-positive tumors, LOH was found in all of the microdissected samples. In 1 of the 10 (10.0%) KLF6 LOH-positive tumors, a single missense mutation was identified. K-ras and B-raf mutations were found in 5 of 55 (9.1%) and 6 of 55 (10.9%) tumors,respectively. However, these mutations were detected only in subsets of microdissected tumor samples.CONCLUSION: These data suggest that KLF6 and p53 mutations are involved in the development of nonpolypoid colorectal carcinoma, whereas K-ras and B-raf mutations are not.

  4. Determination of EGFR and KRAS mutational status in Greek non-small-cell lung cancer patients

    Science.gov (United States)

    PAPADOPOULOU, EIRINI; TSOULOS, NIKOLAOS; TSIRIGOTI, ANGELIKI; APESSOS, ANGELA; AGIANNITOPOULOS, KONSTANTINOS; METAXA-MARIATOU, VASILIKI; ZAROGOULIDIS, KONSTANTINOS; ZAROGOULIDIS, PAVLOS; KASARAKIS, DIMITRIOS; KAKOLYRIS, STYLIANOS; DAHABREH, JUBRAIL; VLASTOS, FOTIS; ZOUBLIOS, CHARALAMPOS; RAPTI, AGGELIKI; PAPAGEORGIOU, NIKI GEORGATOU; VELDEKIS, DIMITRIOS; GAGA, MINA; ARAVANTINOS, GERASIMOS; KARAVASILIS, VASILEIOS; KARAGIANNIDIS, NAPOLEON; NASIOULAS, GEORGE

    2015-01-01

    It has been reported that certain patients with non-small-cell lung cancer (NSCLC) that harbor activating somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene may be effectively treated using targeted therapy. The use of EGFR inhibitors in patient therapy has been demonstrated to improve response and survival rates; therefore, it was suggested that clinical screening for EGFR mutations should be performed for all patients. Numerous clinicopathological factors have been associated with EGFR and Kirsten-rat sarcoma oncogene homolog (KRAS) mutational status including gender, smoking history and histology. In addition, it was reported that EGFR mutation frequency in NSCLC patients was ethnicity-dependent, with an incidence rate of ~30% in Asian populations and ~15% in Caucasian populations. However, limited data has been reported on intra-ethnic differences throughout Europe. The present study aimed to investigate the frequency and spectrum of EGFR mutations in 1,472 Greek NSCLC patients. In addition, KRAS mutation analysis was performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking. High-resolution melting curve (HRM) analysis followed by Sanger sequencing was used to identify mutations in exons 18–21 of the EGFR gene and in exon 2 of the KRAS gene. A sensitive next-generation sequencing (NGS) technology was also employed to classify samples with equivocal results. The use of sensitive mutation detection techniques in a large study population of Greek NSCLC patients in routine diagnostic practice revealed an overall EGFR mutation frequency of 15.83%. This mutation frequency was comparable to that previously reported in other European populations. Of note, there was a 99.8% concordance between the HRM method and Sanger sequencing. NGS was found to be the most sensitive method. In addition, female non-smokers demonstrated a high prevalence of

  5. Telomere length shows no association with BRCA1 and BRCA2 mutation status.

    Directory of Open Access Journals (Sweden)

    Emma Killick

    Full Text Available This study aimed to determine whether telomere length (TL is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years, all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years, half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.

  6. Modification, biological evaluation and 3D QSAR studies of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-ylphenol derivatives as inhibitors of B-Raf kinase.

    Directory of Open Access Journals (Sweden)

    Yu-Shun Yang

    Full Text Available A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-ylphenol derivatives (C1-C24 have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM and WM266.4 human melanoma cell line (GI50 = 1.75 µM, being comparable with the positive control (Vemurafenib and Erlotinib and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.

  7. Analysis of Imatinib and Sorafenib Binding to p38 Compared with c-Abl and b-Raf Provides Structural Insights for Understanding the Selectivity of Inhibitors Targeting the DFG-Out Form of Protein Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Namboodiri, H.; Bukhtiyarova, M; Ramcharan, J; Karpusas, M; Lee, Y; Springman, E

    2010-01-01

    Protein kinases c-Abl, b-Raf, and p38{alpha} are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38{alpha} inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets. Although the discovery of this class of kinase inhibitors has increased the level of emphasis on the design of DFG-out inhibitors, the structural determinants for their binding and stabilization of the DFG-out conformation remain unclear. To improve our understanding of these determinants, we determined cocrystal structures of Imatinib and Sorafenib with p38{alpha}. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38{alpha} in comparison with BIRB-796, including binding kinetics, binding interactions, the solvent accessible surface area (SASA) of the ligands, and stabilization of key structural elements of the protein upon ligand binding. Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases.

  8. EGFR Expression and KRAS and BRAF Mutational Status in Intestinal-Type Sinonasal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Valérie Costes

    2013-03-01

    Full Text Available Accumulation of molecular alterations, including EGFR overexpression and mutations in KRAS and BRAF, contribute to colorectal carcinogenesis. Since intestinal-type adenocarcinoma (ITAC of the nasal cavity and paranasal sinus has morphologic and phenotypic features that are usually indistinguishable from colorectal cancer (CRC, it is likely that both tumor types share equivalent genetic alterations. Data from a series of 43 patients treated surgically for ITAC in Montpellier, France between November 1998 and December 2012 were collected. Tumors were characterized for mutations in KRAS and BRAF as well as EGFR overexpression. Kaplan-Meier survival curves were constructed using overall survival as the primary end points. Patient survival was analyzed using the hazards ratio. Twenty seven tumors (63% showed EGFR positivity and 30% exhibited a high expression level (+2/+3. KRAS mutations were detected in 43% of cases. BRAF mutations were identified in 3.6% of specimens. Patients with age superior to 60 years, metastatic status, and KRAS mutations had significant overall survival values (p = 0.026, p = 0.001 and p = 0.03, respectively. Our results indicate that KRAS mutations and EGFR expression are frequent in ITAC and that KRAS mutations predict good patient prognosis in ITAC. Finally, EGFR directed molecular treatments could be investigated in a subset of patients affected by ITAC.

  9. Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status?

    Institute of Scientific and Technical Information of China (English)

    Guo-Yan Liu; Wei Zhang

    2012-01-01

    In Western countries,the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer,especially for women of the Ashkenazi Jewish ethnicity.Recent studies in the Cancer Genome Atlas project have demonstrated that BRCA2 mutation carriers are more responsive to platinum-based chemotherapy among high-grade serous ovarian cancer patients.Thus,in Western countries,the mutation status of BRCA1 and BRCA2 is recognized to have an important value with which to assess cancer risk and therapeutic response.However,very limited studies of BRCA1 and BRCA2 mutations and their implications for counseling and therapeutic prediction have been conducted in China.Therefore,a potentially important genetic test that is technically simple has not benefited Chinese women with an increased risk of breast or ovarian cancer.This article summarizes the current progress in the study of BRCA1/2 mutation in China and recommends an increased effort in applying advances in genetic testing to the clinical management of Chinese patients with ovarian cancer.

  10. KRAS mutational status as a predictor of epidermal growth factor receptor inhibitor efficacy in colorectal cancer.

    Science.gov (United States)

    Baynes, Roy D; Gansert, Jennifer

    2009-01-01

    Inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated promising potential in the treatment of advanced colorectal cancer. However, a proportion of patients do not respond to therapy with EGFR inhibitors, and therefore, there has been interest in identifying those patients most likely to benefit from therapy with these agents. KRAS, a member of the RAS family of signaling proteins, plays an important role in EGFR-mediated regulation of cellular proliferation and survival. Although there is still some debate regarding the prognostic importance of KRAS mutations in patients with metastatic colorectal cancer, several recent phase 2 and 3 studies have identified the presence of mutations at codons 12 and 13 of KRAS as predictors of poor response to the anti-EGFR monoclonal antibodies panitumumab and cetuximab. Patients with wild-type KRAS were found to have significantly better progression-free survival, overall survival, and/or objective response rate compared with patients harboring KRAS mutations. As a result, there has been growing interest in the development of KRAS mutational status as a biomarker for predicting patient response to EGFR-targeted therapy. Screening colorectal tumors for the absence of KRAS mutations may help identify patients most likely to benefit from anti-EGFR therapies.

  11. Serotonin type-1D receptor stimulation of A-type K(+) channel decreases membrane excitability through the protein kinase A- and B-Raf-dependent p38 MAPK pathways in mouse trigeminal ganglion neurons.

    Science.gov (United States)

    Zhao, Xianyang; Zhang, Yuan; Qin, Wenjuan; Cao, Junping; Zhang, Yi; Ni, Jianqiang; Sun, Yangang; Jiang, Xinghong; Tao, Jin

    2016-08-01

    Although recent studies have implicated serotonin 5-HT1B/D receptors in the nociceptive sensitivity of primary afferent neurons, the underlying molecular and cellular mechanisms remain unclear. In this study, we identified a novel functional role of the 5-HT1D receptor subtype in regulating A-type potassium (K(+)) currents (IA) as well as membrane excitability in small trigeminal ganglion (TG) neurons. We found that the selective activation of 5-HT1D, rather than 5-HT1B, receptors reversibly increased IA, while the sustained delayed rectifier K(+) current was unaffected. The 5-HT1D-mediated IA increase was associated with a depolarizing shift in the voltage dependence of inactivation. Blocking G-protein signaling with pertussis toxin or by intracellular application of a selective antibody raised against Gαo or Gβ abolished the 5-HT1D effect on IA. Inhibition of protein kinase A (PKA), but not of phosphatidylinositol 3-kinase or protein kinase C, abolished the 5-HT1D-mediated IA increase. Analysis of phospho-p38 (p-p38) revealed that activation of 5-HT1D, but not 5-HT1B, receptors significantly activated p38, while p-ERK and p-JNK were unaffected. The p38 MAPK inhibitor SB203580, but not its inactive analogue SB202474, and inhibition of B-Raf blocked the 5-HT1D-mediated IA response. Functionally, we observed a significantly decreased action potential firing rate induced by the 5-HT1D receptors; pretreatment with 4-aminopyridine abolished this effect. Taken together, these results suggest that the activation of 5-HT1D receptors selectively enhanced IA via the Gβγ of the Go-protein, PKA, and the sequential B-Raf-dependent p38 MAPK signaling cascade. This 5-HT1D receptor effect may contribute to neuronal hypoexcitability in small TG neurons. PMID:27156838

  12. TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients

    NARCIS (Netherlands)

    B.J.M. Braakhuis; M.M. Rietbergen; M. Buijze; P.J.F. Snijders; E. Bloemena; R.H. Brakenhoff; C.R. Leemans

    2014-01-01

    Objective Little is known about the molecular carcinogenesis of oral squamous cell carcinoma (OSCC) in young adult patients. The aim of this study was to investigate the detailed TP53 mutation and human papilloma virus (HPV) status of OSCC in patients, younger than 45 years. Methods TP53 mutations w

  13. Concordance of KRAS/BRAF Mutation Status in Metastatic Colorectal Cancer before and after Anti-EGFR Therapy

    Directory of Open Access Journals (Sweden)

    S. Gattenlöhner

    2009-01-01

    Full Text Available Anti-EGFR targeted therapy is a potent strategy in the treatment of metastatic colorectal cancer (mCRC but activating mutations in the KRAS gene are associated with poor response to this treatment. Therefore, KRAS mutation analysis is employed in the selection of patients for EGFR-targeted therapy and various studies have shown a high concordance between the mutation status in primary CRC and corresponding metastases. However, although development of therapy related resistance occurs also in the context of novel drugs such as tyrosine kinase-inhibitors the effect of the anti-EGFR treatment on the KRAS/BRAF mutation status itself in recurrent mCRC has not yet been clarified. Therefore, we analyzed 21 mCRCs before/after anti-EGFR therapy and found a pre-/posttherapeutic concordance of the KRAS/BRAF mutation status in 20 of the 21 cases examined. In the one discordant case, further analyses revealed that a tumor mosaicism or multiple primary tumors were present, indicating that anti-EGFR therapy has no influence on KRAS/BRAF mutation status in mCRC. Moreover, as the preselection of patients with a KRASwt genotype for anti-EGFR therapy has become a standard procedure, sample sets such ours might be the basis for future studies addressing the identification of potential anti-EGFR therapy induced genetic alterations apart from KRAS/BRAF mutations.

  14. Comparison of EGFR Mutation Status in Paired Pre- and Post-chemotherapy Serum for Advanced Pulmonary Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Rubing HAN

    2011-02-01

    Full Text Available Background and objective Non-small cell lung cancer (NSCLC with mutations in the epidermal growth factor receptor (EGFR is a distinct subgroup of NSCLC, which is particularly responsive to EGFR tyrosine kinase inhibitors (TKIs. The aim of this study is to detect EGFR mutations in paired serum of pre- and post-chemotherapy from advanced pulmonary adenocarcinoma patients to evaluate impact of chemotherapy on EGFR mutation status. Methods Magnetic beads were used for DNA extraction from paired serum of pre- and post-chemotherapy of 33 advanced pulmonary adenocarcinoma patients. The EGFR exon 19 and 21 were amplified by mutant-enriched nested PCR and analyzed by direct sequencing. Results EGFR mutations were detected in 39.4% (13/33 and 54.5% (18/33 serum samples of pre- and postchemotherapy, respectively. The EGFR mutation status was consistent in 54.5% (18/33 patients. Among 15 discordant cases, 10 changed from pre-chemo wild-type to post-chemo mutant-type status, while 5 from pre-chemo mutant-type to post-chemo wild-type status. Conclusion Chemotherapy may have influence on serum EGFR mutation status in advanced adenocacinoma patients.

  15. EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Frifeldt Sanne K

    2011-03-01

    Full Text Available Abstract Background As supplement to KRAS mutational analysis, BRAF and PIK3CA mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan. Methods One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of KRAS, BRAF and PIK3CA were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry. Results DNA was available in 94 patients. The frequency of KRAS, BRAF and PIK3CA mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. KRAS and BRAF were mutually exclusive. Supplementing KRAS analysis with BRAF and PIK3CA indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR of 41% (p Conclusion Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.

  16. BRAF Mutation in Colorectal Cancer: An Update.

    Science.gov (United States)

    Barras, David

    2015-01-01

    Colorectal cancer (CRC) is still one of the deadliest cancer-related diseases. About 10% of CRC patients are characterized by a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene resulting in a valine-to-glutamate change at the residue 600 (V600E). This mutation is also present in more than 60% of melanoma patients. BRAF inhibitors were developed and found to improve patient survival; however, most patients at the end of the track ultimately develop resistance to these inhibitors. Melanoma patients benefit from the combination of BRAF inhibitors with mitogen/extracellular signal-regulated kinase (MEK) inhibitors, among others. Unfortunately, colorectal patients do not respond much efficiently, which suggests different resistance mechanisms between the two cancer types. This review aims at shedding light on recent discoveries that improve our understanding of the BRAF mutation biology in CRC.

  17. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    International Nuclear Information System (INIS)

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  18. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

    Directory of Open Access Journals (Sweden)

    İpek Yönal

    2016-05-01

    Full Text Available Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET and primary myelofibrosis (PMF. The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb and hematocrit (Hct levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype.

  19. Bone marrow histomorphology and JAK2 mutation status in essential thrombocythemia

    DEFF Research Database (Denmark)

    Stauffer Larsen, Thomas; Hasselbalch, Hans Carl; Pallisgaard, Niels;

    2007-01-01

    A retrospective study of 38 essential thrombocythemia (ET) patients was conducted, reviewing bone marrow biopsies according to WHO criteria using a semiquantitative scoring system. Four patients did not fulfil the WHO criteria for a myeloproliferative disorder and one biopsy was insufficient for...... evaluation. 14 patients were reclassified as having prefibrotic idiopathic myelofibrosis (IMF), whilst the ET diagnosis was sustained in 19 patients. The individual bone marrow parameters of the reviewed diagnosis showed no correlation with JAK2 V617F mutation status, which was determined by a highly...... recorded as regards bone marrow morphology according to the WHO criteria. Accordingly, the WHO concept of two distinct entities, ET and prefibrotic IMF, does not seem to fit the model of JAK2-positive ET as part of a biological continuum of JAK2 V617F-positive chronic myeloproliferative disorders....

  20. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Directory of Open Access Journals (Sweden)

    Abeer M Mahmoud

    Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  1. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Science.gov (United States)

    Mahmoud, Abeer M; Zhu, Tian; Parray, Aijaz; Siddique, Hifzur R; Yang, Wancai; Saleem, Mohammad; Bosland, Maarten C

    2013-01-01

    Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  2. 18F-FDG uptake for prediction EGFR mutation status in non-small cell lung cancer.

    Science.gov (United States)

    Guan, Jian; Xiao, Nan J; Chen, Min; Zhou, Wen L; Zhang, Yao W; Wang, Shuang; Dai, Yong M; Li, Lu; Zhang, Yue; Li, Qin Y; Li, Xiang Z; Yang, Mi; Wu, Hu B; Chen, Long H; Liu, Lai Y

    2016-07-01

    Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are a response to EGFR-tyrosine kinase inhibitor. However, a lack of sufficient tumor tissue has been a limitation for determining EGFR mutation status in clinical practice. The objective of this study was to predict EGFR mutation status in NSCLC patients based on a model including maximum standardized uptake value (SUVmax) and clinical features.We retrospectively reviewed NSCLC patients undergoing EGFR mutation testing and pretreatment positron emission tomography/computed tomography between March 2009 and December 2013. The relationships of EGFR mutations with both SUVmax and patient characteristics were evaluated, and a multivariate logistic regression analysis was performed. The model was assessed by area under the receiver-operating characteristic curve (AUC) and was prospectively validated during January to June 2014.Three hundred and sixteen patients meeting the criteria were enrolled for model construction. The SUVmax values were significantly lower for EGFR mutations (mean, 9.5 ± 5.74) than for EGFR wild-type (mean, 12.7 ± 6.43; P smoking history and primary tumor size when genetic tests are not available. PMID:27472739

  3. Role of the FGFR3 gene mutation status in predicting progression of non-muscle-invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    A. I. Rolevich

    2015-01-01

    Full Text Available A prospective study was conducted to assess the prognostic value of FGFR3 gene mutation status in patients with non-muscle invasive bladder cancer. A total of 265 patients were included in the study. FGFR3 gene mutations were found in 168 (63.4 % cases. FGFR3 mutation rate was significantly higher in low-grade tumors (p = 0.00 004. With a median follow-up of 34 months hazard ratio of progression in FGFR3 mutant cases compared to FGFR3 wild type was 0.50 (95 % CI 0.17–1.49; p = 0.21. In the subgroup analysis, it was found that FGFR3 mutations in patients with T1 high grade tumors (n = 41 were associated with a significantly better prognosis: 3-year progression-free survival (PFS in FGFR3 mutant cases (n = 17 was 100 % compared to 71.2 % (95 % CI 42.8–99.6 % in the absence of mutations (n = 24. For other subgroups (Ta, T1 low grade no statistically significant difference in PFS by FGFR3 mutation status was noted.

  4. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations

    NARCIS (Netherlands)

    Visser, Nora A; Braun, Kees P J; Leijten, Frans S S; van Nieuwenhuizen, Onno; Wokke, John H J; van den Bergh, Walter M

    2011-01-01

    Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy w

  5. Refined histopathological predictors of BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T;

    2014-01-01

    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to asse...

  6. Does Ataxia Telangiectasia Mutated (ATM) protect testicular and germ cell DNA integrity by regulating the redox status?

    Science.gov (United States)

    Godschalk, Roger W L; Vanhees, Kimberly; Maas, Lou; Drittij, Marie-Jose; Pachen, Daniëlle; van Doorn-Khosrovani, Sahar van Waalwijk; van Schooten, Frederik J; Haenen, Guido R M M

    2016-08-01

    A balanced redox homeostasis in the testis is essential for genetic integrity of sperm. Reactive oxygen species can disturb this balance by oxidation of glutathione, which is regenerated using NADPH, formed by glucose-6-phosphate dehydrogenase (G6PDH). G6PDH is regulated by the Ataxia Telangiectasia Mutated (Atm) protein. Therefore, we studied the redox status and DNA damage in testes and sperm of mice that carried a deletion in Atm. The redox status in heterozygote mice, reflected by glutathione levels and antioxidant capacity, was lower than in wild type mice, and in homozygotes the redox status was even lower. The redox status correlated with oxidative DNA damage that was highest in mice that carried Atm deletions. Surprisingly, G6PDH activity was highest in homozygotes carrying the deletion. These data indicate that defective Atm reduces the redox homeostasis of the testis and genetic integrity of sperm by regulating glutathione levels independently from G6PDH activity. PMID:27318254

  7. Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.

    Science.gov (United States)

    Morabito, Fortunato; Cutrona, Giovanna; Mosca, Laura; D'Anca, Marianna; Matis, Serena; Gentile, Massimo; Vigna, Ernesto; Colombo, Monica; Recchia, Anna Grazia; Bossio, Sabrina; De Stefano, Laura; Maura, Francesco; Manzoni, Martina; Ilariucci, Fiorella; Consoli, Ugo; Vincelli, Iolanda; Musolino, Caterina; Cortelezzi, Agostino; Molica, Stefano; Ferrarini, Manlio; Neri, Antonino

    2015-08-01

    ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B-lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status.

  8. Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer

    Institute of Scientific and Technical Information of China (English)

    HUANG Yi-sheng; WU Yi-long; YANG Jin-ji; ZHANG Xu-chao; YANG Xue-ning; HUANG Yu-juan; XU Chong-rui; ZHOU Qing; WANG Zhen; SU Jian

    2011-01-01

    Background Epidermal growth factor receptor (EGFR) mutations in lung carcinomas can make the disease more responsive to the treatment with tyrosine kinase inhibitors. We aimed to evaluate the prevalence of EGFR mutations in a large series of lung carcinomas.Methods We examined 1195 consecutive lung cancer patients for EGFR mutations in exons 18, 19, and 21 using direct sequencing of polymerase chain reaction products. A detailed smoking history was obtained. Patients were categorized as never smokers (<100 lifetime cigarettes), former smokers (quit >1 year ago), or current smokers (quit <1 year ago).Results There were EGFR mutations in 9 (4.5%) of 201 squamous carcinomas, in 1 (2%) of 50 large cell carcinomas,and in 1 (2.3%) of 44 small cell carcinomas that were investigated. Three hundred and twenty-seven mutations were found in the series of 858 adenocarcinomas (38.1%). Among 858 lung adenocarcinomas, we detected EGFR mutations in 250 (48.6%) of 514 never smokers, 39 (33.9%) of 115 former smokers, and 38 (16.6%) of 229 current smokers.Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P=0.0002) or stopped smoking less than 15 years ago (P=0.033) compared with individuals who never smoked.Conclusions Adenocarcinoma is the most frequent EGFR mutation pathologic type in lung cancer. The likelihood of EGFR mutations in exons 18, 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 15 years ago. These data can assist clinicians in assessing the likelihood of exons 18, 19, or 21 EGFR mutations in Chinese patients with lung cancer when mutational analysis is not feasible.

  9. Paraffin-embedded tissue is less accurate than frozen section analysis for determining VHL mutational status in sporadic renal cell carcinoma.

    OpenAIRE

    Verhoest, Grégory; Patard, Jean-Jacques; Fergelot, Patricia; Jouan, Florence; Zerrouki, Salim; Dréano, Stéphane; Mottier, Stéphanie; Rioux-Leclercq, Nathalie; Denis, Marc,

    2012-01-01

    International audience INTRODUCTION: Literature controversies exist regarding the prognostic value of VHL mutations. The objective was to compare paraffin-embedded and frozen section specimens for VHL mutations detection and to evaluate the reliability of DNA analysis in formalin-fixed tissues. METHODS: Seventy-six patients with clear cell renal cell carcinoma (RCC) previously assessed for VHL status from frozen samples were included. Seventy-three tumor samples were known to be mutated fo...

  10. Spectrum of EGFR gene copy number changes and KRAS gene mutation status in Korean triple negative breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Yoonjung Kim

    Full Text Available Anti-epidermal growth factor receptor (EGFR therapy has been tried in triple negative breast cancer (TNBC patients without evaluation of molecular and clinical predictors in several randomized clinical studies. Only fewer than 20% of metastatic TNBCs showed response to anti-EGFR therapy. In order to increase the overall response rate, first step would be to classify TNBC into good or poor responders according to oncogenic mutation profiles. This study provides the molecular characteristics of TNBCs including EGFR gene copy number changes and mutation status of EGFR and KRAS gene in Korean TNBC patients. Mutation analysis for EGFR, KRAS, BRAF and TP53 from a total of 105 TNBC tissue samples was performed by direct sequencing, peptide nucleic acid-mediated PCR clamping method and real-time PCR. Copy number changes of EGFR gene were evaluated using multiplex ligation-dependent probe amplification. Out of all 105 TNBCs, 15.2% (16/105 showed EGFR copy number changes. Among them, increased or decreased EGFR copy number was detected in 13 (5 single copy gain, 2 amplification and 4 high-copy number amplification and 3 cases (3 hemizygous deletion, respectively. The mutation frequencies of KRAS, EGFR and TP53 gene were 1.9% (G12V and G12D, 1.0% (exon 19 del and 31.4%, respectively. There was no BRAF V600E mutation found. Future studies are needed to evaluate the clinical outcomes of TNBC patients who undergo anti-EGFR therapy according to the genetic status of EGFR.

  11. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

    DEFF Research Database (Denmark)

    McGranahan, Nicholas; Favero, Francesco; de Bruin, Elza C.;

    2015-01-01

    ), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations...... suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified....... during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D...

  12. Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF.

    Science.gov (United States)

    Lang, J C; Borchers, J; Danahey, D; Smith, S; Stover, D G; Agrawal, A; Malone, J P; Schuller, D E; Weghorst, C M; Holinga, A J; Lingam, K; Patel, C R; Esham, B

    2002-08-01

    Inactivation of the p16 tumor suppressor gene is a common phenomenon in squamous cell carcinoma of the head and neck (SCCHN). Less commonly described is the observation of p16 overexpression in SCCHN. Since overexpression of p16 is a potent predictor of outcome in other cancers, we were interested in determining the level of expression of p16 in our SCCHN specimens as a prerequisite to later prognostic studies. We were also interested in determining the mutational status of p16 in these tumors, in order to determine whether the combination of overexpression and gene alteration may predict a different clinical outcome from overexpression alone. A total of 84 specimens of SCCHN were selected for study. These specimens were obtained from all major sites within the oral cavity, oropharynx, pharynx and larynx. The level of expression of p16 in SCCHN specimens was measured by semi-quantitative RT-PCR. In 35 cases, RNA was also isolated from matched normal tissue obtained from a negative tumor margin. In the other 49 cases, the expression level was compared with the level of expression measured in pooled normal RNA obtained from 10 specimens of normal epithelial tissue. Overexpression of p16 was documented when the level of expression in the tumor specimen was 2-fold or greater above the level of expression found in normal tissue. A total of 46 specimens demonstrated overexpression of p16 (55%). All specimens demonstrating overexpression were then subject to sequence analysis. Thirty specimens (65%) showed p16-specific gene alterations, ranging from intragenic deletions to single point mutations, and 15 of these cases concomitantly affect p14ARF. A single specimen demonstrated a silent point mutation within the p16 reading frame. This mutation produces a stop codon at residue 85 in the context of the p14ARF reading frame, predicting premature termination of p14ARF within a previously determined nucleolar localization signal. This observation suggests that in some cases at

  13. The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

    Science.gov (United States)

    Amornwichet, Napapat; Oike, Takahiro; Shibata, Atsushi; Nirodi, Chaitanya S; Ogiwara, Hideaki; Makino, Haruhiko; Kimura, Yuka; Hirota, Yuka; Isono, Mayu; Yoshida, Yukari; Ohno, Tatsuya; Kohno, Takashi; Nakano, Takashi

    2015-06-11

    Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently mutated in NSCLC, and the relative biological effectiveness (RBE) of carbon-ion beams over X-rays. The assessment of 15 NSCLC lines of different EGFR/KRAS mutational status and that of isogenic NSCLC lines expressing wild-type or mutant EGFR revealed that EGFR-mutant NSCLC cells, but not KRAS-mutant cells, show low RBE. This was attributable to (i) the high X-ray sensitivity of EGFR-mutant cells, since EGFR mutation is associated with a defect in non-homologous end joining, a major pathway for DNA double-strand break (DSB) repair, and (ii) the strong cell-killing effect of carbon-ion beams due to poor repair of carbon-ion beam-induced DSBs regardless of EGFR mutation status. These data highlight the potential of EGFR mutation status as a predictor of response to CIRT, i.e., CIRT may show a high therapeutic index in EGFR mutation-negative NSCLC.

  14. Determination of EGFR and KRAS mutational status in Greek non-small-cell lung cancer patients

    OpenAIRE

    Papadopoulou, Eirini; TSOULOS, NIKOLAOS; TSIRIGOTI, ANGELIKI; Apessos, Angela; AGIANNITOPOULOS, KONSTANTINOS; Metaxa-Mariatou, Vasiliki; Zarogoulidis, Konstantinos; Zarogoulidis, Pavlos; KASARAKIS, DIMITRIOS; KAKOLYRIS, STYLIANOS; Dahabreh, Jubrail; VLASTOS, FOTIS; ZOUBLIOS, CHARALAMPOS; Rapti, Aggeliki; PAPAGEORGIOU, NIKI GEORGATOU

    2015-01-01

    It has been reported that certain patients with non-small-cell lung cancer (NSCLC) that harbor activating somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene may be effectively treated using targeted therapy. The use of EGFR inhibitors in patient therapy has been demonstrated to improve response and survival rates; therefore, it was suggested that clinical screening for EGFR mutations should be performed for all patients. Numerous clinicopat...

  15. The Relationship between "MECP2" Mutation Type and Health Status and Service Use Trajectories over Time in a Rett Syndrome Population

    Science.gov (United States)

    Young, Deidra; Bebbington, Ami; de Klerk, Nick; Bower, Carol; Nagarajan, Lakshmi; Leonard, Helen

    2011-01-01

    This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use…

  16. Factor V G1691A (Leiden and prothrombin G20210A gene mutation status, and thrombosis in patients with chronic myeloproliferative disorders

    Directory of Open Access Journals (Sweden)

    Nur Soyer

    2011-12-01

    Full Text Available Objective: The aim of this study was to examine Factor V G1691A (Leiden (FVL and prothrombin G20210A (PT gene mutation status, and their relationship with thrombosis in patients with chronic myeloproliferative disorders (CMPDs.Materials and Methods: The study included 160 patients with a CMPD that were regularly followed-up between 1993 and 2009. FVL and PT mutation status was established based on blood samples analyzed via PCR using specific primers.Results: The frequency of FVL and PT mutation was 12.5% and 4.4%, respectively. In total, 27 episodes of thrombosis occurred in 24 (15% of the patients, and there wasn’t an association between the observed thrombotic events, and FVL or PT mutations. Hepatic vein thrombosis was noted in 3 patients that had FVL mutation, of which 1 also had PT mutation.Conclusion: We did not observe a relationship between thrombosis, and FVL or PT mutations in CMPD patients; however, 3 of the patients that had hepatic vein thrombosis also had FVL mutation. Larger studies are needed to more clearly determine if all CMPD patients with hepatic vein thrombosis need be investigated for FVL and PT mutation.

  17. The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations.

    Directory of Open Access Journals (Sweden)

    Rüediger Hilker

    Full Text Available Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD. The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31P and proton ((1H 3-T magnetic resonance spectroscopic imaging (MRSI in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6 compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA positron emission tomography (PET. The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i values correlated positively with MI (r = 0.879, p<0.001 and inversely with β-ATP (r = -0.784, p = 0.008 and GPC concentrations (r = -0.651, p = 0.030 in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance.

  18. No certain predictors for mutation status in a Danish cohort with familial hypercholesterolemia: a descriptive study

    DEFF Research Database (Denmark)

    Nybo, Mads; Brusgaard, Klaus; Hansen, Annebirthe Bo

    2007-01-01

    OBJECTIVE: In order to enable clinicians to refer the right persons suspected of familial hypercholesterolemia (FH) for mutation screening, a retrospective study was conducted in a Danish FH cohort. DESIGN AND METHODS: The study comprised 643 probands and 395 relatives, of which 421 individuals h...... criteria should therefore be referred in order to facilitate family tracing and genetic counseling......OBJECTIVE: In order to enable clinicians to refer the right persons suspected of familial hypercholesterolemia (FH) for mutation screening, a retrospective study was conducted in a Danish FH cohort. DESIGN AND METHODS: The study comprised 643 probands and 395 relatives, of which 421 individuals had...

  19. Intra-tumoral Heterogeneity of KRAS and BRAF Mutation Status in Patients with Advanced Colorectal Cancer (aCRC and Cost-Effectiveness of Multiple Sample Testing

    Directory of Open Access Journals (Sweden)

    Susan D. Richman

    2011-01-01

    Full Text Available KRAS mutation status is established as a predictive biomarker of benefit from anti-EGFr therapies. Mutations are normally assessed using DNA extracted from one formalin-fixed, paraffin-embedded (FFPE tumor block. We assessed heterogeneity of KRAS and BRAF mutation status intra-tumorally (multiple blocks from the same primary tumor. We also investigated the utility and efficiency of genotyping a ‘DNA cocktail’ prepared from multiple blocks. We studied 68 consenting patients in two randomized clinical trials. DNA was extracted, from ≥2 primary tumor FFPE blocks per patient. DNA was genotyped by pyrosequencing for KRAS codons 12, 13 and 61 and BRAF codon 600. In patients with heterogeneous mutation status, DNA cocktails were prepared and genotyped. Among 69 primary tumors in 68 patients, 7 (10.1% showed intratumoral heterogeneity; 5 (7.2% at KRAS codons 12, 13 and 2 (2.9% at BRAF codon 600. In patients displaying heterogeneity, the relevant KRAS or BRAF mutation was also identified in ‘DNA cocktail’ samples when including DNA from mutant and wild-type blocks. Heterogeneity is uncommon but not insignificant. Testing DNA from a single block will wrongly assign wild-type status to 10% patients. Testing more than one block, or preferably preparation of a ‘DNA cocktail’ from two or more tumor blocks, improves mutation detection at minimal extra cost.

  20. Role of [18F]FDG PET in prediction of KRAS and EGFR mutation status in patients with advanced non-small-cell lung cancer

    International Nuclear Information System (INIS)

    The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [18F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC. Between January 2005 and October 2011, 340 NSCLC patients were tested for KRAS and EGFR mutation status. We identified patients with stage III and IV disease who had undergone [18F]FDG PET/CT scanning for initial staging. SUVpeak, SUVmax and SUVmean of the single hottest tumour lesions were calculated, and their association with KRAS and EGFR mutation status was assessed. A receiver operator characteristic (ROC) curve analysis and a multivariate analysis (including SUVmean, gender, age and AJCC stage) were performed to identify the potential value of [18F]FDG PET/CT for predicting KRAS mutation. From 102 patients staged using [18F]FDG PET/CT, 28 (27 %) had KRAS mutation (KRAS+), 22 (22 %) had EGFR mutation (EGFR+) and 52 (51 %) had wild-type KRAS and EGFR profiles (WT). KRAS+ patients showed significantly higher [18F]FDG uptake than EGFR+ and WT patients (SUVmean 9.5, 5.7 and 6.6, respectively; p 18F]FDG uptake between EGFR+ patients and WT patients. ROC curve analysis for KRAS mutation status discrimination yielded an area under the curve of 0.740 for SUVmean (p 18F]FDG uptake than WT patients, as assessed in terms of SUVpeak, SUVmax and SUVmean. A multivariate model based on age, gender, AJCC stage and SUVmean might be used as a predictive marker of KRAS mutation status in patients with stage III or IV NSCLC. (orig.)

  1. Prognosis of Glioblastoma With Oligodendroglioma Component is Associated With the IDH1 Mutation and MGMT Methylation Status1

    Science.gov (United States)

    Myung, Jae Kyung; Cho, Hwa jin; Kim, Hanna; Park, Chul-Kee; Lee, Se Hoon; Choi, Seung Hong; Park, Peom; Yoon, Jung Min; Park, Sung-Hye

    2014-01-01

    Glioblastoma (GBM) with oligodendroglioma component (GBMO) is a newly described GBM subtype in the 2007 World Health Organization classification. However, its biological and genetic characteristics are largely unknown. We investigated the clinicopathological and molecular features of 34 GBMOs and compared the survival rate of these patients with those of patients with astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma (AOA), and conventional GBMs in our hospital. GBMO could be divided into two groups based on the presence of an IDH1 mutation. The IDH1 mutation was more frequently found in secondary GBMO, which had lower frequencies of EGFR amplification but higher MGMT methylation than the wild type IDH1 group, and patients with mutant IDH1 GBMO were on average younger than those with wild-type IDH1. Therefore, GBMO is a clinically and molecularly heterogeneous subtype, largely belonging to a proneural and classical subtype of GBM. The survival rate of GBMO patients itself was worse than that of AOA patients but not significantly better than that of conventional GBM patients. GBMO survival was independent of the dominant histopathological subtype i.e., astrocyte-dominant or oligodendroglioma -dominant, but it was significantly associated with the IDH1 mutation and MGMT methylation status. Therefore, GBMO should be regarded as a separate entity from AOA and must be classified as a subtype of GBM. However, further study is needed to determine whether it is a pathologic variant or a pattern of GBM because GBMO has a similar prognosis to conventional GBMs. PMID:25500080

  2. Prognosis of Glioblastoma With Oligodendroglioma Component is Associated With the IDH1 Mutation and MGMT Methylation Status

    Directory of Open Access Journals (Sweden)

    Jae Kyung Myung

    2014-12-01

    Full Text Available Glioblastoma (GBM with oligodendroglioma component (GBMO is a newly described GBM subtype in the 2007 World Health Organization classification. However, its biological and genetic characteristics are largely unknown. We investigated the clinicopathological and molecular features of 34 GBMOs and compared the survival rate of these patients with those of patients with astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma (AOA, and conventional GBMs in our hospital. GBMO could be divided into two groups based on the presence of an IDH1 mutation. The IDH1 mutation was more frequently found in secondary GBMO, which had lower frequencies of EGFR amplification but higher MGMT methylation than the wild type IDH1 group, and patients with mutant IDH1 GBMO were on average younger than those with wild-type IDH1. Therefore, GBMO is a clinically and molecularly heterogeneous subtype, largely belonging to a proneural and classical subtype of GBM. The survival rate of GBMO patients itself was worse than that of AOA patients but not significantly better than that of conventional GBM patients. GBMO survival was independent of the dominant histopathological subtype i.e., astrocyte-dominant or oligodendroglioma -dominant, but it was significantly associated with the IDH1 mutation and MGMT methylation status. Therefore, GBMO should be regarded as a separate entity from AOA and must be classified as a subtype of GBM. However, further study is needed to determine whether it is a pathologic variant or a pattern of GBM because GBMO has a similar prognosis to conventional GBMs.

  3. Mutation Status and Immunoglobulin Gene Rearrangements in Patients from Northwest and Central Region of Spain with Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    I. González-Gascón y Marín

    2014-01-01

    Full Text Available The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL, and to correlate it with cytogenetic abnormalities, overall survival (OS and time to first treatment (TTFT. 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.

  4. Dual surrogate markers for rapid prediction of epidermal growth factor receptor mutation status in advanced adenocarcinoma of the lung: A novel approach in resource-limited setting

    Directory of Open Access Journals (Sweden)

    K S Udupa

    2015-01-01

    Full Text Available Introduction: Tyrosine kinase inhibitors have revolutionized the treatment of metastatic lung cancer in patients with epidermal growth factor receptor (EGFR mutations. Amplified refractory mutation system (ARMS-reverse transcription-polymerase chain reaction (RT-PCR, the current standard for detecting EGFR mutation status is time-consuming and highly expensive. Consequently any surrogate test which are cheaper, faster and as accurate as the PCR method will help in early diagnosis and management of patients with lung cancer, especially in resource-limited settings. Materials and Methods: Eighty-five patients, all of South Indian origin, with adenocarcinoma of lung, registered between October 2009 and January 2013, were evaluated for EGFR mutation status by using scorpion probe based ARMS RT-PCR method. Immunohistochemical (IHC was performed using the phosphorylated AKT (P-AKT and thyroid transcription factor-1 (TTF-1 on above patient's sample, and the results were compared with EGFR mutation tests. Results: EGFR mutation was positive in 34 of 85 patients (40%. P-AKT and TTF-1 were positive in 50 (58.8% and 68 (80% patients respectively. Both P-AKT and TTF-1 had statistically significant correlation with EGFR mutation status. Positive and negative predictive value of P-AKT in diagnosing EGFR mutation was 58% and 85.5% and that for TTF-1 was 48.5% and 94.1%, respectively. The problem of low positive predictive value can partly be overcome by testing P-AKT and TTF-1 simultaneously. Conclusion: P-AKT and TTF-1 using IHC had statistically significant correlation with EGFR mutation with high negative predictive value. In the case of urgency of starting treatment, EGFR mutation testing may be avoided in those patients who are negative for these IHC markers and can be started on chemotherapy.

  5. Changes in mutational status during third-line treatment for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund;

    2014-01-01

    and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma...

  6. Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice.

    Science.gov (United States)

    Kemter, Elisabeth; Prueckl, Petra; Sklenak, Stefanie; Rathkolb, Birgit; Habermann, Felix A; Hans, Wolfgang; Gailus-Durner, Valérie; Fuchs, Helmut; Hrabě de Angelis, Martin; Wolf, Eckhard; Aigner, Bernhard; Wanke, Ruediger

    2013-10-15

    Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line Umod(C93F), leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and compare the phenotype of this new mouse line with the recently published mouse line Umod(A227T). In both mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to a maturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and Cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and to ER hyperplasia. Further, this study was able to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status.

  7. BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis.

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    Soo Kyung Nam

    Full Text Available Anti-EGFR antibody-based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC; despite this, several mutations--including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification--are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.KRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.Mutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%, 6 (3.1%, and 25 (13.1% cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6% and 16 (8.4% cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3% than KRAS wild type (6.9% (P = 0.020. In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively. In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004. When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7% CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%.KRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

  8. Assessment of Isocitrate Dehydrogenase mutational status in cerebral gliomas by in vivo Magnetic Resonance Spectroscopy

    DEFF Research Database (Denmark)

    Tietze, Anna; Oettingen, Gorm von; Sangill, Ryan;

    ) system. Material and Methods: We performed pre-surgical MRS in four grade 3 glioma patients. A standard MR protocol was combined with an optimized MRS sequence (single-voxel point-resolved spectroscopy)[3]. Metabolite quantification was performed using an unsuppressed water signal as reference...... and has the potential to open up for more personalized treatment approaches. It is usually assessed by immunohistochemistry or polymerase chain reaction (PCR) in tumor tissue obtained by surgical biopsies. IDH-mutated tumor cells accumulate 2-hydroxyglutarate (2-HG) that is present in very low...

  9. Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

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    Tianle Chen

    2012-01-01

    work, we use the expectation-maximization (EM algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

  10. DEPENDENCE OF YKL-40 mRNA TISSUE LEVELS ON KRAS MUTATION STATUS IN COLORECTAL CANCER - PRELIMINARY RESULTS

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    Yana Feodorova

    2015-08-01

    Full Text Available Colorectal cancer (CRC is one of the most deadly cancers worldwide. Despite the introduction of targeted molecular therapies in the last 10 years, overall survival has not increased substantially. CRC progression is accompanied by numerous genetic and epigenetic alterations and dysregulation of several signaling pathways, among which activation of Wnt and inactivation of TGF-β signaling. The molecular heterogeneity of CRC, however, hinders the molecular subtyping of CRC and thus the identification of common biomarkers for this pathology. The only three well established biomarkers for advanced-colorectal-cancer drug treatment are negative biomarkers. These are mutations in the genes KRAS, NRAS and BRAF which determine resistance to therapy with anti-EGFR antibodies. YKL-40 is a chitin-binding glycoprotein that has been shown to play a role in extracellular tissue remodeling, angiogenesis, cell migration and inflammation. Increased serum levels of this protein have been detected in patients with CRC but the role of YKL-40 in this neoplastic disease has not been studied extensively and the precise function of YKL-40 in CRC progression is not known. In the present study we determined the KRAS mutation status and measured the mRNA levels of YKL-40 of 24 patients with sporadic CRC. In addition, we assessed the association between these two parameters by statistical analysis. We are the first to show that in CRC YKL-40 mRNA levels are dependent on the presence of KRAS mutations, being prominently elevated in the wild type background. Our results indicate the potential role of YKL-40 as a target molecule for CRC therapy.

  11. Detection and Evaluation of EGFR Mutation Status in Serum of Patients with Advanced Non-small Cell Lung Cancer Treated with EGFR-TKIs

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    Ling MA

    2013-06-01

    Full Text Available Background and objective Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs has shown a high response rate in the treatment of lung cancer in patients with (EGFR mutation. The aim of this study is to evaluate the relationship between EGFR mutation status in serum and predicting benefit from EGFR-TKIs therapy in patients with advanced non-small cell lung cancer (NSCLC. Methods We examined EGFR mutation status in serum of 80 patients with advanced, EGFR-TKIs given as first-line therapy NSCLC. All patients were received long-term follow-up, and the drug efficacy were observed and evaluated. Results The EGFR mutation in serum was detected in 33.8% (27/80 of NSCLC patients examined, in which exon 19 deletion mutation was present at a frequency of 44.4% (12/27 and exon 21 point mutation was 55.6% (15/27; The response rate to EGFR-TKI in patients with EGFR mutation in serum was (55.6%, 15/27, which was remarkably higher than that in EGFR wild-type patients (17.0%, 9/53, the difference was statistically significant (χ2=0.370, P<0.001; The median progression free survival (PFS of patients with EGFR mutation in serum was remarkably better than that of EGFR wild-type patients (9.8 months vs 5.7 months, P=0.014. Conclusion In patients with advanced, EGFR-positive in serum NSCLC, EGFR-TKIs given as first-line therapy is associated with improved drug efficacy. The results suggest that it is feasible to use serum to detect EGFR mutation, which can predict a benefit from EGFR-TKIs given as first-line therapy.

  12. Surface antigen expression and correlation with variable heavy-chain gene mutation status in chronic lymphocytic leukemia.

    Science.gov (United States)

    Vilpo, Juhani; Tobin, Gerard; Hulkkonen, Janne; Hurme, Mikko; Thunberg, Ulf; Sundström, Christer; Vilpo, Leena; Rosenquist, Richard

    2003-01-01

    Recent studies have demonstrated that B-cell chronic lymphocytic leukemia (CLL) consists of two clinical entities with either somatically hypermutated (M-CLL) or unmutated (UM-CLL) immunoglobulin variable heavy-chain (VH) regions. In view of the fact that the cellular biology of these two subsets of disease is currently unexplored, we performed an extensive analysis of the surface antigen expression and correlated this with the VH gene mutation status in a cohort of 32 CLL patients. Using polymerase chain reaction amplification and nucleotide sequencing, the VH genes were shown to be mutated in 10 cases (31%) and unmutated in 22 (69%). The expression of 27 surface membrane antigens in peripheral blood leukemic cells was analyzed by flow cytometry, measuring both the percentage of positive cells as well as the geometric mean fluorescence intensity (GMF). Most of the surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD40, CD45, VD79b, CD80, CD95, CD122, CD124, CD126, CD130, CD154, IgM, and IgD) showed a similar expression pattern in both UM-CLL and M-CLL patients. The similarity of M-CLL and UM-CLL, as demonstrated here for the first time with many protein markers, indicates a considerably homogeneous phenotype in both subsets. Furthermore, CD27 was strongly expressed in all cases, which may suggest a memory cell phenotype for both M-CLL and UM-CLL. More positive cells in the UM-CLL group were observed regarding CD38, but CD38 was not a good predictor of VH gene mutation status. Seventy percent of the M-CLL cases, but only 36% of UM-CLL cases, were Ig-lambda+. The most striking differential expression, however, was observed in the two slicing variants of the common leukocyte antigen CD45, namely CD45RO and CD45RA. CD45RO expression was significantly associated with M-CLL, whereas the GMF intensity of CD45RA tended to be associated with UM-CLL. The role of these CD45 splicing variants in the pathogenesis of CLL deserves further investigation

  13. Analysis of the DF508 mutation in a Brazilian cystic fibrosis population: comparison of pulmonary status of homozygotes with other patients

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    Maróstica P.J.C.

    1998-01-01

    Full Text Available Sixty-one cystic fibrosis patients admitted for check-up or antibiotic treatment were enrolled for genetic and clinical evaluation. Genetic analysis was performed on blood samples stored on neonatal screening cards using PCR techniques to determine the presence of DF508 mutations. Clinical evaluation included Shwachman and Chrispin-Norman scores, age at onset of symptoms and diagnosis, spirometry, awake and sleep pulse oximetry, hyponychial angle measurement and presence of chronic Pseudomonas aeruginosa colonization. Eighteen patients (29.5% were homozygous for the DF508 mutation, 26 (42.6% had one DF508 mutation and 17 (27.9% were noncarriers, corresponding to a 50.8% prevalence of the mutation in the whole population. Analysis by the Kruskal-Wallis test for comparison of genetic status with continuous variables or by the chi-square test and logistic regression for dichotomous variables showed no significant differences between any two groups for a = 0.05. We conclude that genetic status in relation to the DF508 mutation is not associated with pulmonary status as evaluated by the above variables

  14. Role of [{sup 18}F]FDG PET in prediction of KRAS and EGFR mutation status in patients with advanced non-small-cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Caicedo, Carlos; Garcia-Velloso, Maria Jose; Vigil Diaz, Carmen; Richter Echevarria, Jose Angel [University of Navarra, Nuclear Medicine Department, University Clinic of Navarra, Pamplona (Spain); Lozano, Maria Dolores; Labiano, Tania [University of Navarra, Pathology Department, University Clinic of Navarra, Pamplona (Spain); Lopez-Picazo, Jose Maria; Gurpide, Alfonso; Perez Gracia, Jose Luis [University of Navarra, Oncology Department, University Clinic of Navarra, Pamplona (Spain); Zulueta, Javier [University of Navarra, Pulmonology Department, University Clinic of Navarra, Pamplona (Spain)

    2014-11-15

    The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [{sup 18}F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC. Between January 2005 and October 2011, 340 NSCLC patients were tested for KRAS and EGFR mutation status. We identified patients with stage III and IV disease who had undergone [{sup 18}F]FDG PET/CT scanning for initial staging. SUVpeak, SUVmax and SUVmean of the single hottest tumour lesions were calculated, and their association with KRAS and EGFR mutation status was assessed. A receiver operator characteristic (ROC) curve analysis and a multivariate analysis (including SUVmean, gender, age and AJCC stage) were performed to identify the potential value of [{sup 18}F]FDG PET/CT for predicting KRAS mutation. From 102 patients staged using [{sup 18}F]FDG PET/CT, 28 (27 %) had KRAS mutation (KRAS+), 22 (22 %) had EGFR mutation (EGFR+) and 52 (51 %) had wild-type KRAS and EGFR profiles (WT). KRAS+ patients showed significantly higher [{sup 18}F]FDG uptake than EGFR+ and WT patients (SUVmean 9.5, 5.7 and 6.6, respectively; p < 0.001). No significant differences were observed in [{sup 18}F]FDG uptake between EGFR+ patients and WT patients. ROC curve analysis for KRAS mutation status discrimination yielded an area under the curve of 0.740 for SUVmean (p < 0.001). The multivariate analysis showed a sensitivity and specificity of 78.6 % and 62.2 %, respectively, and the AUC was 0.773. NSCLC patients with tumours harbouring KRAS mutations showed significantly higher [{sup 18}F]FDG uptake than WT patients, as assessed in terms of SUVpeak, SUVmax and SUVmean. A multivariate model based on age, gender, AJCC stage and SUVmean might be used as a predictive marker of KRAS mutation status in patients with stage III or IV NSCLC. (orig.)

  15. Association between different EGFR mutation status and survival in pemetrexed-based chemotherapy for advanced non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    郏博

    2014-01-01

    Objective To explore the association between different epidermal growth factor receptor(EGFR)mutation status and survival in pemetrexed-based chemotherapy for advanced non-small-cell lung cancer(NSCLC).Methods A retrospective cohort study was performed to assess146 patients with advanced NSCLC at Cancer

  16. Current Status of Mungbean and the Use of Mutation Breeding in Thailand

    International Nuclear Information System (INIS)

    Seeds of mungbean varieties Khampang Saen 1 (KPS1) and Chai Nat 36 (CN36) were irradiated with a dose of 500Gy Gamma-rays and treated with 1% ethyl methane sulphonate. The objectives of this experiment were seed yield improvement and powdery mildew resistance. A number of mutant lines were selected from M2 onwards. Three promising mutants, M4-2, M5-1 and M5-5, gave 8-11% and 2-5% higher mean yield than those of KPS1 and CN36, but showed similar disease infection to their original parents tested during 1997-2006. The objective of the second experiment was to improve mungbean variety tolerance to beanfly, a key pest of mungbean. Seeds of var Khampang Saen 2 (KPS2) were irradiated with 600Gy Gamma-rays. A mutant line was selected and subsequently officially released as Chai Nat 72 (CN72) in 2000. It is the first mungbean variety released and developed through mutation techniques in Thailand. CN72 had lower beanfly infestation than a susceptible variety, CN36. The result of an addition trial conducted on calcareous soil showed that grain yield of mutant CN72 was superior to that of KPS2. The third experiment of the Mungbean Mutant Multi-location trials was conducted in two sites during 2003-2005. All mutants retained most traits of the original varieties, including yield. The highest yielding mutant across all five trials was CN72 which was similar to its progenitor (KPS2) and the local check, CN36. These three entries bore large seeds (70 g per 1,000 seeds), which is a desirable trait for Thai and international markets. An exotic entry, native variety showed least incidence of powdery mildew disease. It will be used as a source of disease resistance in the breeding programme. (author)

  17. Association between acquired uniparental disomy and homozygous mutations and HER2/ER/PR status in breast cancer.

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    Musaffe Tuna

    Full Text Available BACKGROUND: Genetic alterations in cellular signaling networks are a hallmark of cancer, however, effective methods to discover them are lacking. A novel form of abnormality called acquired uniparental disomy (aUPD was recently found to pinpoint the region of mutated genes in various cancers, thereby identifying the region for next-generation sequencing. METHODS/PRINCIPAL FINDINGS: We retrieved large genomic data sets from the Gene Expression Omnibus database to perform genome-wide analysis of aUPD in breast tumor samples and cell lines using approaches that can reliably detect aUPD. aUPD was identified in 52.29% of the tumor samples. The most frequent aUPD regions were located at chromosomes 2q, 3p, 5q, 9p, 9q, 10q, 11q, 13q, 14q and 17q. We evaluated the data for any correlation between the most frequent aUPD regions and HER2/neu, ER, and PR status, and found a statistically significant correlation between the recurrent regions of aUPD and triple negative (TN breast cancers. aUPD at chromosome 17q (VEZF1, WNT3, 3p (SUMF1, GRM7, 9p (MTAP, NFIB and 11q (CASP1, CASP4, CASP5 are predictors for TN. The frequency of aUPD was found to be significantly higher in TN breast cancer cases compared to HER2/neu-positive and/or ER or PR-positive cases. Furthermore, using previously published mutation data, we found TP53 homozygously mutated in cell lines having aUPD in that locus. CONCLUSIONS/SIGNIFICANCE: We conclude that aUPD is a common and non-random molecular feature of breast cancer that is most prominent in triple negative cases. As aUPD regions are different among the main pathological subtypes, specific aUPD regions may aid the sub-classification of breast cancer. In addition, we provide statistical support using TP53 as an example that identifying aUPD regions can be an effective approach in finding aberrant genes. We thus conclude that a genome-wide scale analysis of aUPD regions for homozygous sequence alterations can provide valuable insights

  18. Prognostic Value of Baseline 18F-FDG PET/CT Functional Parameters in Patients with Advanced Lung Adenocarcinoma Stratified by EGFR Mutation Status.

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    Dalong Wang

    Full Text Available The study objective was to retrospectively analyze the metabolic variables derived from 18 F-fluorodeoxyglucose (18F-FDG positron emission tomography/computed tomography (PET/CT as predictors of progression-free survival (PFS and overall survival (OS in advanced lung adenocarcinoma stratified by epidermal growth factor receptor (EGFR mutation status. A total of 176 patients (91, EGFR mutation; 85, wild-type EGFR who underwent 18F-FDG PET/CT before treatment were enrolled. The main 18F-FDG PET/CT-derived variables: primary tumor maximum standardized uptake value (SUVmaxT, primary tumor total lesion glycolysis (TLGT, the maximum SUVmax of all selected lesions in whole body determined using the Response Evaluation Criteria In Solid Tumors (RECIST 1.1 criteria (SUVmaxWBR, and whole-body total TLG determined using the RECIST 1.1 criteria (TLGWBR were measured. Survival analysis regarding TLGWBR, and other factors in advanced lung adenocarcinoma patients stratified using EGFR mutation status, were evaluated. The results indicated that high TLGWBR (≥259.85, EGFR wild-type, and high serum LDH were independent predictors of worse PFS and OS in all patients with advanced lung adenocarcinoma. Among patients with wild-type EGFR, only TLGWBR retained significance as an independent predictor of both PFS and OS. Among patients with the EGFR mutation, high serum LDH level was an independent predictor of worse PFS and OS, and high TLGWBR (≥259.85 was an independent predictor of worse PFS but not worse OS. In conclusion, TLGWBR is a promising parameter for prognostic stratification of patients with advanced lung adenocarcinoma and EGFR status; however, it cannot be used to further stratify the risk of worse OS for patients with the EGFR mutation. Further prospective studies are needed to validate our findings.

  19. Utility of BRAF V600E Immunohistochemistry Expression Pattern as a Surrogate of BRAF Mutation Status in 154 Patients with Advanced Melanoma.

    Science.gov (United States)

    Tetzlaff, Michael T; Pattanaprichakul, Penvadee; Wargo, Jennifer; Fox, Patricia S; Patel, Keyur P; Estrella, Jeannelyn S; Broaddus, Russell R; Williams, Michelle D; Davies, Michael A; Routbort, Mark J; Lazar, Alexander J; Woodman, Scott E; Hwu, Wen-Jen; Gershenwald, Jeffrey E; Prieto, Victor G; Torres-Cabala, Carlos A; Curry, Jonathan L

    2015-08-01

    Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (ρ = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation.

  20. Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status.

    Science.gov (United States)

    Steiner, Florian; Hauser-Kronberger, Cornelia; Rendl, Gundula; Rodrigues, Margarida; Pirich, Christian

    2016-01-01

    Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 (TTF-1) is involved in rearranged during transfection (RET) transcription in Hirschsprung's disease. Tenascin C, EGFR, E-cadherin, TTF-1-expression, and their correlations with RET mutation status were investigated in 30 patients with medullary thyroid carcinoma (MTC) (n = 26) or C-cell hyperplasia (n = 4). Tenascin C was found in all, EGFR in 4/26, E-cadherin in 23/26, and TTF-1 in 25/26 MTC. Tenascin C correlated significantly with tumor proliferation (overall, r = 0.61, p < 0.005; RET-mutated, r = 0.81, p < 0.01). E-cadherin showed weak correlation, whereas EGFR and TTF-1 showed no significant correlation with tumor proliferation. EGFR, E-cadherin, and TTF-1 showed weak correlation with proliferation of RET-mutated tumors. Correlation between TTF-1 and tenascin C, E-cadherin, and EGFR was r = -0.10, 0.37, and 0.21, respectively. In conclusion, MTC express tenascin C, E-cadherin, and TTF-1. Tenascin C correlates significantly with tumor proliferation, especially in RET-mutated tumors. EGFR is low, and tumors expressing EGFR do not exhibit higher proliferation. TTF-1 does not correlate with RET mutation status and has a weak correlation with tenascin C, E-cadherin, and EGFR expression. PMID:27409604

  1. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.

    Science.gov (United States)

    De Roock, Wendy; De Vriendt, Veerle; Normanno, Nicola; Ciardiello, Fortunato; Tejpar, Sabine

    2011-06-01

    The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

  2. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    Directory of Open Access Journals (Sweden)

    Joanna Mangana

    Full Text Available Ipilimumab and tremelimumab are human monoclonal antibodies (Abs against cytotoxic T-lymphocyte antigen-4 (CTLA-4. Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62 was 10.12 months (95% CI 6.78-13.2 compared to 8.26 months (95% CI 6.02-19.9 in BRAFV600/NRASwt subpopulation (n = 39 (p = 0.67. The median OS of NRAS mutated patients (n = 24 was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months the difference didn't reach statistical significance (p = 0.56. 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

  3. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    Science.gov (United States)

    Mangana, Joanna; Cheng, Phil F; Schindler, Katja; Weide, Benjamin; Held, Ulrike; Frauchiger, Anna L; Romano, Emanuella; Kähler, Katharina C; Rozati, Sima; Rechsteiner, Markus; Moch, Holger; Michielin, Olivier; Garbe, Claus; Hauschild, Axel; Hoeller, Christoph; Dummer, Reinhard; Goldinger, Simone M

    2015-01-01

    Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

  4. Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status.

    Science.gov (United States)

    Steiner, Florian; Hauser-Kronberger, Cornelia; Rendl, Gundula; Rodrigues, Margarida; Pirich, Christian

    2016-07-09

    Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 (TTF-1) is involved in rearranged during transfection (RET) transcription in Hirschsprung's disease. Tenascin C, EGFR, E-cadherin, TTF-1-expression, and their correlations with RET mutation status were investigated in 30 patients with medullary thyroid carcinoma (MTC) (n = 26) or C-cell hyperplasia (n = 4). Tenascin C was found in all, EGFR in 4/26, E-cadherin in 23/26, and TTF-1 in 25/26 MTC. Tenascin C correlated significantly with tumor proliferation (overall, r = 0.61, p C, E-cadherin, and EGFR was r = -0.10, 0.37, and 0.21, respectively. In conclusion, MTC express tenascin C, E-cadherin, and TTF-1. Tenascin C correlates significantly with tumor proliferation, especially in RET-mutated tumors. EGFR is low, and tumors expressing EGFR do not exhibit higher proliferation. TTF-1 does not correlate with RET mutation status and has a weak correlation with tenascin C, E-cadherin, and EGFR expression.

  5. Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay

    Directory of Open Access Journals (Sweden)

    Hamel Christian

    2003-01-01

    Full Text Available Abstract Background X-linked ocular albinism type 1 (OA1 is caused by mutations in OA1 gene, which encodes a membrane glycoprotein localised to melanosomes. OA1 mainly affects pigment production in the eye, resulting in optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers and reduced visual acuity. Affected Caucasian males usually appear to have normal skin and hair pigment. Results We identified three previously undescribed mutations consisting of two intragenic deletions (one encompassing exon 6, the other encompassing exons 7–8, and a point mutation (310delG in exon 2. We report the development of a new method for diagnosis of heterozygous deletions in OA1 gene based on measurement of gene copy number using real-time quantitative PCR from genomic DNA. Conclusion The identification of OA1 mutations in families earlier reported as families with hereditary nystagmus indicate that ocular albinism type 1 is probably underdiagnosed. Our method of real-time quantitative PCR of OA1 exons with DMD exon as external standard performed on the LightCycler™ allows quick and accurate carrier-status assessment for at-risk females.

  6. Prognostic Stratification of GBMs Using Combinatorial Assessment of IDH1 Mutation, MGMT Promoter Methylation, and TERT Mutation Status: Experience from a Tertiary Care Center in India

    Directory of Open Access Journals (Sweden)

    Suvendu Purkait

    2016-08-01

    Based on above findings, we recommend assessment of three markers, viz., IDH1, MGMT, and TERT, for GBM prognostication in routine practice. We show for the first time that IDH1 wild-type GBMs which constitute majority of the GBMs can be effectively stratified into three distinct prognostic subgroups based on MGMT and TERT status, irrespective of other genetic alterations.

  7. The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

    Science.gov (United States)

    Molenaar, Remco J.; Verbaan, Dagmar; Lamba, Simona; Zanon, Carlo; Jeuken, Judith W.M.; Boots-Sprenger, Sandra H.E.; Wesseling, Pieter; Hulsebos, Theo J.M.; Troost, Dirk; van Tilborg, Angela A.; Leenstra, Sieger; Vandertop, W. Peter; Bardelli, Alberto; van Noorden, Cornelis J.F.; Bleeker, Fonnet E.

    2014-01-01

    Background Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O6-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients. Methods We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor. Results Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets. Discussion The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials. PMID:24510240

  8. Carrier status for the common R501X and 2282del4 filaggrin mutations is not associated with hearing phenotypes in 5,377 children from the ALSPAC cohort.

    Directory of Open Access Journals (Sweden)

    Santiago Rodriguez

    Full Text Available BACKGROUND: Filaggrin is a major protein in the epidermis. Several mutations in the filaggrin gene (FLG have been associated with a number of conditions. Filaggrin is expressed in the tympanic membrane and could alter its mechanical properties, but the relationship between genetic variation in FLG and hearing has not yet been tested. METHODOLOGY/PRINCIPAL FINDINGS: We examined whether loss-of function mutations R501X and 2282del4 in the FLG gene affected hearing in children. Twenty eight hearing variables representing five different aspects of hearing at age nine years in 5,377 children from the Avon Longitudinal Study of Parents and Children (ALSPAC cohort were tested for association with these mutations. No evidence of association was found between R501X or 2282del4 (or overall FLG mutation carrier status and any of the hearing phenotypes analysed. CONCLUSIONS/SIGNIFICANCE: In conclusion, carrier status for common filaggrin mutations does not affect hearing in children.

  9. Comparative analysis of BRAF, NRAS and c-KIT mutation status between tumor tissues and autologous tumor cell-lines of stage III/IV melanoma.

    Science.gov (United States)

    Knol, Anne-Chantal; Pandolfino, Marie-Christine; Vallée, Audrey; Nguyen, Frédérique; Lella, Virginie; Khammari, Amir; Denis, Marc; Puaux, Anne-Laure; Dréno, Brigitte

    2015-01-01

    In the last decade, advances in molecular biology have provided evidence of the genotypic heterogeneity of melanoma. We analysed BRAF, NRAS and c-KIT alterations in tissue samples from 63 stage III/IV melanoma patients and autologous cell-lines, using either allele-specific or quantitative PCR. The expression of BRAF V600E protein was also investigated using an anti-BRAF antibody in the same tissue samples. 81% of FFPE samples and tumor cell-lines harboured a genetic alteration in either BRAF (54%) or NRAS (27%) oncogenes. There was a strong concordance (100%) between tissue samples and tumor cell-lines. The BRAF V600E mutant-specific antibody showed high sensitivity (96%) and specificity (100%) for detecting the presence of a BRAF V600E mutation. The correlation was of 98% between PCR and immunohistochemistry results for BRAF mutation. These results suggest that BRAF and NRAS mutation status of tumor cells is not affected by culture conditions.

  10. A possible association between a dysfunctional skin barrier (filaggrin null-mutation status) and diabetes: a cross-sectional study

    DEFF Research Database (Denmark)

    Thyssen, Jacob P; Linneberg, Allan; Carlsen, Berit C;

    2011-01-01

    Background Filaggrin proteins are located in the skin and prevent epidermal water loss and impede the entry of micro-organisms, allergens and chemicals. Filaggrin null mutations are strongly associated with ichthyosis vulgaris and atopic dermatitis. Objective The authors aimed to investigate...

  11. Can EGFR mutation status be reliably determined in pre-operative needle biopsies from adenocarcinomas of the lung?

    DEFF Research Database (Denmark)

    Lindahl, Kim Hein; Sørensen, Flemming Brandt; Jonstrup, Søren Peter;

    2015-01-01

    The identification of EGFR mutations in non-small-cell lung cancer is important for selecting patients, who may benefit from treatment with EGFR tyrosine kinase inhibitors. The analysis is usually performed on cytological aspirates and/or histological needle biopsies, representing a small fractio...

  12. Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients

    Directory of Open Access Journals (Sweden)

    Mekenkamp Leonie JM

    2012-07-01

    Full Text Available Abstract Background KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR antibodies in metastatic colorectal cancer (mCRC. Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA and microRNAs (miRNAs in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Methods Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17 or poor (n = 17 progression-free survival (PFS upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Results Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. Conclusions Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

  13. Malathion Resistance Status and Mutations in Acetylcholinesterase Gene (Ace) in Japanese Encephalitis and Filariasis Vectors from Endemic Area in India.

    Science.gov (United States)

    Misra, Brij Ranjan; Gore, Milind

    2015-05-01

    Japanese encephalitis (JE) and lymphatic filariasis (LF) are endemic in estern part of Uttar Pradesh in India and transmitted by Culex mosquitoes (Diptera: Culicidae). JE vaccination and mass drug administration for JE and LF management is being undertaken respectively. In addition to this, indoor residual spraying and fogging are used for the control of mosquito vectors. Organophosphate resistance in mosquito is dependent on alteration in acetylcholinesterase (Ace) gene. Hence, it is important to evaluate organophosphate resistance in Culex tritaeniorhynchus Giles (JE vector) and Culex quinquefasciatus Say (LF vector). The current study showed the presence of resistant populations and F331W mutation in Cx. tritaeniorhynchus and G119S mutation in Cx. quinquefasciatus insensitive Ace genes. Resistant populations of these two vectors increase the chances of spreading of resistance in the natural population and may cause failure of intervention programs that include organophosphates against these two vectors in future. PMID:26334819

  14. Malathion Resistance Status and Mutations in Acetylcholinesterase Gene (Ace) in Japanese Encephalitis and Filariasis Vectors from Endemic Area in India.

    Science.gov (United States)

    Misra, Brij Ranjan; Gore, Milind

    2015-05-01

    Japanese encephalitis (JE) and lymphatic filariasis (LF) are endemic in estern part of Uttar Pradesh in India and transmitted by Culex mosquitoes (Diptera: Culicidae). JE vaccination and mass drug administration for JE and LF management is being undertaken respectively. In addition to this, indoor residual spraying and fogging are used for the control of mosquito vectors. Organophosphate resistance in mosquito is dependent on alteration in acetylcholinesterase (Ace) gene. Hence, it is important to evaluate organophosphate resistance in Culex tritaeniorhynchus Giles (JE vector) and Culex quinquefasciatus Say (LF vector). The current study showed the presence of resistant populations and F331W mutation in Cx. tritaeniorhynchus and G119S mutation in Cx. quinquefasciatus insensitive Ace genes. Resistant populations of these two vectors increase the chances of spreading of resistance in the natural population and may cause failure of intervention programs that include organophosphates against these two vectors in future.

  15. Epidermal growth factor receptor (EGFR mutation status and Rad51 determine the response of glioblastoma (GBM to multimodality therapy with cetuximab, temozolomide and radiation

    Directory of Open Access Journals (Sweden)

    Phyllis Rachelle Wachsberger

    2013-02-01

    Full Text Available Purpose: EGFR amplification and mutation (i.e., EGFRvIII are found in 40% of primary GBM tumors and are believed to contribute to tumor development and therapeutic resistance. This study was designed to investigate how EGFR mutational status modulates response to multimodality treatment with cetuximab, an anti-EGFR inhibitor, the chemotherapeutic agent, temozolamide (TMZ and radiation therapy (RT Methods and Materials: In vitro and in vivo experiments were performed on two isogenic U87 GBM cell lines: one overexpressing wildtype EGFR (U87wtEGFR and the other overexpressing EGFRvIII (U87EGFRvIII. Results: Xenografts harboring EGFRvIII were more sensitive to TMZ alone and TMZ in combination with RT and/or cetuximab than xenografts expressing wtEGFR. In vitro experiments demonstrated that U87EGFRvIII-expressing tumors appear to harbor defective DNA homologous recombination repair in the form of Rad51 processing, Conclusions: The difference in sensitivity between EGFR-expressing and EGFRvIII-expressing tumors to combined modality treatment may help in the future tailoring of GBM therapy to subsets of patients expressing more or less of the EGFR mutant.

  16. Prognostic value of the extent of resection in supratentorial WHO grade II astrocytomas stratified for IDH1 mutation status: a single-center volumetric analysis.

    Science.gov (United States)

    Jungk, Christine; Scherer, Moritz; Mock, Andreas; Capper, David; Radbruch, Alexander; von Deimling, Andreas; Bendszus, Martin; Herold-Mende, Christel; Unterberg, Andreas

    2016-09-01

    Current evidence supports a maximized extent of resection (EOR) in low-grade gliomas (LGG), regardless of different histological subtypes and molecular markers. We therefore evaluated the prognostic impact of extensive, mainly intraoperative (i)MRI-guided surgery in low-grade astrocytomas stratified for IDH1 mutation status. Retrospective assessment of 46 consecutive cases of newly diagnosed supratentorial WHO grade II astrocytomas treated during the last decade was performed. IDH1 mutation status was obtained for all patients. Volumetric analysis of tumor volumes was performed pre-, intra-, early postoperatively and at first follow-up. Survival analysis was conducted with uni-and multivariate regression models implementing clinical parameters and continuous volumetric variables. Median EOR was 90.4 % (range 17.5-100 %) and was increased to 94.9 % (range 34.8-100 %) in iMRI-guided resections (n = 33). A greater EOR was prognostic for increased progression-free survival (HR 0.23, p = 0.031) and time to re-intervention (TTR) (HR 0.23, p = 0.03). In IDH1 mutant patients, smaller residual tumor volumes were associated with increased TTR (HR 1.01, p = 0.03). IDH1 mutation (38/46 cases) was an independent positive prognosticator for overall survival (OS) in multivariate analysis (HR 0.09, p = 0.002), while extensive surgery had limited impact upon OS. In a subgroup of patients with ≥40 % EOR (n = 39), however, initial and residual tumor volumes were prognostic for OS (HR 1.03, p = 0.005 and HR 1.08, p = 0.007, respectively), persistent to adjustment for IDH1. No association between EOR and neurologic morbidity was found. In this analysis of low-grade astrocytomas stratified for IDH1, extensive tumor resections were prognostic for progression and TTR and, in patients with ≥40 % EOR, for OS. PMID:27344556

  17. Fetal-juvenile origins of point mutations in the adult human tracheal-bronchial epithelium: Absence of detectable effects of age, gender or smoking status

    Energy Technology Data Exchange (ETDEWEB)

    Sudo, Hiroko [Massachusetts Institute of Technology, Department of Biological Engineering, 21 Ames St., 16-743 Cambridge, MA 02139 (United States); Toray Industries, Inc., New Frontiers Research Laboratories 10-1, Tebiro 6-chome, Kamakura, Kanagawa 248-8555 (Japan); Li-Sucholeiki, Xiao-Cheng [Massachusetts Institute of Technology, Department of Biological Engineering, 21 Ames St., 16-743 Cambridge, MA 02139 (United States); Agencourt Bioscience Corp., 500 Cummings Center, Suite 2450, Beverly, MA 01915 (United States); Marcelino, Luisa A. [Massachusetts Institute of Technology, Department of Biological Engineering, 21 Ames St., 16-743 Cambridge, MA 02139 (United States); Biomedical Engineering Department, Northwestern University, 633 Clark Street, Evanston, IL 60208 (United States); Gruhl, Amanda N. [Massachusetts Institute of Technology, Department of Biological Engineering, 21 Ames St., 16-743 Cambridge, MA 02139 (United States); Herrero-Jimenez, Pablo [Massachusetts Institute of Technology, Department of Biological Engineering, 21 Ames St., 16-743 Cambridge, MA 02139 (United States); SLC Ontario, 690 Dorval Drive, Suite 200, Oakville, Ontario L6K 3W7 Canada (Canada); Zarbl, Helmut [UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, 170 Freylinghuysen Road, Room 426, Piscataway, NJ 08854 (United States); Willey, James C. [Medical College of Ohio, 3120 Glendale Avenue, Room 12, Toledo, OH 43614 (United States); Furth, Emma E. [University of Pennsylvania Medical Center, Department of Pathology, 3400 Spruce Street, 6 Founders Building, Philadelphia, PA 19104 (United States); Morgenthaler, Stephan [Institute of Applied Mathematics, Swiss Federal Institute of Technology (EPFL), SB/IMA, 1015 Lausanne (Switzerland)] (and others)

    2008-11-10

    Allele-specific mismatch amplification mutation assays (MAMA) of anatomically distinct sectors of the upper bronchial tracts of nine nonsmokers revealed many numerically dispersed clusters of the point mutations C742T, G746T, G747T of the TP53 gene, G35T of the KRAS gene and G508A of the HPRT1 gene. Assays of these five mutations in six smokers have yielded quantitatively similar results. One hundred and eighty four micro-anatomical sectors of 0.5-6 x 10{sup 6} tracheal-bronchial epithelial cells represented en toto the equivalent of approximately 1.7 human smokers' bronchial trees to the fifth bifurcation. Statistically significant mutant copy numbers above the 95% upper confidence limits of historical background controls were found in 198 of 425 sector assays. No significant differences (P = 0.1) for negative sector fractions, mutant fractions, distributions of mutant cluster size or anatomical positions were observed for smoking status, gender or age (38-76 year). Based on the modal cluster size of mitochondrial point mutants, the size of the adult bronchial epithelial maintenance turnover unit was estimated to be about 32 cells. When data from all 15 lungs were combined the log 2 of nuclear mutant cluster size plotted against log 2 of the number of clusters of a given cluster size displayed a slope of {approx}1.1 over a range of cluster sizes from {approx}2{sup 6} to 2{sup 15} mutant copies. A parsimonious interpretation of these nuclear and previously reported data for lung epithelial mitochondrial point mutant clusters is that they arose from mutations in stem cells at a high but constant rate per stem cell doubling during at least ten stem cell doublings of the later fetal-juvenile period. The upper and lower decile range of summed point mutant fractions among lungs was about 7.5-fold, suggesting an important source of stratification in the population with regard to risk of tumor initiation.

  18. Study of the correlations between fractional exhaled nitric oxide in exhaled breath and atopic status, blood eosinophils, FCER2 mutation, and asthma control in Vietnamese children

    Directory of Open Access Journals (Sweden)

    Nguyen-Thi-Bich H

    2016-09-01

    Full Text Available Hanh Nguyen-Thi-Bich,1 Huong Duong-Thi-Ly,2 Vu Thi Thom,2 Nhung Pham-Thi-Hong,2 Long Doan Dinh,2 Huong Le-Thi-Minh,1 Timothy John Craig,3 Sy Duong-Quy3,4 1Department of Immunology, Allergology, and Rheumatology, National Hospital of Pediatrics, Hanoi, Vietnam; 2School of Medicine and Pharmacy, Vietnam National University Hanoi, Vietnam; 3Department of Medicine, Penn State University, Hershey, PA, USA; 4Department of Respiratory Diseases, Lam Dong Medical College, Dalat, Vietnam Introduction: Fractional exhaled nitric oxide (FENO is a biomarker of airway inflammation in asthma. The measurement of FENO is utilized to assist in the diagnosis and treatment of children with asthma, especially for those treated with inhaled corticosteroids. Objectives: The aims of this study were to evaluate the correlations between FENO and atopic status, blood eosinophil levels, FCER2 mutation, and asthma control in Vietnamese children. Subjects and methods: This was a prospective and descriptive study approved by the local Ethical Board. All children with uncontrolled asthma, seen in the National Hospital of Pediatrics (Hanoi, Vietnam, were included. Exhaled breath FENO, blood eosinophils, skin prick test, total IgE, asthma control test (ACT, and FCER2 gene polymorphism were performed at inclusion. They were followed up at 3 months to evaluate clinical status, FENO levels, and ACT. Results: Forty-two children with uncontrolled asthma with a mean age of 10±3 years (6–16 years were included. The male/female ratio was 2.5/1. The mean FENO levels were 26±25 ppb. FENO was significantly higher in patients with a positive skin prick test for respiratory allergens (P<0.05. FENO was significantly correlated with blood eosinophil levels (r=0.5217; P=0.0004. Five of the 32 subjects (15.6% had a mutation of FCER2 gene (rs28364072 SNP. In this group, the levels of FENO were highest (37±10 ppb; P<0.05. The levels of FENO were significantly decreased after 3 months of

  19. Diagnosis of metachronous multiple lung adenocarcinoma at the cut-end by epidermal growth factor receptor mutation status discordance 4 years after sublobar resection for adenocarcinoma in situ: report of a case.

    Science.gov (United States)

    Isaka, Tetsuya; Yokose, Tomoyuki; Ito, Hiroyuki; Imamura, Naoko; Watanabe, Masato; Imai, Kentaro; Nishii, Teppei; Yamada, Kouzo; Nakayama, Haruhiko; Masuda, Munetaka

    2015-10-01

    We report a case of metachronous multiple lung adenocarcinoma at the cut-end, diagnosed 4 years after sublobar resection for adenocarcinoma in situ (AIS), on the basis of discordance of epidermal growth factor receptor (EGFR) mutation status between the first and second tumor. The patient was an 81-year-old Japanese man, whose chest computer tomography (CT) scan showed mixed ground-glass opacity in the right upper lobe of the lung. Wedge resection was performed and a diagnosis of AIS, non-mucinous (18 × 14 mm), with a margin of 6 mm, was made. A tumor at the cut-end was seen on a CT scan 4 years later, and abnormal uptake was identified by fluorine-18 fluorodeoxyglucose-positron emission tomography. Right upper lobectomy and lymph node dissection were performed and the tumor was diagnosed as invasive adenocarcinoma, acinar predominant. Discordance of EGFR mutation status between the first tumor, harboring exon 19 deletion, and the second tumor, having an L858R point mutation in exon 21, revealed that the second tumor was metachronous multiple lung cancer. This case demonstrates the necessity of comparing EGFR mutation status between the first tumor and the second tumor at the cut-end.

  20. Chemical analysis and mutational assay of distilled oils from the H-coal direct liquefaction process: a status report

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, B.W.; Later, D.W.; Wright, C.W.; Stewart, D.L.

    1985-01-01

    Samples from the H-Coal process, a catalytic, single-stage, coal liquefaction technology, were chemically characterized and screened for microbial mutagenicity. For these investigations, a blend of light and heavy H-Coal process oils was fractionally distilled into 50/sup 0/F boiling point cuts. The chemical analyses and biological testing results presented in this status report deal primarily with the blended material and the distillate fractions boiling above 650/sup 0/F. Results from the microbial mutagenicity assays indicated that onset of biological activity in the crude materials occurred above 700/sup 0/F. Similar trends have been observed for Solvent Refined Coal (SRC) I, SRC II, Integrated Two-Stage Liquefaction (ITSL) and Exxon EDS process materials. After chemical class fractionation, the primary source of microbial mutagenicity of the crude boiling point cuts was the nitrogen-containing polycyclic aromatic compound (N-PAC) fractions. Amino polycyclic aromatic hydrocarbons (amino-PAH) were present at sufficient concentration levels in the N-PAC fractions to account for the observed mutagenic responses. In general, the chemical composition of the H-Coal materials studied was similar to that of other single-stage liquefaction materials. The degree of alkylation in these materials was determined to be greater than in the SRC and less than in the EDS process distillate cuts. 13 references, 8 figures, 11 tables.

  1. Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas.

    Science.gov (United States)

    Hacker, Elke; Olsen, Catherine M; Kvaskoff, Marina; Pandeya, Nirmala; Yeo, Abrey; Green, Adèle C; Williamson, Richard M; Triscott, Joe; Wood, Dominic; Mortimore, Rohan; Hayward, Nicholas K; Whiteman, David C

    2016-04-01

    Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports. PMID:26807515

  2. Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas.

    Science.gov (United States)

    Hacker, Elke; Olsen, Catherine M; Kvaskoff, Marina; Pandeya, Nirmala; Yeo, Abrey; Green, Adèle C; Williamson, Richard M; Triscott, Joe; Wood, Dominic; Mortimore, Rohan; Hayward, Nicholas K; Whiteman, David C

    2016-04-01

    Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF(V600E) (26%), BRAF(V600K) (8%), BRAF(other) (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF(V600E) mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF(V600K) mutations were also associated with high nevus counts. Both BRAF(V600K) and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports.

  3. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

    NARCIS (Netherlands)

    A.B. Spurdle (Amanda); F.J. Couch (Fergus); M. Parsons (Marilyn); L. McGuffog (Lesley); D. Barrowdale (Daniel); M.K. Bolla (Manjeet); Q. Wang (Qing); S. Healey (Sue); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); D. Niederacher (Dieter); C. Sutter (Christian); S. Wang-Gohrke (Shan); D. Steinemann (Doris); S. Preisler-Adams (Sabine); K. Kast (Karin); R. Varon-Mateeva (Raymonda); S.D. Ellis (Steve); D. Frost (Debra); R. Platte (Radka); J. Perkins (Jo); D.G. Evans (Gareth); L. Izatt (Louise); R. Eeles (Rosalind); L. Adlard; R. Davidson (Rosemarie); T.J. Cole (Trevor); G. Scuvera (Giulietta); S. Manoukian (Siranoush); B. Bonnani (Bernardo); F. Mariette (F.); S. Fortuzzi (S.); A. Viel (Alessandra); B. Pasini (Barbara); L. Papi (Laura); L. Varesco (Liliana); R. Balleine (Rosemary); K.L. Nathanson (Katherine); S.M. Domchek (Susan); K. Offitt (Kenneth); A. Jakubowska (Anna); N.M. Lindor (Noralane); M. Thomassen (Mads); U.B. Jensen; J. Rantala (Johanna); Å. Borg (Åke); I.L. Andrulis (Irene); A. Miron (Alexander); T.V.O. Hansen (Thomas); T. Caldes (Trinidad); S.L. Neuhausen (Susan); A.E. Toland (Amanda); H. Nevanlinna (Heli); M. Montagna (Marco); J. Garber (Judy); A.K. Godwin (Andrew); A. Osorio (Ana); R.E. Factor (Rachel E.); M.B. Terry (Mary B.); R. Rebbeck (Timothy); B. Karlan; M.C. Southey (Melissa); M.U. Rashid (Muhammad); N. Tung (Nadine); P.D.P. Pharoah (Paul); F. Blows (Fiona); A.M. Dunning (Alison); E. Provenzano (Elena); P. Hall (Per); K. Czene (Kamila); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); S. Verhoef; P.A. Fasching (Peter); M.W. Beckmann (Matthias); A.B. Ekici (Arif); D.J. Slamon (Dennis); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); J. Chang-Claude (Jenny); D. Flesch-Janys (Dieter); A. Rudolph (Anja); P. Seibold (Petra); K. Aittomäki (Kristiina); T.A. Muranen (Taru); P. Heikkilä (Päivi); C. Blomqvist (Carl); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); L.A. Brinton (Louise); J. Lissowska (Jolanta); J.E. Olson (Janet); V.S. Pankratz (Shane); E.M. John (Esther); A.S. Whittemore (Alice); D. van West; U. Hamann (Ute); D. Torres (Diana); H.U. Ulmer (Hans); T. Rud̈iger (Thomas); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); D. Eccles (Diana); W. Tapper (William); L. Durcan (Lorraine); L. Jones (Louise); J. Peto (Julian); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); N. Johnson (Nichola); M. Dwek (Miriam); R. Swann (Ruth); A.L. Bane (Anita L.); G. Glendon (Gord); A.M. Mulligan (Anna Marie); G.G. Giles (Graham); R.L. Milne (Roger); L. Baglietto (Laura); C.A. McLean (Catriona Ann); J. Carpenter (Jane); C. Clarke (Christine); R.J. Scott (Rodney); H. Brauch (Hiltrud); T. Brüning (Thomas); Y-D. Ko (Yon-Dschun); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); J. Gronwald (Jacek); T. Dörk (Thilo); N.V. Bogdanova (Natalia); T.-W. Park-Simon; P. Hillemanns (Peter); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); B. Burwinkel (Barbara); F. Marme (Federick); H. Surovy (Harald); R. Yang (Rongxi); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); M.J. Hooning (Maartje); J.M. Collee (Margriet); J.W.M. Martens (John); M.M.A. Tilanus-Linthorst (Madeleine); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); A. Lindblom (Annika); S. Margolin (Sara); V. Joseph (Vijai); M. Robson (Mark); R. Rau-Murthy (Rohini); A. González-Neira (Anna); J.I. Arias Pérez (José Ignacio); P. Zamora (Pilar); J. Benítez (Javier); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Peterlongo (Paolo); D. Zaffaroni (D.); M. Barile (Monica); F. Capra (Fabio); P. Radice (Paolo); S.-H. Teo; D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); G. Chenevix-Trench (Georgia); D. Goldgar (David)

    2014-01-01

    textabstractIntroduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modelin

  4. High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort

    DEFF Research Database (Denmark)

    Sorbye, Halfdan; Dragomir, Anca; Sundström, Magnus;

    2015-01-01

    micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF...... patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF...

  5. Prevalence of HFE mutations and relation to serum iron status in patients with chronic hepatitis C and patients with nonalcoholic fatty liver disease in Taiwan

    Institute of Scientific and Technical Information of China (English)

    Tsung-Jung Lin; Chih-Lin Lin; Chaur-Shine Wang; Shu-O Liu; Li-Ying Liao

    2005-01-01

    AIM: To assess the prevalence of the two mutations, C282Y and H63D of HFE gene, in healthy subjects, patients with chronic hepatitis C (CHC), and patients with nonalcoholic fatty liver disease (NAFLD) in Taiwan and to explore the contribution of the HFE mutation on serum iron stores in CHC and NAFLD groups.METHODS: We examined C282Y and H63D mutations of HFE gene in 125 healthy subjects, 29 patients with CHC,and 33 patients with NAFLD. The serum iron markers,including ferritin, iron, and total iron binding capacity (TIBC),were assessed in all patients.RESULTS: All of the healthy subjects and patients were free from C282Y mutation. The prevalence of H63D heterozygosity was 4/125 (3.20%) in healthy subjects, 2/29(6.90%) in CHC group, and 1/33 (3.03%) in NAFLD group.The healthy subjects showed no significant difference in the prevalence of H63D mutation as compared with the CHC or NAFLD group. Increased serum iron store was found in 34.48% of CHC patients and 36.36% of NAFLD patients.In three patients of H63D heterozygosity, only one CHC patient had increased serum iron store. There was no significant difference in the prevalence of HFE mutations between patients with increased serum iron store and those without in CHC or NAFLD group.CONCLUSION: The HFE mutations may not contribute to iron accumulation in the CHC or NAFLD group even when serum iron overload is observed in more than one-third of these patients in Taiwan.

  6. 晚期肺腺癌患者化疗前后血清EGFR基因突变状态的比较%Comparison of EGFR Mutation Status in Paired Pre- and Post-chemotherapy Serum for Advanced Pulmonary Adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    韩如冰; 钟巍; 赵静; 张力; 夏莹; 王寒; 李龙芸; 王孟昭

    2011-01-01

    背景与目的 存在表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)作为NSCLC的一个特殊亚群,对于表皮生长因子酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)的治疗显示出良好的疗效.本研究旨在检测晚期肺腺癌患者化疗前后血清EGFR基因外显子19和外显子21的突变状态,并分析化疗是否对EGFR基因突变状态产生影响.方法 磁珠法提取血清游离DNA后,使用酶切富集巢式PCR分别对血清游离DNA中EGFR外显子19和外显子21进行特异性扩增,应用直接测序法对EGFR基因突变状态进行榆测.结果 33例肺腺癌患者化疗前EGFR基凶突变率为39.4%(13/33),化疗后为54.5%(18/33),化疗前后EGFR基因突变状态的一致率为54.5%(18/33);在不一致的15例患者中,10例由化疗前EGFR基因突变阴性变为阳性,5例由化疗前阳性变为阴性.结论 化疗可能导致血清EGFR基因突变状态的改变.%Background and objective Non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLC, which is particularly responsive to EGFR tyrosine kinase inhibitors (TKIs).Ihe aim of this study is to detect EGFR mutations in paired serum of pre- and post-chemotherapy from advanced pulmonary adenocarcinoma patients to evaluate impact of chemotherapy on EGFR mutation status.Methods Magnetic beads were used for DNA extraction from paired serum of pre- and post-chemotherapy of 33 advanced pulmonary adenocarcinoma patients.The EGFR exon 19 and 21 were amplified by mutant-enriched nested PCR and analyzed by direct sequencing.Results EGFR mutations were detected in 39.4% (13/33) and 54.5% (18/33) serum samples of pre- and postchemotherapy, respectively.The EGFR mutation status was consistent in 54.5% (18/33) patients.Among 15 discordant cases,10 changed from pre-chemo wild

  7. The possible role of TP53 mutation status in the treatment of squamous cell carcinomas of the head and neck (HNSCC) with radiotherapy with different overall treatment times

    DEFF Research Database (Denmark)

    Eriksen, Jesper Grau; Alsner, Jan; Steiniche, Torben;

    2005-01-01

    for the outcome of radiotherapy. PATIENTS AND METHODS: DNA extracted from 180 paraffin-embedded formalin-fixed pretreatment biopsies of HNSCC was screened for mutations in exon 4C-10 by denaturing high-pressure liquid chromatography (DHPLC) followed by sequencing. Treatment was 66-68Gy, 2Gy/fx with overall...

  8. Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age : individual patient data meta-analysis

    NARCIS (Netherlands)

    Phi, Xuan-Anh; Saadatmand, Sepideh; De Bock, Geertruida H; Warner, Ellen; Sardanelli, Francesco; Leach, Martin O; Riedl, Christopher C; Trop, Isabelle; Hooning, Maartje J; Mandel, Rodica; Santoro, Filippo; Kwan-Lim, Gek; Helbich, Thomas H; Tilanus-Linthorst, Madeleine Ma; van den Heuvel, Edwin R; Houssami, Nehmat

    2016-01-01

    BACKGROUND: We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials. METHODS: Sensitivity and specificity of MRI, mammography and the combinatio

  9. A novel pseudoderivative-based mutation operator for real-coded adaptive genetic algorithms [v2; ref status: indexed, http://f1000r.es/1td

    Directory of Open Access Journals (Sweden)

    Maxinder S Kanwal

    2013-11-01

    Full Text Available Recent development of large databases, especially those in genetics and proteomics, is pushing the development of novel computational algorithms that implement rapid and accurate search strategies. One successful approach has been to use artificial intelligence and methods, including pattern recognition (e.g. neural networks and optimization techniques (e.g. genetic algorithms. The focus of this paper is on optimizing the design of genetic algorithms by using an adaptive mutation rate that is derived from comparing the fitness values of successive generations. We propose a novel pseudoderivative-based mutation rate operator designed to allow a genetic algorithm to escape local optima and successfully continue to the global optimum. Once proven successful, this algorithm can be implemented to solve real problems in neurology and bioinformatics. As a first step towards this goal, we tested our algorithm on two 3-dimensional surfaces with multiple local optima, but only one global optimum, as well as on the N-queens problem, an applied problem in which the function that maps the curve is implicit. For all tests, the adaptive mutation rate allowed the genetic algorithm to find the global optimal solution, performing significantly better than other search methods, including genetic algorithms that implement fixed mutation rates.

  10. Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein-Barr virus status and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type

    Institute of Scientific and Technical Information of China (English)

    WANG Ting-ting; XU Chen; LIU Shan-ling; KAN Bei; RAN Yu-ping; LIU Wei-ping; LI Gan-di

    2013-01-01

    Background Extranodal natural killer/T-cell (NK/T cell) lymphoma,nasal-type,is a rare lymphoma.Skin is the second most common site of involvement after the nasal cavity/nasalpharynx.The aim of this study was to investigate the clinicopathologic features,immunophenotype,T cell receptor (TCR) gene rearrangement,the association with Epstein-Barr virus (EBV) infection and p53 gene mutations of the lymphoma.Methods The clinicopathologic analysis,immunohistochemistry,in situ hybridization for EBER1/2,TCR gene rearrangement by polymerase chain reaction (PCR),mutations of p53 gene analyzed by PCR and sequence analysis were employed in this study.Results In the 19 cases,the tumor primarily involved the dermis and subcutaneous layer.Immunohistochemical staining showed that most of the cases expressed CD45RO,CD56,CD3ε,TIA-1 and GrB.Three cases were positive for CD3 and two cases were positive for CD30.Monoclonal TCRY gene rearrangement was found in 7 of 18 cases.The positive rate of EBER1/2 was 100%.No p53 gene mutation was detected on the exon 4-9 in the 18 cases.Fifteen cases showed Pro (proline)/Arg (arginine) single nucleotide polymorphisms (SNPs) on the exon 4 at codon 72.The expression of p53 protein was 72% (13/18) immunohistochemically.Conclusions Cutaneous NK/T-cell lymphoma is a rare but highly aggressive lymphoma with poor prognosis.No p53 gene mutation was detected on the exon 4-9,and Pro/Arg SNPs on p53 codon 72 were detected in the cutaneous NK/T-cell lymphoma.The overexpression of p53 protein may not be the result of p53 gene mutation.

  11. EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients%维吾尔族肺腺癌患者的EGFR基因突变分析

    Institute of Scientific and Technical Information of China (English)

    单莉; 张琰; 赵峰; 郑立谋; 张国庆

    2013-01-01

    Background and objective Epidermal growth factor receptor (EGFR), a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS) PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2%) of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2%) of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7%) of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.00l). Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2%) is significantly lower than that in Han lung adenocarcinoma patients (45.7%).%背景与目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种跨细胞膜糖蛋白,属于受体型酪氨酸激酶家族.以吉非替尼为代表的EGFR酪氨酸激酶抑制剂对于EGFR突变的肺癌患者显示出良好的治疗效果,然而EGFR的突变率在不同民族和不同种族的人群中表现出较大差异.本研究旨在分析维吾尔族中肺腺癌患者肿瘤组织

  12. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention

    DEFF Research Database (Denmark)

    Meur, Gargi; Simon, Albane; Harun, Nasret;

    2009-01-01

    the molecular mechanisms involved. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at insulin mutants were...... quantitated by real-time PCR. RESULTS: A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17-36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6...

  13. Production of truncated MBD4 protein by frameshift mutation in DNA mismatch repair-deficient cells enhances 5-fluorouracil sensitivity that is independent of hMLH1 status.

    Science.gov (United States)

    Suzuki, Satoshi; Iwaizumi, Moriya; Tseng-Rogenski, Stephanie; Hamaya, Yasushi; Miyajima, Hiroaki; Kanaoka, Shigeru; Sugimoto, Ken; Carethers, John M

    2016-07-01

    Methyl-CpG binding domain protein 4 (MBD4) is a DNA glycosylase that can remove 5-fluorodeoxyuracil from DNA as well as repair T:G or U:G mismatches. MBD4 is a target for frameshift mutation with DNA mismatch repair (MMR) deficiency, creating a truncated MBD4 protein (TruMBD4) that lacks its glycosylase domain. Here we show that TruMBD4 plays an important role for enhancing 5-fluorouracil (5FU) sensitivity in MMR-deficient colorectal cancer cells. We found biochemically that TruMBD4 binds to 5FU incorporated into DNA with higher affinity than MBD4. TruMBD4 reduced the 5FU affinity of the MMR recognition complexes that determined 5FU sensitivity by previous reports, suggesting other mechanisms might be operative to trigger cytotoxicity. To analyze overall 5FU sensitivity with TruMBD4, we established TruMBD4 overexpression in hMLH1-proficient or -deficient colorectal cancer cells followed by treatment with 5FU. 5FU-treated TruMBD4 cells demonstrated diminished growth characteristics compared to controls, independently of hMLH1 status. Flow cytometry revealed more 5FU-treated TruMBD4 cells in S phase than controls. We conclude that patients with MMR-deficient cancers, which show characteristic resistance to 5FU therapy, may be increased for 5FU sensitivity via secondary frameshift mutation of the base excision repair gene MBD4.

  14. Chemotherapy drugs affect terminal lung cancer EGFR mutation status%化疗药物对晚期肺癌 EGFR 基因突变状态的影响

    Institute of Scientific and Technical Information of China (English)

    程永红; 阎克里; 徐天锁

    2016-01-01

    目的:通过对比晚期非小细胞肺癌患者化疗前、后外周血 EGFR 的突变状态,了解化疗药物对晚期非小细胞肺癌患者 EGFR 突变状态是否产生影响,从而提高 EGFR-TKIs 用药的精准度。方法采集30例晚期非小细胞肺癌患者化疗前及化疗6周期后的外周血。采用 DHPLC(高效液相色谱)技术检测EGFR-19外显子与 EGFR-21外显子的突变状态。结果在30例患者中,化疗前 EGFR 的突变阳性率为53.3%(16/30)。6周期化疗结束后 EGFR 的突变阳性率为36.6%(11/30),化疗前后一致率为56.6(17/30),不一致率53.4%(13/30)。10例从化疗前的阳性转变为阴性,3例从化疗前的阴性转变为阳性(P =0.046),有统计学意义。6个 EGFR19外显子发生转变,转变率为20%,8个 EGFR21外显子发生转变转变率为26%。EGFR19、21共同发生转变的有1例,差异无统计学意义(P =0.39,P >0.05)。结论(1)晚期非小细胞肺癌患者治疗前、后外周血 EGFR 的突变状态有所改变,故在开始靶向治疗前必须即时检测外周血 EG-FR 的突变状态,以便决定是否选择 EGFR-TKIs 靶向药物的治疗;(2)EGFR21外显子的转变率高于 EGFR19外显子的转变率,但差异无统计学意义,此种现象可能与 EGFR19外显子突变的患者 EGFR-TKIs 治疗有效率较高有关。%Objective To compare the advanced non -small cell lung cancer (NSCLC)patients before and after chemotherapy peripheral blood EGFR mutation status,we understand whether the chemotherapy drug impacts the EGFR mutation status of the advanced NSCLC patients,so as to improve the precision of EGFR TKIs -drug use. Methods To collect the peripheral blood of 30 cases of advanced NSCLC before chemotherapy and after chemotherapy for 6 cycles.DHPLC technique was used to detect the EGFR mutation states of EGFR exon 19 and in exon 21.Results In 30 patients

  15. Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Iriyama, Chisako [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Tomita, Akihiro, E-mail: atomita@med.nagoya-u.ac.jp [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Hoshino, Hideaki; Adachi-Shirahata, Mizuho [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Furukawa-Hibi, Yoko; Yamada, Kiyofumi [Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya (Japan); Kiyoi, Hitoshi; Naoe, Tomoki [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Circulating DNAs (CDs) can be used to detect genetic/epigenetic abnormalities in MDS. Black-Right-Pointing-Pointer Epigenetic changes can be detected more sensitively when using plasma DNA than PBMNC. Black-Right-Pointing-Pointer Mutation ratio in CDs may reflect the ratio in stem cell population in bone marrow. Black-Right-Pointing-Pointer Using CDs can be a safer alternate strategy compared to bone marrow aspiration. -- Abstract: Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder. Several genetic/epigenetic abnormalities are deeply associated with the pathogenesis of MDS. Although bone marrow (BM) aspiration is a common strategy to obtain MDS cells for evaluating their genetic/epigenetic abnormalities, BM aspiration is difficult to perform repeatedly to obtain serial samples because of pain and safety concerns. Here, we report that circulating cell-free DNAs from plasma and serum of patients with MDS can be used to detect genetic/epigenetic abnormalities. The plasma DNA concentration was found to be relatively high in patients with higher blast cell counts in BM, and accumulation of DNA fragments from mono-/di-nucleosomes was confirmed. Using serial peripheral blood (PB) samples from patients treated with hypomethylating agents, global methylation analysis using bisulfite pyrosequencing was performed at the specific CpG sites of the LINE-1 promoter. The results confirmed a decrease of the methylation percentage after treatment with azacitidine (days 3-9) using DNAs from plasma, serum, and PB mono-nuclear cells (PBMNC). Plasma DNA tends to show more rapid change at days 3 and 6 compared with serum DNA and PBMNC. Furthermore, the TET2 gene mutation in DNAs from plasma, serum, and BM cells was quantitated by pyrosequencing analysis. The existence ratio of mutated genes in plasma and serum DNA showed almost equivalent level with that in the CD34+/38- stem cell population in BM. These data suggest that genetic

  16. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016.

    Science.gov (United States)

    Tan, Daniel S W; Yom, Sue S; Tsao, Ming S; Pass, Harvey I; Kelly, Karen; Peled, Nir; Yung, Rex C; Wistuba, Ignacio I; Yatabe, Yasushi; Unger, Michael; Mack, Philip C; Wynes, Murry W; Mitsudomi, Tetsuya; Weder, Walter; Yankelevitz, David; Herbst, Roy S; Gandara, David R; Carbone, David P; Bunn, Paul A; Mok, Tony S K; Hirsch, Fred R

    2016-07-01

    Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients. PMID:27229180

  17. KRAS mutation testing in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Cong Tan; Xiang Du

    2012-01-01

    The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers,and KRAS mutational status testing has been highlighted in recent years.The most frequent mutations in this gene,point substitutions in codons 12 and 13,were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies.Therefore,determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers.Currently,a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however,several challenges remain related to standardized and uniform testing,including the selection of tumor samples,tumor sample processing and optimal testing methods.Moreover,new testing strategies,in combination with the mutation analysis of BRAF,PIK3CA and loss of PTEN proposed by many researchers and pathologists,should be promoted.In addition,we recommend that microsatellite instability,a prognostic factor,be added to the abovementioned concomitant analysis.This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing.This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.

  18. Oncogene mutational profile in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang ZC

    2014-03-01

    Full Text Available Zi-Chen Zhang,1,* Sha Fu,1,* Fang Wang,1 Hai-Yun Wang,1 Yi-Xin Zeng,2 Jian-Yong Shao11Department of Molecular Diagnostics, 2Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Nasopharyngeal carcinoma (NPC is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1% NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%, five NRAS mutations (4.1%, four KIT mutations (3.3%, two PDGFRA mutations (1.6%, two ABL mutations (1.6%, and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%. Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019. No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis. Keywords: NPC, oncogene, mutation

  19. Driver Mutations in Uveal Melanoma

    Science.gov (United States)

    Decatur, Christina L.; Ong, Erin; Garg, Nisha; Anbunathan, Hima; Bowcock, Anne M.; Field, Matthew G.; Harbour, J. William

    2016-01-01

    IMPORTANCE Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. OBJECTIVE To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. MAIN OUTCOMES AND MEASURES Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. RESULTS The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1–28.5) and

  20. Influences of storage status and time on the mutations of EGFR gene%组织样本保存状态及时间对EGFR基因突变检测结果的影响

    Institute of Scientific and Technical Information of China (English)

    钱坤; 张毅

    2014-01-01

    目的:探讨不同组织保存状态(原始样本或基因组DNA)及保存时间对非小细胞肺癌( NSCLC)中表皮生长因子受体( EGFR)基因突变检测结果的影响。方法收集 EGFR基因突变阳性 NSCLC患者的新鲜冰冻组织和石蜡包埋(FFPE)组织各例,每保存个月提取次DNA(共次),设为冰冻新提取组和FFPE新提取组;同时分别选取初检后剩余基因组DNA作对照,设为冰冻预留组和FFPE预留组。分别采用检测试剂盒定性和定量检测上述组EGFR基因的突变情况,同时采用荧光定量PCR技术检测内参基因的Ct值。比较组不同保存时间的内参基因Ct值和EGFR基因突变频度情况。结果例原始组织样本均可以检出EGFR基因突变,与临床信息相符。新鲜冰冻组织、FFPE组织的DNA浓度均>50ng/μl,且A260/A280为.8±0.2。新鲜冰冻组织保存个月后,冰冻预留组的内参基因Ct值高于冰冻新提取组,差异有统计学意义( P<0.05);FFPE保存个月内,FFPE新提取组和FFPE预留组内参基因Ct值的差异均无统计学意义( P>0.05)。冰冻新提取组保存个月后和FFPE新提取组保存个月后的EGFR基因突变频度高于对应预留组,差异均有统计学意义( P<0.05)。结论原始样本相对于预留基因组DNA更适合用于回顾性研究的材料。%Objective To explore the influences of storage status ( original sample or genomic DNA) and time on the muta-tions of EGFR gene in non-small cell lung cancer ( NSCLC) . Methods Ten fresh frozen tissues and 10 formalin-fixed paraffin-embed-ded ( FFPE) tissues of NSCLC harboring EGFR mutations were collected. During the twelve months after the first detection, DNA was drawn from fresh frozen tissues ( new frozen extraction group) and FFPE tissues ( new FFPE extraction group) at an interval of one month. The remaining genomic DNA from fresh frozen tissues ( reserved frozen group) and FFPE tissues

  1. 非小细胞肺癌290例表皮生长因子受体基因突变和拷贝数的检测分析%Status of gene mutation and copy number of EGFR in 290 cases of non-small cell lung carcinoma

    Institute of Scientific and Technical Information of China (English)

    梁智勇; 曾瑄; 张静; 武莎斐; 高洁; 刘彤华

    2008-01-01

    目的 检测非小细胞肺癌(NSCLC)组织中表皮生长因子受体(EGFR)基因突变和拷贝数,明确中国NSCLC人群中EGFR基因状态.方法 应用显微切割技术和蝎形探针扩增阻滞突变系统(Scorpions ARMS)联合检测290例石蜡包埋、甲醛固定的NSCLC组织中其EGFR基因突变状态,并应用荧光原位杂交(FISH)技术检测其中209例EGFR基因拷贝数的情况,分析EGFR基因突变和EGFR摹因拷贝数二者之间的关系,探讨EGFR基因状态与肺癌临床病理特点的相关性.结果 NSCLC组织EGFR突变率为41.7%(121/290),其中腺癌为48.4%,大细胞癌为16.7%,鳞癌为0.EGFR基因突变以第19、21外显子突变为主(92/121),其中6例存在两种类型的突变.EGFR基因FISH阳性率为51.2%(107/209),包括29例扩增,78例高多体性.其中腺癌FISH阳性率为52.1%,大细胞癌为75.0%,鳞癌为11.1%.检测结果显示NSCLC组织EGFR基因突变与EGFR基因高拷贝数主要存在于腺癌,EGFR基因突变与EGFR基因拷贝数之间有显著的相关性.结论 中国人NSCLC组织具有较高的EGFR基因突变率和FISH阳性率;联合检测EGFR基因拷贝数和基因突变可能更有利于靶向药物的筛选.%Objective To investigate EGFR mutations and gene copy number status in non-small cell lung carcinomas in the Chinese patients. Methods Using formalin fixed and paraffin embedded tissue samples, EGFR mutations were investigated in 290 cases of non-small cell lung carcinomas by microdissection and scorpions amplification refractory mutation system. The status of EGFR gene copy number was investigated by FISH. Furthermore, the relationship between EGFR mutations and gene copy number, and the relationship between EGFR gene status and elinieopathologieal variables of non-small cell lung carcinoma were analyzed. Results The overall mutation rate of EGFR was 41.7% (121/290). The mutation rates in adenocarcinoma, large cell carcinoma and squamons carcinoma were 48.4%, 16.7% and O

  2. Skin pH, Atopic Dermatitis, and Filaggrin Mutations

    DEFF Research Database (Denmark)

    Bandier, Josefine; Johansen, Jeanne Duus; Petersen, Lars Jelstrup;

    2014-01-01

    mutations may influence skin pH. OBJECTIVE: We aimed to determine the epidermal pH in different groups stratified by filaggrin mutations and atopic dermatitis. Further, we investigated the changes in pH according to severity of mutational status among patients with dermatitis, irrespective of skin condition....... METHODS: pH was measured with a multiprobe system pH probe (PH 905), and the study population was composed of 67 individuals, who had all been genotyped for 3 filaggrin mutations (R501X, 2282del4, R2447X). RESULTS: We found no clear pattern in relation to filaggrin mutation carrier status. Individuals...... with wild-type filaggrin displayed both the most acidic and most alkaline values independent of concomitant skin disease; however, no statistical differences between the groups were found. CONCLUSIONS: The lack of significant diversity in skin pH in relation to filaggrin mutation carrier status suggests...

  3. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy

    International Nuclear Information System (INIS)

    Background and purpose: KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. Materials and methods: DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. Results: Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p = 0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p = 0.012). Conclusion: We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

  4. Frequent PIK3CA-activating mutations in hidradenoma papilliferums.

    Science.gov (United States)

    Liau, Jau-Yu; Lan, Jui; Hong, Jin-Bon; Tsai, Jia-Huei; Kuo, Kuan-Tin; Chu, Chia-Yu; Sheen, Yi-Shuan; Huang, Wen-Chang

    2016-09-01

    Hidradenoma papilliferum (HP) is a benign epithelial tumor most commonly seen in the vulva. It is proposed to be derived from the anogenital mammary-like glands and is histologically very similar to the mammary intraductal papilloma (IP). Approximately 60% of mammary IPs have activating mutations in either PIK3CA or AKT1, with each gene accounting for 30% of cases. In this study, we screened the mutation statuses of PIK3CA, AKT1, RAS, and BRAF in 30 HPs. The results showed that activating mutations in either PIK3CA or AKT1 were identified in 20 tumors (67%); 19 tumors had PIK3CA mutations (63%; 13 in exon 20 and 6 in exon 9), and 1 had an AKT1 E17K mutation (3%). BRAF V600E mutation was found in an HP that also had a PIK3CA H1047R mutation. No RAS mutation was found. The mutation status was not correlated with the degree of epithelial cell hyperplasia. We conclude that although there might be site-related variations in the mutation frequencies of PIK3CA and AKT1 genes, HP is histologically and also genetically very similar to the mammary IP, suggesting that HP can be viewed as the extramammary counterpart of mammary IP. PMID:27184479

  5. Diagnostic RAS mutation analysis by polymerase chain reaction (PCR

    Directory of Open Access Journals (Sweden)

    Ian A. Cree

    2016-06-01

    Full Text Available RAS mutation analysis is an important companion diagnostic test. Treatment of colorectal cancer with anti-Epidermal Growth Factor Receptor (EGFR therapy requires demonstration of RAS mutation status (both KRAS and NRAS, and it is good practice to include BRAF. In Non-Small Cell Lung Cancer (NSCLC and melanoma, assessment of RAS mutation status can be helpful in triaging patient samples for more extensive testing. This mini-review will discuss the role of PCR methods in providing rapid diagnostic information for cancer patients.

  6. KRAS and BRAF mutations in anal carcinoma

    DEFF Research Database (Denmark)

    Serup-Hansen, Eva; Linnemann, Dorte; Høgdall, Estrid;

    2015-01-01

    The EGF receptor (EGFR) is expressed in most cases of anal carcinomas. Anecdotal benefit from EGFR-targeted therapy has been reported in anal cancer and a negative correlation with Kirsten Ras (KRAS) mutation status has been proposed. The purpose of this retrospective study was to investigate...... the frequency and the prognostic value of KRAS and BRAF mutations in a large cohort of patients with anal cancer. One hundred and ninety-three patients with T1-4N0-3M0-1 anal carcinoma were included in the study. Patients were treated with curative (92%) or palliative intent (8%) between January 2000...... and January 2010. KRAS mutations were detected using Therascreen(®)KRAS real-time PCR assay (Qiagen) and V600E or V600D/K BRAF mutations were uncovered using Pyrosequencing. The frequency of KRAS and BRAF mutations was low; KRAS mutations were detected in 1.6% and BRAF mutations in 4.7% of the biopsies...

  7. Diet, lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas.

    NARCIS (Netherlands)

    Wark, P.A.; Kuil, W. van der; Ploemacher, J.; Muijen, G.N.P. van; Mulder, C.J.J.; Weijenberg, M.P.; Kok, F.J.; Kampman, E.

    2006-01-01

    K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of K

  8. Diet, Lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas

    NARCIS (Netherlands)

    Wark, P.A.; Kuil, van der W.; Ploemacher, J.; Muijen, van G.N.P.; Mulder, Ch.J.J.; Weijenberg, M.P.; Kok, F.J.; Kampman, E.

    2006-01-01

    K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of K

  9. Transgenic Animal Mutation Assays

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Ph.D.D.A.B.T.

    2005-01-01

    @@ The novel transgenic mouse and rat mutation assays have provided a tool for analyzing in vivo mutation in any tissue, thus permitting the direct comparison of cancer incidence with mutant frequency.

  10. 应用高分辨率熔解曲线分析石蜡标本中KRAS基因突变%KRAS Mutational Status Analysis in Formalin-fixed, Paraffin-Embedded Tissues using High-resolution Melting Analysis

    Institute of Scientific and Technical Information of China (English)

    张海燕; 王捷; 吴小丽; 冼江

    2013-01-01

    Objective:Mutations in the KRAS gene occur in 30-50 % of colorectal cancers (CRCs),and represent a marker of clinical resistance to anti-EGFR therapy.Traditional methods,such as PCR and direct sequencing,cannot detect low-level mutations in cancer,resulting in false negative diagnoses.Improved screening methods for the reliable detection of mutations in human cancer cells are required to more accurately predict the most effective targeted therapies.To evaluate the feasibility of detecting the mutations of KRAS in colorectal cancer patients with high resolution melting curve analysis.Methods:In this study,we designed a protocol to detect mutation of KRAS (exon 2 and exon 3) in sporadic CRCs based on high resolution melting (HRM).Using a KRAS positive tumors sample 14,we compared the mutation detection sensitivity of high resolution melting (HRM) with sequencing.The DNA isolated from 20 formalin-fixed,paraffin-embedded samples of colorectal cancer was screened for mutations using HRM analysis.Results:Five samples bearing mutations in KRAS exon 2 were identified:mutation p.G12D in two samples,p.G12V in two samples,and p.G13D in one sample.We compared the sensitivity of HRM analysis to direct sequencing by serially diluting the p.G 12D mutant transcript in wild type KRAS exon 2 at 40,20,10,and 2 %.While direct sequencing could only detect the KRAS mutation at 20 % (5-fold dilution),HRM readily detected the mutant sequence at 2 % (50-fold dilution).Conclusion:Therefore,this developed HRM analysis protocol permits the accurate identification of less represented mutations in CRC tissue and might allow for better selection of eligible patients for specific therapies without the need for multiple screening and sequencing procedures.%目的:KRAS基因在结直肠癌患者突变率为30%~50%,并且KRAS基因状态与抗EGFR抗体疗效的密切相关.常用的直接测序法其检测灵敏度低、容易出现假阴性结果.采用高分辨

  11. Maize Mutator transposon

    Institute of Scientific and Technical Information of China (English)

    Yijun WANG; Mingliang XU; Dexiang DENG; Yunlong BIAN

    2008-01-01

    Transposable elements are widely distributed in eukaryotes. Due to its high copy numbers, high forward mutation rate and preferential insertion into low-copy DNA sequences, among others, the Mutator system has been widely used as a mutagen in genomic research. The discovery, classification, transposition specificity and epige-netic regulation of Mutator transposons were described. The application of Mutator tagging in plant genomic research was also presented. The role of Mu-like elements in genome evolution was briefly depicted. Moreover, the direction of Mutator transposon research in the future was discussed.

  12. Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Baliakas, P; Hadzidimitriou, A; Sutton, L-A; Rossi, D; Minga, E; Villamor, N; Larrayoz, M; Kminkova, J; Agathangelidis, A; Davis, Z; Tausch, E; Stalika, E; Kantorova, B; Mansouri, L; Scarfò, L; Cortese, D; Navrkalova, V; Rose-Zerilli, M J J; Smedby, K E; Juliusson, G; Anagnostopoulos, A; Makris, A M; Navarro, A; Delgado, J; Oscier, D; Belessi, C; Stilgenbauer, S; Ghia, P; Pospisilova, S; Gaidano, G; Campo, E; Strefford, J C; Stamatopoulos, K; Rosenquist, R

    2015-02-01

    Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

  13. Reversion of the Arabidopsis rpn12a-1 exon-trap mutation by an intragenic suppressor that weakens the chimeric 5’ splice site [v2; ref status: indexed, http://f1000r.es/18y

    Directory of Open Access Journals (Sweden)

    Jasmina Kurepa

    2013-06-01

    Full Text Available Background: In the Arabidopsis 26S proteasome mutant rpn12a-1, an exon-trap T-DNA is inserted 531 base pairs downstream of the RPN12a STOP codon. We have previously shown that this insertion activates a STOP codon-associated latent 5' splice site that competes with the polyadenylation signal during processing of the pre-mRNA. As a result of this dual input from splicing and polyadenylation in the rpn12a-1 mutant, two RPN12a transcripts are produced and they encode the wild-type RPN12a and a chimeric RPN12a-NPTII protein. Both proteins form complexes with other proteasome subunits leading to the formation of wild-type and mutant proteasome versions. The net result of this heterogeneity of proteasome particles is a reduction of total cellular proteasome activity. One of the consequences of reduced proteasomal activity is decreased sensitivity to the major plant hormone cytokinin. Methods: We performed ethyl methanesulfonate mutagenesis of rpn12a-1 and isolated revertants with wild-type cytokinin sensitivity. Results: We describe the isolation and analyses of suppressor of rpn12a-1 (sor1. The sor1 mutation is intragenic and located at the fifth position of the chimeric intron. This mutation weakens the activated 5' splice site associated with the STOP codon and tilts the processing of the RPN12a mRNA back towards polyadenylation. Conclusions: These results validate our earlier interpretation of the unusual nature of the rpn12a-1 mutation. Furthermore, the data show that optimal 26S proteasome activity requires RPN12a accumulation beyond a critical threshold. Finally, this finding reinforces our previous conclusion that proteasome function is critical for the cytokinin-dependent regulation of plant growth.

  14. Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

    OpenAIRE

    Yun, Jihye; Rago, Carlo; Cheong, Ian; Pagliarini, Ray; Angenendt, Philipp; Rajagopalan, Harith; Schmidt, Kerstin; Wilson, James K. V.; Markowitz, Sandy; Zhou, Shibin; Diaz, Luis A.; Velculescu, Victor; Lengauer, Christoph; Kinzler, Kenneth W.; Vogelstein, Bert

    2009-01-01

    Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived i...

  15. Analysis of gene mutations and clinical features in elderly patients with melanoma

    Institute of Scientific and Technical Information of China (English)

    王轩

    2013-01-01

    Objective To investigate the gene mutation status in Chinese elderly patients with melanoma and to explore the correlation of gene mutation with clinical characteristics and prognosis.Methods Melanoma tissue samples from Chinese elderly patients were analyzed for gene mutations of KIT,BRAF and NRAS in genomic DNA by polymerase chain reaction (PCR) amplification and Sanger sequencing.The correlations of gene mutations with clinicopathologic features and prognosis were statistically

  16. Three kinds of mutation

    CERN Document Server

    Buan, Aslak Bakke; Thomas, Hugh

    2010-01-01

    For a finite dimensional hereditary algebra, we consider: exceptional sequences in the category of finite dimensional modules, silting objects in the bounded derived category, and m-cluster tilting objects in the m-cluster category. There are mutation operations on both the set of m-cluster tilting objects and the set of exceptional sequences. It is also possible to define a mutation operation for silting objects. We compare these three different notions of mutation.

  17. Mapping Mutations on Phylogenies

    DEFF Research Database (Denmark)

    Nielsen, Rasmus

    2005-01-01

    This chapter provides a short review of recent methodologies developed for mapping mutations on phylogenies. Mapping of mutations, or character changes in general, using the maximum parsimony principle has been one of the most powerful tools in phylogenetics, and it has been used in a variety of ...... uncertainty in the mapping. Recently developed probabilistic methods can incorporate statistical uncertainty in the character mappings. In these methods, focus is on a probability distribution of mutational mappings instead of a single estimate of the mutational mapping....

  18. Gestational mutations in radiation carcinogenesis

    Science.gov (United States)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  19. Detection and Evaluation of EGFR Mutation Status in Serum of Patients with Advanced Non-small Cell Lung Cancer Treated with EGFR-TKIs%晚期NSCLC患者血清EGFR基因突变状态的测定及意义

    Institute of Scientific and Technical Information of China (English)

    马玲; 刘莉; 张涛; 单莉

    2013-01-01

    Background and objective Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has shown a high response rate in the treatment of lung cancer in patients with (EGFR) mutation.The aim of this study is to evaluate the relationship between EGFR mutation status in serum and predicting benefit from EGFR-TKIs therapy in patients with advanced non-small cell lung cancer (NSCLC).Methods We examined EGFR mutation status in serum of 80 patients with advanced,EGFR-TKIs given as first-line therapy NSCLC.All patients were received long-term follow-up,and the drug efficacy were observed and evaluated.Results The EGFR mutation in serum was detected in 33.8% (27/80) of NSCLC patients examined,in which exon 19 deletion mutation was present at a frequency of 44.4% (12/27) and exon 21 point mutation was 55.6% (15/27); The response rate to EGFR-TKI in patients with EGFR mutation in serum was (55.6%,15/27),which was remarkably higher than that in EGFR wild-type patients (17.0%,9/53),the difference was statistically significant (x2=0.370,P<0.001); The median progression free survival (PFS) of patients with EGFR mutation in serum was remarkably better than that of EGFR wild-type patients (9.8 months vs 5.7 months,P=0.014).Conclusion In patients with advanced,EGFR-positive in serum NSCLC,EGFR-TKIs given as first-line therapy is associated with improved drug efficacy.The results suggest that it is feasible to use serum to detect EGFR mutation,which can predict a benefit from EGFR-TKIs given as first-line therapy.%背景与目的 小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)对于表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变的肺癌患者显示出良好的治疗效果.本研究旨在探讨晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者血清EGFR基因突变状态与EGFR-TKIs疗效的关系.方法 检测80例一线口服EGFR-TKIs晚期NSCLC患者血清EGFR基因的突变状态,对患者进行

  20. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

    Science.gov (United States)

    Baxter, E.J.; Nice, F.L.; Gundem, G.; Wedge, D.C.; Avezov, E.; Li, J.; Kollmann, K.; Kent, D.G.; Aziz, A.; Godfrey, A.L.; Hinton, J.; Martincorena, I.; Van Loo, P.; Jones, A.V.; Guglielmelli, P.; Tarpey, P.; Harding, H.P.; Fitzpatrick, J.D.; Goudie, C.T.; Ortmann, C.A.; Loughran, S.J.; Raine, K.; Jones, D.R.; Butler, A.P.; Teague, J.W.; O’Meara, S.; McLaren, S.; Bianchi, M.; Silber, Y.; Dimitropoulou, D.; Bloxham, D.; Mudie, L.; Maddison, M.; Robinson, B.; Keohane, C.; Maclean, C.; Hill, K.; Orchard, K.; Tauro, S.; Du, M.-Q.; Greaves, M.; Bowen, D.; Huntly, B.J.P.; Harrison, C.N.; Cross, N.C.P.; Ron, D.; Vannucchi, A.M.; Papaemmanuil, E.; Campbell, P.J.; Green, A.R.

    2014-01-01

    BACKGROUND Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with

  1. Mutation and premating isolation.

    Science.gov (United States)

    Woodruff, R C; Thompson, J N

    2002-11-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  2. The association of pathological type、IDH-1 mutations and MGMT promoter methylation status on “pseudo-progress” of anaplastic gliomas%病理类型、IDH-1突变和MGMT启动子甲基化状态与间变性胶质瘤假性进展的相关性

    Institute of Scientific and Technical Information of China (English)

    李宏; 陆云涛; 漆松涛; 俞磊; 欧阳辉; 刘亚伟

    2013-01-01

    目的:明确间变性胶质瘤(Anaplastic glioma,AG)组织中病理类型、IDH-1基因突变以及MGMT启动子甲基化与患者综合治疗后发生假性进展(Pseudoprogression,PsPD)之间的相互关系.方法:对47例间变性胶质瘤标本采用基因片段测序的方法检测异柠檬酸脱氢酶(IDH-1)突变和MGMT启动子甲基化状态情况.对所有病例进行临床随访,结合肿瘤的病理类型,探讨其对术后PsPD发生的提示作用.结果:47例AG患者中有24例出现早期进展(6个月内).9例PsPD中IDH-1突变和MGMT启动子甲基化分别是6例和7例;另15例真性复发患者IDH-1突变和MGMT启动子甲基化分别是3例和5例,IDH-1突变对PsPD检出率与MGMT启动子甲基化相比,无明显差异(x2<0.02,P>0.9);PsPD中含少突胶质细胞病理成分的4例病例,包括3例间变性少突胶质细胞瘤(AO)和1例间变性少突显形细胞瘤(AOA),全部发生IDH-1突变,另5例间变性显形细胞瘤(AA)中有2例发生IDH-1突变,IDH-1突变对PsPD检出率与病理类型中含少突胶质细胞成分相比,无明显差异(x2=0.5,P>0.5).结论:病理类型中含有少突胶质细胞成分、存在IDH-1突变和MGMT启动子甲基化可以作为间变性胶质瘤中预测PsPD的可靠客观预计指标,有利于鉴别肿瘤PsPD和真性复发.%Aim:To identify the relationship between Pathological type,IDH mutation,MGMT promoter methylation in clinical samples of anaplastic gliomas (AG) with Pseudoprogression (PsPD) in patients received comprehensive treatment.Methods:DNA direct sequencing was used to detect IDH-1 mutation and MGMT promoter methylation status of the 47 clinical samples of AG.Clinical data of all patients with AG treated with surgery followed by radiotherapy plus (or not) concomitant temozolomide (TMZ) were followed up.IDH mutation and MGMT promoter methylation were analyzed statistically combined with pathological type of tumor to identify the predictive role of them on postoperative Ps

  3. Telomerase reverse transcriptase promoter mutations in bladder cancer

    DEFF Research Database (Denmark)

    Allory, Yves; Beukers, Willemien; Sagrera, Ana;

    2014-01-01

    for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription...... surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease...

  4. KRAS Gene Mutations and Gender Differences in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Dmitriy I. Vodolazhskiy

    2015-03-01

    Full Text Available The aim of this study was to investigate the frequency and spectrum of KRAS mutations in men and women with colorectal cancer (CRC, and an impact of KRAS-mutation status on the clinical and morphological features of CRC. The study included 303 patients (168/55.4% women and 135/44.6% men with CRC T2-4N0-2M0-1. We defined 7 KRAS SNP-mutations (G12D, G12A, G12R, G12C, G12S, G12V and G13D located within codons 12 and 13 using Bio-Rad real-time thermal cyclers CFX96 and Real-Time-PCR- KRAS-7M Kit. The frequency of KRAS mutations was 35.6% in the CRC patients with a predominant presence of G>A transitions. The KRAS codon 12 and 13 mutations are predictive of poor prognosis The KRAS-mutated CRC has clinical features in view of the gender differences. KRAS-mutation status is a promising predictive biomarker of personalized treatment.

  5. Non-fatherhood or mutation? A probabilistic approach to parental exclusion in paternity testing.

    Science.gov (United States)

    Dawid, A P; Mortera, J; Pascali, V L

    2001-12-15

    The occurrence of germline mutations at microsatellite loci poses problems in ascertaining non-fatherhood status in paternity testing. We describe the appropriate probabilistic analysis for computing the likelihood ratio in favour of paternity while allowing for mutation, for all 18 relevant combinations of seemingly incompatible parental genotypes. We allow arbitrary and possibly different mutation rates in paternal and maternal germlines. We describe a stationary mutation model for expressing the required allele-specific transition mutation rates in terms of overall mutation rates, and compare the likelihood ratios calculated from this and from other mutation models suggested in the literature. We also show how to derive an upper bound on the likelihood ratio, depending only on the overall mutation rate.

  6. Immunohistochemical detections of EGFR status in NSCLC

    Directory of Open Access Journals (Sweden)

    Jie WANG

    2015-04-01

    Full Text Available Background and objective Patients with non-small cell lung cancer (NSCLC harboring mutations of the epidermal growth factor receptor (EGFR respond well to EGFR-tyrosine kinase inhibitor therapy. Immunohistochemistry (IHC is a simple and widely used technique in clinical pathology laboratories. IHC also features cost effectiveness and rapid detection of EGFR mutations compared with molecular methods. This study aims to determine the accuracy of IHC for EGFR mutation detection in NSCLC. Methods Specimens (obtained from surgery or biopsy from 97 NSCLC cases were stained through IHC with mutation-specific antibodies. The clinicopathological features of patients with positive immunostaining results were analyzed. Positive specimens were subjected to liquid chip technology to detect the actual EGFR status. Forty NSCLC specimens obtained from surgery and confirmed to have EGFR mutations through liquid chip technology were collected. These specimens were then subjected to IHC analyses with mutation-specific antibodies. The sensitivity of IHC in detecting EGFR mutations was calculated. Results Seventeen of the 97 NSCLC specimens were stained positive, and positive results were mostly observed in females, patients with adenocarcinoma, and non-smokers. About 76.9% of specimens with positive IHC results harbored mutations. The sensitivity of IHC was 40% among the 40 cases identified as containing EGFR mutations through liquid chip technology. Conclusion The strong positive immunostaining result is accurate, but the sensitivity of the method may not be optimal and significantly varies in different studies. The widespread application of IHC in clinics must be further investigated.

  7. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features.

    Science.gov (United States)

    Rosty, Christophe; Young, Joanne P; Walsh, Michael D; Clendenning, Mark; Walters, Rhiannon J; Pearson, Sally; Pavluk, Erika; Nagler, Belinda; Pakenas, David; Jass, Jeremy R; Jenkins, Mark A; Win, Aung Ko; Southey, Melissa C; Parry, Susan; Hopper, John L; Giles, Graham G; Williamson, Elizabeth; English, Dallas R; Buchanan, Daniel D

    2013-06-01

    KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; Pcarcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; Pcarcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

  8. Mutations in Lettuce Improvement

    OpenAIRE

    2012-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic stu...

  9. Mutation breeding in peas

    International Nuclear Information System (INIS)

    The pea as an ancient crop plant still today has wide uses and is an import source of food protein. It is also an important object for genetic studies and as such has been widely used in mutation induction experiments. However, in comparison with cereals this ancient crop plant (like several other grain legumes) has gained relatively little from advances in breeding. The review focuses on the prospects of genetic improvement of pea by induced mutations, discusses principles and gives methodological information. (author)

  10. Mutation Breeding in Sugarcane

    International Nuclear Information System (INIS)

    The present position of sugar industry particularly cane sugar production in the world has been discussed. The role of African Countries which can contribute more than the present 11% to world cane sugar production is presented. The breeding methods employed in cane growing court-tries indicate the biparental crossing and selection in F1 has been the major method used to develop varieties. Due to cytogenetical peculiarities, thousands of seedlings are grown to select the desirable genotype. Mutations or sports has been a source of variation for selection in nature. Induced mutations have only enhanced the mutation rate and has enabled the plant breeders to get better variation for selection. Though many mutagens have been used gamma rays have been most effective. Induced mutations for nonflowering, spineless leaf-sheath, higher sugar content, yield md resistance to diseases like smut and downy mildew have been reported. The methods of making mutated tissues express itself have been indicated. Mutation breeding holds out promise in sugarcane in that the basic variety or genotype can be kept intact and a few characters changed as desired by the plant breeder provided proper selection methods are employed. (author)

  11. Subquivers of mutation-acyclic quivers are mutation-acyclic

    CERN Document Server

    Warkentin, Matthias

    2011-01-01

    Quiver mutation plays a crucial role in the definition of cluster algebras by Fomin and Zelevinsky. It induces an equivalence relation on the set of all quivers without loops and two-cycles. A quiver is called mutation-acyclic if it is mutation-equivalent to an acyclic quiver. The aim of this note is to show that full subquivers of mutation-acyclic quivers are mutation-acyclic.

  12. Status epilepticus

    NARCIS (Netherlands)

    Hensiek, AE; Absalom, Anthony

    2006-01-01

    Status epilepticus is defined as epileptic activity that continues for more than 30 minutes as a single seizure or as recurrent seizures without inter-ictal return of consciousness. The seizure activity is usually classified as partial or generalized. Although status epilepticus is an uncommon admis

  13. Xeroderma Pigmentosum: Low Prevalence of Germline XPA Mutations in a Brazilian XP Population

    OpenAIRE

    Karina Miranda Santiago; Amanda França de Nóbrega; Rafael Malagoli Rocha; Silvia Regina Rogatto; Maria Isabel Achatz

    2015-01-01

    Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by DNA repair defects that cause photophobia, sunlight-induced cancers, and neurodegeneration. Prevalence of germline mutations in the nucleotide excision repair gene XPA vary significantly in different populations. No Brazilian patients have been reported to carry a germline mutation in this gene. In this study, the germline mutational status of XPA was determined in Brazilian patients exhibiting major clinical...

  14. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in non-Hodgkin lymphoma patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines.

  15. p53 Mutations and Protein Overexpression in Primary Colorectal Cancer and its Liver Metastasis

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To compare p53 status in primary and hepatic metastatic colorectal cancer in 34 patients. Methods: p53 gene status (exons 5- 9) was examined by PCR, denaturing gradient gel electrophoresis (DGGE) and automated sequencing. P53 protein was detected by immunohistochemistry using monoclonal antibody DO-7. Results: p53 mutations were found in exons 5 through 9 in 21 of 34 patients (61.8%). Among them, 5 patients had mutation in liver metastasis but not in their primary tumors while in the other patients the same mutations were found in both primary and metastatic colorectal cancers. In no patients was p53 mutation exclusively found in the primary colorectal tumors. Moreover, additional mutation was detected in the metastatic lesions in two cases. Of the 37 mutations within the exons examined, 73% was missense mutation and 16% was nonsense mutation. There were 4 microinsertions. P53 protein was overexpressed in both primary and metastatic colorectal cancers with p53 gene mutations. The presence of p53 mutation significantly correlated with p53 protein accumulation (r=0.96, p< 0.001). However, in 4 patients with p53 nonsense mutation, immunohistochemical staining was negative. In three patients who showed no p53 mutation of the primary tumor, p53 protein was consistently overexpressed. Conclusion: In colorectal cancers, p53 gene mutation usually appears first in the primary tumor and maintains as such but is more prominent when metastasized to the liver. However, p53 gene mutation may occur only after being metastasized.Although p53 gene mutation and p53 protein overexpression correlate with each other, either parameter examined alone may lead to false positive or negative results.

  16. Induced mutation in tropical fruit trees

    International Nuclear Information System (INIS)

    This publication is based on an FAO/IAEA coordinated research project (CRP) and provides insight into the application of induced mutation and in vitro techniques for the improvement of well known fruit trees such as citrus, mango, avocado and papaya, as well as more exotic fruit trees such as litchi, annona, jujube, carambola, pitanga and jaboticaba. The latter are of particular importance due to their adaptation to harsh environments and their high potential as basic food and micronutrient providers for populations in poorer and more remote regions. The findings of the CRP show that application of radiation induced mutation techniques in tropical and subtropical fruit trees can contribute to improving nutritional balance food security, and to enhancing the economic status of growers

  17. Household income is associated with the p53 mutation frequency in human breast tumors.

    Directory of Open Access Journals (Sweden)

    Adrienne M Starks

    Full Text Available BACKGROUND: A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation. METHODS: We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI among 173 breast cancer patients from the greater Baltimore area, United States. RESULTS: p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%, followed by the income group between $15,000 and $60,000 (18%, while those above $60,000 HI had the fewest mutations (5%. When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05. In the adjusted logistic regression analysis with 3 income categories (trend test, the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER-negative disease. Within this group, 42% of the low income patients (< $15,000 HI carried a mutation, followed by the middle income group (21%, while those above $60,000 HI did not carry mutations (Ptrend < 0.05. CONCLUSIONS: HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.

  18. Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas:A Retrospective Study

    Institute of Scientific and Technical Information of China (English)

    Ying-qiu Pan; Wei-wu Shi; Dan-ping Xu; Hui-hui Xu; Mei-ying Zhou; Wei-hua Yan

    2014-01-01

    Objective To investigate the associations between epidermal growth factor receptor (EGFR) gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGFR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42 (43%) advanced lung adenocarcinoma patients. Gender (P=0.003), smoking status (P=0.001), and abnormal serum status of carcinoembryonic antigen (CEA, P=0.028) were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation (P=0.046) with an odds ratio of 2.613 (95%CI:1.018-6.710). However, receiver operating characteristic (ROC) curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma (the area under the ROC curve was 0.608, P=0.069). Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

  19. Mutations in lettuce improvement.

    Science.gov (United States)

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  20. Stock Status

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — These data inform the public of the most recent stock status for all stocks (FSSI and non-FSSI) in the fishery management unit contained in a fishery managment...

  1. Silting mutation in triangulated categories

    CERN Document Server

    Aihara, Takuma

    2010-01-01

    In representation theory of algebras the notion of `mutation' often plays important roles, and two cases are well known, i.e. `cluster tilting mutation' and `exceptional mutation'. In this paper we focus on `tilting mutation', which has a disadvantage that it is often impossible, i.e. some of summands of a tilting object can not be replaced to get a new tilting object. The aim of this paper is to take away this disadvantage by introducing `silting mutation' for silting objects as a generalization of `tilting mutation'. We shall develope a basic theory of silting mutation. In particular, we introduce a partial order on the set of silting objects and establish the relationship with `silting mutation' by generalizing the theory of Riedmann-Schofield and Happel-Unger. We show that iterated silting mutation act transitively on the set of silting objects for local, hereditary or canonical algebras. Finally we give a bijection between silting subcategories and certain t-structures.

  2. The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism.

    Science.gov (United States)

    Batista, Rui; Cruvinel-Carloni, Adriana; Vinagre, João; Peixoto, Joana; Catarino, Telmo A; Campanella, Nathalia Cristina; Menezes, Weder; Becker, Aline Paixão; de Almeida, Gisele Caravina; Matsushita, Marcus M; Clara, Carlos; Neder, Luciano; Viana-Pereira, Marta; Honavar, Mrinalini; Castro, Lígia; Lopes, José Manuel; Carvalho, Bruno; Vaz, Rui Manuel; Máximo, Valdemar; Soares, Paula; Sobrinho-Simões, Manuel; Reis, Rui Manuel; Lima, Jorge

    2016-07-15

    Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis. PMID:26914704

  3. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  4. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  5. Estimation of mutation rates from paternity cases using a Bayesian network

    DEFF Research Database (Denmark)

    Vicard, P.; Dawid, A.P.; Mortera, J.;

    We present a statistical model and methodology for making inferences about mutation rates from paternity casework. This takes proper account of a number of sources of potential bias, including hidden mutation, incomplete family triplets, uncertain paternity status and differing maternal...... and paternal mutation rates, while allowing a wide variety of mutation models. A Bayesian network is constructed to facilitate computation of the likelihood function for the mutation parameters. It can process both full and summary genotypic information, from both complete putative father-mother-child triplets...... and defective cases where only the child and one of its parents are observed. Detailed analysis of a specific dataset is used to illustrate the effects of the various types of biases, and of the assumed mutation model, on inferences about mutation parameters....

  6. Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling.

    Science.gov (United States)

    Abramson, Vandana G; Cooper Lloyd, M; Ballinger, Tarah; Sanders, Melinda E; Du, Liping; Lai, Darson; Su, Zengliu; Mayer, Ingrid; Levy, Mia; LaFrance, Delecia R; Vnencak-Jones, Cindy L; Shyr, Yu; Dahlman, Kimberly B; Pao, William; Arteaga, Carlos L

    2014-06-01

    Mutations in the PIK3CA gene are common in breast cancer and represent a clinically useful therapeutic target. Several larger, population-based studies have shown a positive prognostic significance associated with these mutations. This study aims to further identify characteristics of patients harboring PIK3CA mutations while evaluating the clinical impact of genomic testing for these mutations. Tumors from 312 patients at Vanderbilt-Ingram Cancer Center were analyzed for PIK3CA mutations using a multiplex screening assay (SNaPshot). Mutation rates, receptor status, histopathologic characteristics, and time to recurrence were assessed. The number of patients participating in clinical trials, specifically trials relating to the PIK3CA mutation, was examined. Statistically significant differences between wild-type and mutated tumors were determined using the Wilcoxon, Pearson, and Fischer exact tests. The PIK3CA mutation was found in 25 % of tumors tested. Patients with PIK3CA mutations were significantly more likely to express hormone receptors, be of lower combined histological grade, and have a reduced time to recurrence. Patients found to have a PIK3CA mutation were significantly more likely to enter a PIK3CA-specific clinical trial. In addition to confirming previously established positive prognostic characteristics of tumors harboring PIK3CA mutations, this study demonstrates the feasibility and utility of mutation profiling in a clinical setting. PIK3CA mutation testing impacted treatment and resulted in more patients entering mutation-specific clinical trials. PMID:24722917

  7. Prevalence and Clinicopathological Characteristics of HER2 and BRAF Mutation in Chinese Patients with Lung Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Ling Shan

    Full Text Available To determine the prevalence and clinicopathological characteristics of BRAF V600E mutation and HER2 exon 20 insertions in Chinese lung adenocarcinoma (ADC patients.Given the fact that the driver mutations are mutually exclusive in lung ADCs, 204 EGFR/KRAS wild-type cases were enrolled in this study. Direct Sanger sequencing was performed to examine BRAF V600E and HER2 exon 20 mutations. The association of BRAF and HER2 mutations with clinicopathological characteristics was statistically analyzed.Among the 204 lung ADCs tested, 11 cases (5.4% carried HER2 exon 20 insertions and 4 cases (2.0% had BRAF V600E mutation. HER2 mutation status was identified to be associated with a non-smoking history (p<0.05. HER2 mutation occurs in 9.4% of never smokers (10/106, 8.7% of female (8/92 and 2.7% of male (3/112 in this selected cohort. All four BRAF mutated patients were women and three of them were never-smokers. No HER2 mutant patients harbor BRAF mutation.HER2 and BRAF mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer and the availability of targeted therapy, Chinese lung ADC patients without EGFR and KRAS mutations are recommended for HER2 and BRAF mutations detection, especially for those never smokers.

  8. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.

    2011-01-01

    selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...

  9. Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors.

    Science.gov (United States)

    Lavallée, Vincent-Philippe; Krosl, Jana; Lemieux, Sébastien; Boucher, Geneviève; Gendron, Patrick; Pabst, Caroline; Boivin, Isabel; Marinier, Anne; Guidos, Cynthia J; Meloche, Sylvain; Hébert, Josée; Sauvageau, Guy

    2016-06-16

    In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease. PMID:27034432

  10. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)

    1995-10-01

    This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

  11. Evolutionary Stability Against Multiple Mutations

    CERN Document Server

    Ghatak, Anirban; Shaiju, A J

    2012-01-01

    It is known (see e.g. Weibull (1995)) that ESS is not robust against multiple mutations. In this article, we introduce robustness against multiple mutations and study some equivalent formulations and consequences.

  12. Mutation breeding newsletter. No. 45

    International Nuclear Information System (INIS)

    This issue of the Mutation Breeding newsletter contains 39 articles dealing with radiation induced mutations and chemical mutagenesis techniques in plant breeding programs with the aims of improving crop productivity and disease resistance as well as exploring genetic variabilities

  13. Mutation breeding newsletter. No. 33

    International Nuclear Information System (INIS)

    This issue of the newsletter reports a number of research news and research abstracts on application of radiation induced mutation techniques to increase mutagenesis and mutation frequency in plant breeding projects

  14. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

    LENUS (Irish Health Repository)

    Stordal, Britta

    2013-06-01

    Mutations in BRCA1\\/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1\\/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1\\/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1\\/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1\\/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1\\/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1\\/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1\\/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1\\/2 deleterious mutations 1\\/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective

  15. Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer.

    LENUS (Irish Health Repository)

    Gonzalez-Angulo, Ana M

    2011-03-01

    To investigate the incidence of germline and somatic BRCA1\\/2 mutations in unselected patients with triple-negative breast cancer (TNBC) and determine the prognostic significance of carrying a mutation. Methods: DNA was obtained from 77 TNBC and normal tissues. BRCA1\\/2 exons\\/flanking regions were sequenced from tumor and patients classified as mutant or wild type (WT). Sequencing was repeated from normal tissue to identify germline and somatic mutations. Patient characteristics were compared with chi-square. Survival was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of mutation status with outcome.

  16. Compliance status

    Energy Technology Data Exchange (ETDEWEB)

    Black, D.G.

    1995-06-01

    This section of the 1994 Hanford Site Environmental Report summarizes the activities conducted to ensure that the Hanford Site is in compliance with federal environmental protection statutes and related Washington State and local environmental protection regulations and the status of Hanford`s compliance with these requirements. Environmental permits required under the environmental protection regulations are discussed under the applicable statute.

  17. Mutation breeding in pepper

    International Nuclear Information System (INIS)

    Pepper (Capsicum sp.) is an important vegetable and spice crop widely grown in tropical as well as in temperate regions. Until recently the improvement programmes were based mainly on using natural sources of germ plasma, crossbreeding and exploiting the heterosis of F1 hybrids. However, interest in using induced mutations is growing. A great number of agronomically useful mutants as well as mutants valuable for genetic, cytological and physiological studies have been induced and described. In this review information is presented about suitable mutagen treatment procedures with radiation as well as chemicals, M1 effects, handling the treated material in M1, M2 and subsequent generations, and mutant screening procedures. This is supplemented by a description of reported useful mutants and released cultivars. Finally, general advice is given on when and how to incorporate mutation induction in Capsicum improvement programmes. (author)

  18. Mutation of Auslander generators

    CERN Document Server

    Lada, Magdalini

    2009-01-01

    Let $\\Lambda$ be an artin algebra with representation dimension equal to three and $M$ an Auslander generator of $\\Lambda$. We show how, under certain assumptions, we can mutate $M$ to get a new Auslander generator whose endomorphism ring is derived equivalent to the endomorphism ring of $M$. We apply our results to selfinjective algebras with radical cube zero of infinite representation type, where we construct an infinite set of Auslander generators.

  19. GNAS gene mutation may be present only transiently during colorectal tumorigenesis

    Science.gov (United States)

    Zauber, Peter; Marotta, Stephen P; Sabbath-Solitare, Marlene

    2016-01-01

    Mutations of the gene GNAS have been shown to activate the adenylate cyclase gene and lead to constitutive cAMP signaling. Several preliminary reports have suggested a role for GNAS gene mutations during colorectal carcinogenesis, particularly mucinous carcinomas. The aim of this study was to clarify the incidence of GNAS mutations in adenomas (tubular, tubulovillous, and villous), carcinomas with residual adenoma, and carcinomas, and to relate these findings to mutations of the KRAS gene and to the mucinous status of the tumors. We used standard PCR techniques and direct gene sequencing to evaluate tumors for gene mutations. No GNAS mutations were identified in 25 tubular adenomas, but were present in 6.4% of tubulovillous adenomas and 11.2% of villous adenomas. A GNAS mutation was found in 9.7% of the benign portion of carcinoma with residual adenoma, but in none of 86 carcinomas. A similar trend was seen for KRAS mutation across the five groups of tumors. GNAS mutations may function as an important driver mutation during certain phases of colorectal carcinogenesis, but may then be lost once the biological advantage gained by the mutated gene is no longer necessary to sustain or advance tumor development. PMID:27186325

  20. Impact of RAS and BRAF mutations on carcinoembryonicantigen production and pattern of colorectal metastases

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    AIM To investigate the impact of RAS and BRAFmutations on the pattern of metastatic disease andcarcinoembryonic antigen (CEA) production.METHODS: In this retrospective study, we investigatedthe impact of RAS and BRAF mutational status on patternof metastatic disease and CEA production. Only patientspresenting with a newly diagnosed metastatic colorectalcancer (CRC) were included. Patients' characteristics,primary tumor location, site of metastatic disease andCEA at presentation were compared between those withand without RAS and BRAF mutations.RESULTS: Among 174 patients, mutations in KRAS ,NRAS and BRAF were detected in 47%, 3% and 6%respectively. RAS mutations (KRAS and NRAS ) weremore likely to be found in African American patients(87% vs 13%; P value = 0.0158). RAS mutations wereassociated with a higher likelihood of a normal CEA (〈5 ng/mL) at presentation. BRAF mutations were morelikely to occur in females. We were not able to confirm any association between mutational status and site ofmetastatic disease at initial diagnosis.CONCLUSION: No association was found between RASand BRAF mutations and sites of metastatic disease atthe time of initial diagnosis in our cohort. Patients withRAS mutations were more likely to present with CEAlevels 〈 5 ng/mL. These findings may have clinical implicationson surveillance strategies for RAS mutant patientswith earlier stages of CRC.

  1. Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations.

    Science.gov (United States)

    Wang, Zheng; Zhang, Weimin; Wang, Yun; Meng, Yan; Su, Liang; Shi, Huiping; Huang, Shangzhi

    2010-08-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.

  2. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi

    2014-10-01

    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  3. Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience

    OpenAIRE

    LaRochelle, Olivier; Bertoli, Sarah; Vergez, François; Sarry, Jean-Emmanuel; Mansat-De Mas, Véronique; Dobbelstein, Sophie; Dastugue, Nicole; Strzelecki, Anne-Claire; Cavelier, Cindy; Creancier, Laurent; Pillon, Arnaud; Kruczynski, Anna; Demur, Cécile; Sarry, Audrey; Huguet, Françoise

    2011-01-01

    Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated ...

  4. ANALYSIS OF C-HA-RAS GENE AMPLIFICATION AND MUTATION IN LARYNGEAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    刘世喜; 林代诚; 洪邦泰; 黄光琦

    1995-01-01

    In order to study the ahered molecular events during laryngeal carcinogenesis and elucidate the role of Ha-ras oncogene amplification and mutation, we have examined their profile by polymerase chain reaction (PCR) and selective oligonucleoride hybridization. We analyzed the mutational status of codon 12 of Ha-ras in 22 laryngeal carcinomas and 10 normal tissues, and found that 7 of 22 laryngeal carcinomas con-tained a Ha-ras mutation at codon 12. The frequency of mutation was 32%. None of the normal tissues re-vealed mutation. Moreover, no amplification was found in cancers when compared to the normal. Our findings indicated that the aefivmed Ha-ras gene existed in laryngeal carcinoma, and activation of the Ha-ras gene by mutation at codon 12 might play a key role in laryngeal carcinogenesis.

  5. Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Heikkilä, Pirjo;

    2010-01-01

    The causal role of work-related exposure to wood dust in the development of sinonasal cancer has long been established by numerous epidemiologic studies. To study molecular changes in these tumors, we analyzed TP53 gene mutations in 358 sinonasal cancer cases with or without occupational exposure...... occurred in all histologies, with an overall frequency of 77%. TP53 mutation positive status was most common in adenocarcinoma (OR 2.0, 95% CI, 1.1-3.7; compared with squamous cell carcinoma), and mutation positivity showed an overall, nonsignificant association with wood-dust exposure (OR 1.6, 95% CI, 0...... affected the ORs only slightly. Smoking did not influence the occurrence of TP53 mutation; however, it was associated with multiple mutations (p = 0.03). As far as we are aware, this is the first study to demonstrate a high prevalence of TP53 mutation-positive cases in a large collection of sinonasal...

  6. Somatic mutations associated with MRI-derived volumetric features in glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Gutman, David A.; Dunn, William D. [Emory University School of Medicine, Departments of Neurology, Atlanta, GA (United States); Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Grossmann, Patrick; Alexander, Brian M. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Cooper, Lee A.D. [Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Georgia Institute of Technology, Department of Biomedical Engineering, Atlanta, GA (United States); Holder, Chad A. [Emory University School of Medicine, Radiology and Imaging Sciences, Atlanta, GA (United States); Ligon, Keith L. [Brigham and Women' s Hospital, Harvard Medical School, Pathology, Dana-Farber Cancer Institute, Boston, MA (United States); Aerts, Hugo J.W.L. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Brigham and Women' s Hospital, Harvard Medical School, Radiology, Dana-Farber Cancer Institute, Boston, MA (United States)

    2015-12-15

    MR imaging can noninvasively visualize tumor phenotype characteristics at the macroscopic level. Here, we investigated whether somatic mutations are associated with and can be predicted by MRI-derived tumor imaging features of glioblastoma (GBM). Seventy-six GBM patients were identified from The Cancer Imaging Archive for whom preoperative T1-contrast (T1C) and T2-FLAIR MR images were available. For each tumor, a set of volumetric imaging features and their ratios were measured, including necrosis, contrast enhancing, and edema volumes. Imaging genomics analysis assessed the association of these features with mutation status of nine genes frequently altered in adult GBM. Finally, area under the curve (AUC) analysis was conducted to evaluate the predictive performance of imaging features for mutational status. Our results demonstrate that MR imaging features are strongly associated with mutation status. For example, TP53-mutated tumors had significantly smaller contrast enhancing and necrosis volumes (p = 0.012 and 0.017, respectively) and RB1-mutated tumors had significantly smaller edema volumes (p = 0.015) compared to wild-type tumors. MRI volumetric features were also found to significantly predict mutational status. For example, AUC analysis results indicated that TP53, RB1, NF1, EGFR, and PDGFRA mutations could each be significantly predicted by at least one imaging feature. MRI-derived volumetric features are significantly associated with and predictive of several cancer-relevant, drug-targetable DNA mutations in glioblastoma. These results may shed insight into unique growth characteristics of individual tumors at the macroscopic level resulting from molecular events as well as increase the use of noninvasive imaging in personalized medicine. (orig.)

  7. Muller's ratchet with compensatory mutations

    CERN Document Server

    Pfaffelhuber, Peter; Wakolbinger, Anton

    2011-01-01

    We consider an infinite dimensional system of stochastic differential equations which describes the evolution of type frequencies in a large population. Random reproduction is modeled by a Wright-Fisher noise whose inverse diffusion coefficient $N$ corresponds to the total population size. The type of an individual is the number $k$ of deleterious mutations it carries. We assume that fitness of individuals carrying $k$ mutations is decreased by $\\alpha k$ for some $\\alpha >0$. Along the individual lines of descent, (new) mutations accumulate at rate $\\lambda$ per generation, and each of these mutations has a small probability $\\gamma$ per generation to disappear. While the case $\\gamma =0 $ is known as (the Fleming-Viot version of) {\\em Muller's ratchet}, the case $\\gamma > 0$ is referred to as that of {\\em compensatory mutations} in the biological literature. In the former case ($\\gamma=0$), an ever increasing number of mutations is accumulated over time, while in the latter ($\\gamma > 0$) this is prevented ...

  8. Mutation Breeding Newsletter. No. 39

    International Nuclear Information System (INIS)

    This newsletter contains brief articles on the use of radiation to induce mutations in plants; radiation-induced mutants in Chrysanthemum; disrupting the association between oil and protein content in soybean seeds; mutation studies on bougainvillea; a new pepper cultivar; and the use of mutation induction to improve the quality of yam beans. A short review of the seminar on the use of mutation and related biotechnology for crop improvement in the Middle East and Mediterranean regions, and a description of a Co-ordinated Research Programme on the application of DNA-based marker mutations for the improvement of cereals and other sexually reproduced crop species are also included. Two tables are given: these are based on the ''FAO/IAEA Mutant Varieties Database'' and show the number of mutated varieties and the number of officially released mutant varieties in particular crops/species. Refs and tabs

  9. Filaggrin mutations and the skin.

    Science.gov (United States)

    De, Dipankar; Handa, Sanjeev

    2012-01-01

    Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  10. Filaggrin mutations and the skin

    Directory of Open Access Journals (Sweden)

    Dipankar De

    2012-01-01

    Full Text Available Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  11. Calreticulin Mutations in Myeloproliferative Neoplasms

    OpenAIRE

    Noa Lavi

    2014-01-01

    With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs) in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (...

  12. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)

    1984-10-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  13. Mutation breeding in mangosteen

    International Nuclear Information System (INIS)

    Mangosteen the queen of the tropical fruits is apomitic and only a cultivar is reported and it reproduces asexually. Conventional breeding is not possible and the other methods to create variabilities are through genetic engineering and mutation breeding. The former technique is still in the infantry stage in mangosteen research while the latter has been an established tool in breeding to improve cultivars. In this mutation breeding seeds of mangosteen were irradiated using gamma rays and the LD 50 for mangosteen was determined and noted to be very low at 10 Gy. After sowing in the seedbed, the seedlings were transplanted in polybags and observed in the nursery bed for about one year before planted in the field under old oil palm trees in Station MARDI, Kluang. After evaluation and screening, about 120 mutant mangosteen plants were selected and planted in Kluang. The plants were observed and some growth data taken. There were some mutant plants that have good growth vigour and more vigorous that the control plants. The trial are now in the fourth year and the plants are still in the juvenile stage. (Author)

  14. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    Chickpea is an important food legume in Turkey. Turkey is one of the most important gene centers in the world for legumes. Realizing the potential of induced mutations, a mutation breeding programme was initiated at the Nuclear Agriculture Section of the Saraykoy Nuclear Research and Training Center in 1994. The purpose of the study was to obtain high yielding chickpea mutants with large seeds, good cooking quality and high protein content. Beside this some characters such as higher adaptation ability, tolerant to cold and drought, increased machinery harvest type, higher yield, resistant to diseases especially to antracnose and pest were investigated too. Parent varieties were ILC-482, AK-7114 and AKCIN-91 had been used in these experiments. The irradiation doses were 0 (control), 50, 100, 150, 200, 250, 300, 350 and 400 Gy for field experiments, respectively. As a result of these experiments, two promising mutant lines were chosen and given to the Seed Registration and Certification Center for official registration These two promising mutants were tested at five different locations of Turkey, in 2004 and 2005 years. After 2 years of registration experiments one of outstanding mutants was officially released as mutant chickpea variety under the name TAEK-SAGEL, in 2006. Some basic characteristics of this mutant are; earliness (95-100 day), high yield capacity (180-220 kg/da), high seed protein (22-25 %), first pot height (20-25 cm), 100 seeds weight (42-48 g), cooking time (35-40 min) and resistance to Ascochyta blight.

  15. KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay

    Directory of Open Access Journals (Sweden)

    Reinthaller Alexander

    2009-04-01

    Full Text Available Abstract Background Mutations in the KRAS gene are one of the most frequent genetic abnormalities in ovarian carcinoma. They are of renewed interest as new epidermal growth factor receptor (EGFR-targeted therapies are being investigated for use in ovarian carcinoma. As KRAS mutations are associated with poor response and resistance to EGFR-targeting drugs, this study was conducted to obtain more information on the spectrum of KRAS mutations in ovarian carcinoma. Methods The presence of KRAS mutations in codon 12 and 13 was analyzed in frozen and formalin-fixed paraffin-embedded (FFPE tissue with a low density biochip platform. 381 malignant (29 borderline malignancy, 270 primary carcinomas, and 82 recurrent carcinomas and 22 benign tissue samples from a total of 394 patients were examined. KRAS mutational status of each sample was correlated with dignity, FIGO stage, grade, histology, and survival. Results KRAS mutations were found in 60 (15% samples with 58 samples deriving from malignant tissue and 2 samples deriving from benign tissue. In 55 (92% samples codon 12 was found to be mutated. Frozen and FFPE samples concurred with respect to KRAS mutation status. Conclusion KRAS mutation is a common event in ovarian cancer primarily in carcinomas of lower grade, lower FIGO stage, and mucinous histotype. The KRAS mutational status is no prognostic factor for patients treated with standard therapy. However, in line with experience from colorectal cancer and non-small-cell-lung cancer (NSCLC, it may be important for prediction of response to EGFR-targeted therapies.

  16. A nonsense mutation in FMR1 causing fragile X syndrome

    DEFF Research Database (Denmark)

    Grønskov, Karen; Brøndum-Nielsen, Karen; Dedic, Alma;

    2011-01-01

    Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent....... Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense...... mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be...

  17. KRAS Gene Mutations and Gender Differences in Colorectal Cancer

    OpenAIRE

    Dmitriy I. Vodolazhskiy; Yuriy A. Gevorkyan; Natalia V. Soldatkina

    2015-01-01

    The aim of this study was to investigate the frequency and spectrum of KRAS mutations in men and women with colorectal cancer (CRC), and an impact of KRAS-mutation status on the clinical and morphological features of CRC. The study included 303 patients (168/55.4% women and 135/44.6% men) with CRC T2-4N0-2M0-1. We defined 7 KRAS SNP-mutations (G12D, G12A, G12R, G12C, G12S, G12V and G13D) located within codons 12 and 13 using Bio-Rad real-time thermal cyclers CFX96 and Real-Time-PCR- KRAS-7M K...

  18. Finding all BRCA pathogenic mutation carriers: best practice models.

    Science.gov (United States)

    Hoogerbrugge, Nicoline; Jongmans, Marjolijn Cj

    2016-09-01

    Identifying germline BRCA pathogenic mutations in patients with ovarian or breast cancer is a crucial component in the medical management of affected patients. Furthermore, the relatives of affected patients can be offered genetic testing. Relatives who test positive for a germline BRCA pathogenic mutation can take appropriate action to prevent cancer or have cancer diagnosed as early as possible for better treatment options. The recent discovery that BRCA pathogenic mutation status can inform treatment decisions in patients with ovarian cancer has led to an increased demand for BRCA testing, with testing taking place earlier in the patient care pathway. New approaches to genetic counselling may be required to meet this greater demand for BRCA testing. This review discusses the need for best practices for genetic counselling and BRCA testing; it examines the challenges facing current practice and looks at adapted models of genetic counselling. PMID:27514840

  19. Tevatron status

    International Nuclear Information System (INIS)

    The Fermilab Tevatron is both the world's highest energy accelerator system and first large-scale superconducting synchrotron. Since Tevatron commissioning in July 1983, the accelerator has operated in 1984, 1985 and 1987 with extracted beams of 800 GeV for three runs of fixed target physics, and in 1987, and 1988, with proton-antiproton colliding beams at 900 /times/ 900 GeV. This paper will focus on the collider operation of the Tevatron: its present status and the outlook for its longer-term future evolution. 18 refs., 3 figs., 2 tabs

  20. Mutation breeding newsletter. No. 43

    International Nuclear Information System (INIS)

    This issue of the Newsletter includes articles dealing with radiation induced mutation based plant breeding research findings aimed at improving productivity, disease resistance and tolerance of stress conditions

  1. Targeting EZH2 methyltransferase activity in ARID1A mutated cancer cells is synthetic lethal

    Science.gov (United States)

    Biter, Benjamin G.; Aird, Katherine M.; Garipov, Azat; Li, Hua; Amatangelo, Michael; Kossenkov, Andrew V.; Schultz, David C.; Liu, Qin; Shih, Ie-Ming; Conejo-Garcia, Jose R.; Speicher, David W.; Zhang, Rugang

    2015-01-01

    ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently has no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated ovarian cancer cells. ARID1A mutational status correlates with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct ARID1A/EZH2 target, which is upregulated by EZH2 inhibition and contributes to the observed synthetic lethality by inhibiting PI3K/AKT signaling. Significantly, EZH2 inhibition causes regression of ARID1A mutated ovarian tumors in vivo. Together, these data demonstrate for the first time a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers. PMID:25686104

  2. Functional features of gene expression profiles differentiating gastrointestinal stromal tumours according to KIT mutations and expression

    International Nuclear Information System (INIS)

    Gastrointestinal stromal tumours (GISTs) represent a heterogeneous group of tumours of mesenchymal origin characterized by gain-of-function mutations in KIT or PDGFRA of the type III receptor tyrosine kinase family. Although mutations in either receptor are thought to drive an early oncogenic event through similar pathways, two previous studies reported the mutation-specific gene expression profiles. However, their further conclusions were rather discordant. To clarify the molecular characteristics of differentially expressed genes according to GIST receptor mutations, we combined microarray-based analysis with detailed functional annotations. Total RNA was isolated from 29 frozen gastric GISTs and processed for hybridization on GENECHIP® HG-U133 Plus 2.0 microarrays (Affymetrix). KIT and PDGFRA were analyzed by sequencing, while related mRNA levels were analyzed by quantitative RT-PCR. Fifteen and eleven tumours possessed mutations in KIT and PDGFRA, respectively; no mutation was found in three tumours. Gene expression analysis identified no discriminative profiles associated with clinical or pathological parameters, even though expression of hundreds of genes differentiated tumour receptor mutation and expression status. Functional features of genes differentially expressed between the two groups of GISTs suggested alterations in angiogenesis and G-protein-related and calcium signalling. Our study has identified novel molecular elements likely to be involved in receptor-dependent GIST development and allowed confirmation of previously published results. These elements may be potential therapeutic targets and novel markers of KIT mutation status

  3. DETECTION OF p53 GENE MUTATION IN PLASMA OF PATIENTS WITH GASTRIC CANCER

    Institute of Scientific and Technical Information of China (English)

    苏鹏程; 李子禹; 张连海; 万文徽; 任晖; 张桂国; 王怡; 邓国仁; 季加孚

    2004-01-01

    Objective: To investigated p53 gene mutation in plasma of gastric cancer patients. Methods: DNA extracted from plasma and matched tumor and tumor-adjacent non-cancerous tissues of 96 gastric cancer patients, and DNA from 20 healthy volunteers were studied. Exon 5, 6, 7, and 8 of p53 were amplified by Polymerase Chain Reaction (PCR). The mutation status was analyzed by denaturing high-performance liquid chromatography (DHPLC), followed by direct sequencing of cases with aberrant chromatographic patterns. Results: Heterozygous mutations of p53 gene were detected in 19.9% (19/96) of primary tumor tissues and 5.2% (5/96) of corresponding plasma. All p53 gene mutations detected in plasma DNA consisted with mutations in the matched primary tumor samples. Neither the tumor-adjacent gastric mucosa tissues nor control plasma from healthy volunteers showed p53 gene mutation. No correlation was found between p53 mutation status and clinicopathological features of gastric cancer patients. Conclusion: p53 gene mutation in plasma can be detected in tissues and plasma of gastric cancer patients, which could be applied in screening and surveillance of this disease.

  4. Reliability of KRAS mutation testing in metastatic colorectal cancer patients across five laboratories

    Directory of Open Access Journals (Sweden)

    Feigelson Heather

    2012-04-01

    Full Text Available Abstract Background Mutations in the KRAS gene are associated with poor response to epidermal growth factor receptor inhibitors used in the treatment of metastatic colorectal cancer. Factors influencing KRAS test results in tumor specimens include: tumor heterogeneity, sample handling, slide preparation, techniques for tumor enrichment, DNA preparation, assay design and sensitivity. We evaluated comparability and consistency of KRAS test results among five laboratories currently being used to determine KRAS mutation status of metastatic colorectal cancer specimens in a large, multi-center observational study. Findings Twenty formalin-fixed paraffin-embedded human colorectal cancer samples from colon resections previously tested for KRAS mutations were selected based on mutation status (6 wild type, 8 codon 12 mutations, and 6 codon 13 mutations. We found good agreement across laboratories despite differences in mutation detection methods. Eighteen of twenty samples (90% were concordant across all five labs. Discordant results are likely not due to laboratory error, but instead to tumor heterogeneity, contamination of the tumor sample with normal tissue, or analytic factors affecting assay sensitivity. Conclusions Our results indicate commercial and academic laboratories provide reliable results for the common KRAS gene mutations at codons 12 and 13 when an adequate percentage of tumor cells is present in the sample.

  5. Mutation breeding in soybean

    International Nuclear Information System (INIS)

    In Indonesia, soybean is one of the important crop after rice. It is generally cultivated in the lowlands and rarely in the highlands. Seeds of soybean variety ORBA were treated with various doses of fast neutrons, gamma rays, EMS and NaN3 with the aims of studying the mutagen effects in M-1 and M-2 generations and also to select mutants adapted to highland conditions. D-50 doses for gamma rays, fast neutrons and EMS were around 23 krad, 2,300 rad, 0.3%, respectively. Much higher chlorophyll mutation frequency was observed in EMS treatment of 0.3%. Seven mutants were shorter and four early mutants matured from 4 to 20 days earlier than the control plants. Two early mutants were quite adaptable in both the low and highlands and produced better yields than the parental material. (author)

  6. Analysis of EML4-ALK Gene Fusion Mutation in Patients 
with Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xuzhou WANG

    2015-02-01

    Full Text Available Background and objective Non-small cell lung cancer (NSCLC is the main type of lung cancer, and the related locus mutation detection research has become a hot direction of molecular targeted therapy, studying on gene mutation status of echinodem microtubule associated protein like 4-Anaplastic lymphoma kinase (EML4-ALK and epidermal growth factor receptor (EGFR, detecting the sensitivity of EML4-ALK gene fusion and gene mutation of EGFR. Methods EML4-ALK gene fusion in 85 cases of paraffin embedded tumor tissue and adjacent lung tissue was detected with the application of immunohistochemistry (IHC, Scorpions amplification refractory mutation system (Scorpions ARMS fluorescence quantitative PCR and fluorescence in situ hybridization (FISH technology, and EGFR gene in 18, 19, 20 and 21 exon mutation status was detected with the application of ARMS method. Results In 115 cases of NSCLC, IHC showed 32 cases with ALK (D5F3 expression, the expression rate was 27.8%; ARMS showed 27 cases with EML4-ALK fusion gene mutation, the mutation detection rate was 23.5%; 53 cases were detected with EGFR mutation, the mutation rate was 46%. While FISH showed 23 cases with EML4-ALK fusion gene mutation, the detection rate was 20%, slightly lower than the ARMS detection results, suggesting that ARMS more sensitive. Conclusion The application of IHC, ARMS fluorescence quantitative PCR and FISH technology can make a rapid and accurate evaluation of EML4-ALK gene fusion.

  7. The Frequency of Epidermal Growth Factor Receptor Mutation of Nonsmall Cell Lung Cancer according to the Underlying Pulmonary Diseases

    Directory of Open Access Journals (Sweden)

    Kazuhiro Usui

    2011-01-01

    Full Text Available Background. Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs are effective in patients with nonsmall cell lung cancer with epidermal growth factor receptor (EGFR mutation, EGFR-TKIs have a risk of inducing fatal interstitial lung disease (ILD. The selection of chemotherapy based on the EGFR mutation status is recommended, however, the frequency of EGFR mutation in patients with ILD and the efficacy and safety of EGFR-TKI in patients with ILD and EGFR mutation are unknown. Methods. We retrospectively reviewed the association of the EGFR mutation status of nonsmall cell lung cancer and pulmonary diseases. Based on high-resolution computed tomography (HRCT performed at diagnosis of lung cancer, patients were categorized into three groups: normal, emphysema, and fibrosis. Results. Of 198 patients with nonsmall cell lung cancer, we identified 52 (26.3% patients with an EGFR mutation. EGFR mutations were identified in 43 (35.2% of 122 patients with normal lungs, 8 (13.6% of 59 with emphysema, and 1 (5.9% of 17 with pulmonary fibrosis. Of the 52 patients with EGFR mutation, 43 patients received gefitinib. One patient with an EGFR mutation and fibrosis developed fatal ILD. There was not a significant difference in median overall survival from gefitinib treatment between never-smokers and smokers (797 days versus not reached; =0.96. Conclusions. Patients with sensitive EGFR mutation and normal lungs may benefit from an EGFR-TKI treatment even if they have smoking history.

  8. Founder Mutations in Xeroderma Pigmentosum

    OpenAIRE

    Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.

    2010-01-01

    In this issue, Soufir et al. report a founder mutation in the XPC DNA repair gene in 74% of families with xeroderma pigmentosum (XP) in the Maghreb region (Algeria, Morocco, and Tunisia) of northern Africa. These patients have a high frequency of skin cancer. The presence of this founder mutation provides an opportunity for genetic counseling and early diagnosis of XP.

  9. Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer

    Directory of Open Access Journals (Sweden)

    Wang Yu-Fen

    2006-04-01

    Full Text Available Abstract Background The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer. Methods The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE, followed by direct DNA sequencing to identify the mutations. Results Fourteen somatic mtDNA mutations were identified in 55% (11/20 of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64% were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status. Conclusion Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.

  10. High throughput interrogation of somatic mutations in high grade serous cancer of the ovary.

    Directory of Open Access Journals (Sweden)

    Ursula A Matulonis

    Full Text Available BACKGROUND: Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, and high grade serous ovarian cancer (HGSC is the most common subtype of ovarian cancer. The objective of this study was to determine the frequency and types of point somatic mutations in HGSC using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology. METHODOLOGY/PRINCIPAL FINDINGS: The Center for Cancer Genome Discovery (CCGD Program at the Dana-Farber Cancer Institute (DFCI has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection protocol, termed OncoMap has been expanded to detect more than 1000 mutations in 112 oncogenes in formalin-fixed paraffin-embedded (FFPE tissue samples. We performed OncoMap on a set of 203 FFPE advanced staged HGSC specimens. We isolated genomic DNA from these samples, and after a battery of quality assurance tests, ran each of these samples on the OncoMap v3 platform. 56% (113/203 tumor samples harbored candidate mutations. Sixty-five samples had single mutations (32% while the remaining samples had ≥ 2 mutations (24%. 196 candidate mutation calls were made in 50 genes. The most common somatic oncogene mutations were found in EGFR, KRAS, PDGRFα, KIT, and PIK3CA. Other mutations found in additional genes were found at lower frequencies (<3%. CONCLUSIONS/SIGNIFICANCE: Sequenom analysis using OncoMap on DNA extracted from FFPE ovarian cancer samples is feasible and leads to the detection of potentially druggable mutations. Screening HGSC for somatic mutations in oncogenes may lead to additional therapies for this patient population.

  11. MPL mutations in myeloproliferative disorders

    DEFF Research Database (Denmark)

    Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.;

    2008-01-01

    Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet c......DNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F......(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin...

  12. Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera.

    Science.gov (United States)

    Franchini, Massimo; de Matteis, Giovanna; Federici, Francesca; Solero, Pietro; Veneri, Dino

    2004-01-01

    A literature review reports increased erythrocyte indices [hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH), MCH concentration] in subjects with hereditary hemochromatosis (HH). We, therefore, screened 52 consecutive patients with polycythemia vera for 12 HH gene mutations, comparing iron status and red cell parameters between patients positive or negative for HH gene mutations. Our results support the evidence that there is no association between these two conditions.

  13. FAK overexpression and p53 mutations are highly correlated in human breast cancer

    OpenAIRE

    Golubovskaya, Vita M; Conway, Kathleen; Edmiston, Sharon N; Tse, Chiu-Kit; Lark, Amy L.; Livasy, Chad A.; Moore, Dominic; Millikan, Robert C.; Cance, William G

    2009-01-01

    Focal Adhesion Kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors rev...

  14. Fertility preservation in BRCA mutation carriers.

    Science.gov (United States)

    Revelli, Alberto; Salvagno, Francesca; Delle Piane, Luisa; Casano, Simona; Evangelista, Francesca; Pittatore, Giulia; Razzano, Alessandra; Marchino, Gian L; Gennarelli, Gianluca; Benedetto, Chiara

    2016-10-01

    According to enhanced long-term survival rates of these patients, interest in fertility preservation for young women facing gonadotoxic therapies is increasing. Women who carry a mutation in the BRCA1 or BRCA2 gene have a specifically increased lifetime risk of developing breast and tubo-ovarian cancer. Moreover, they are at high risk of undergoing premature infertility due to the medical interventions that are often performed in order to reduce cancer risk or treat an already existing malignancy. Fertility issues are relevant for healthy BRCA mutation carriers, whose family-planning decisions are often influenced by the need of prophylactic bilateral salpingo-oophorectomy at young age. In BRCA mutation carriers who have a breast cancer at young age, the oncostatic treatment is associated with a significant ovarian toxicity linked to chemotherapy as well as to the long lasting hormonotherapy and to the need of delaying pregnancy for several years. Prompt counselling about different fertility preservation options should be offered to all young girls and women at high risk of ovarian insufficiency and infertility. Validated techniques to preserve fertility include oocyte and embryo cryopreservation, while experimental techniques include ovarian suppression with GnRH-analogs during chemotherapy and ovarian tissue cryopreservation. The choice of the best strategy depends on age, type of chemotherapy, partner status, cancer type, time available for fertility preservation intervention and the risk of ovarian metastasis. All available options should be offered and can be performed alone or in combination. A crucial point is to avoid a significant delay to cancer treatment. PMID:26997146

  15. Survey of CF mutations in the clinical laboratory

    Directory of Open Access Journals (Sweden)

    Myers Angela

    2002-11-01

    Full Text Available Abstract Background Since it is impossible to sequence the complete CFTR gene routinely, clinical laboratories must rely on test systems that screen for a panel of the most frequent mutations causing disease in a high percentage of patients. Thus, in a cohort of 257 persons that were referred to our laboratory for analysis of CF gene mutations, reverse line probe assays for the most common CF mutations were performed. These techniques were evaluated as routine first-line analyses of the CFTR gene status. Methods DNA from whole blood specimens was extracted and subjected to PCR amplification of 9 exons and 6 introns of the CFTR gene. The resulting amplicons were hybridised to probes for CF mutations and polymorphisms, immobilised on membranes supplied by Roche Molecular Systems, Inc. and Innogenetics, Inc.. Denaturing gradient gel electrophoresis and sequencing of suspicious fragments indicating mutations were done with CF exon and intron specific primers. Results Of the 257 persons tested over the last three years (referrals based on 1 clinical symptoms typical for/indicative of CF, 2 indication for in vitro fertilisation, and 3 gene status determination because of anticipated parenthood and partners or relatives affected by CF, the reverse line blots detected heterozygote or homozygote mutations in the CFTR gene in 68 persons (26%. Eighty-three percent of those affected were heterozygous (47 persons or homozygous (10 persons for the ΔF508 allele. The only other CF-alleles that we found with these tests were the G542X allele (3 persons, the G551D allele (3 persons, the 3849+10kb C-T allele (2 persons the R117H allele (2 persons and the 621+1G-T allele (1 person. Of the fifteen IVS8-5T-polymorphisms detected in intron 8, seven (47% were found in males referred to us from IVF clinics. These seven 5T-alleles were all coupled with a heterozygous ΔF508 allele, they make up 35% of the males with fertility problems (20 men referred to us. Conclusions

  16. Mutational meltdown in laboratory yeast populations

    NARCIS (Netherlands)

    Zeyl, C.; Mizesko, M.; Visser, de J.A.G.M.

    2001-01-01

    In small or repeatedly bottlenecked populations, mutations are expected to accumulate by genetic drift, causing fitness declines. In mutational meltdown models, such fitness declines further reduce population size, thus accelerating additional mutation accumulation and leading to extinction. Because

  17. BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens.

    Science.gov (United States)

    Thomas, Carla; Amanuel, Benhur; Finlayson, Jill; Grieu-Iacopetta, Fabienne; Spagnolo, Dominic V; Erber, Wendy N

    2015-06-01

    Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the BRAF p.Val600Glu (V600E) mutation in HCL makes it a valuable molecular diagnostic marker. We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample. DNA was amplified and BRAF mutation status determined by the three methods above. V600E mutation was identified in 94%, 89% and 72% of HCL cases by F-SSCP, HRM and Sanger sequencing, respectively. In one case, in addition to the p.Val600Glu mutation, a p.Lys601Thr (K601T) mutation was identified. DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity, especially using HRM/F-SSCP. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL and the presence of the mutation may provide a target for therapy. PMID:25938346

  18. Chromosomal Instability, Aneuploidy, and Gene Mutations in Human Sporadic Colorectal Adenomas

    Directory of Open Access Journals (Sweden)

    Walter Giaretti

    2004-01-01

    Full Text Available Whether in vivo specific gene mutations lead to chromosomal instability (CIN and aneuploidy or viceversa is so far not proven. We hypothesized that aneuploidy among human sporadic colorectal adenomas and KRAS2 and APC mutations were not independent. Additionally, we investigated if 1p34–36 deletions by dual target FISH were associated with aneuploidy. Among 116 adenomas, 29 were DNA aneuploid by flow cytometry (25% and 29 were KRAS2 mutated (25%. KRAS2 mutations were associated with aneuploidy (P=0.02. However, while G–C and G–T transversions were strongly associated with DNA aneuploidy (P=0.007, G–A transitions were not. Within a second series of 61 adenomas, we found, instead, that APC mutational status and aneuploidy by flow cytometry were not associated. However, a statistically significant association was found with specific APC mutations, i.e., occurring in the mutation cluster region (MCR, codons 1200–1500 or downstream (P=0.016. Finally, the correlation of 1p34–36 deletions with flow cytometric and FISH detected aneuploidy was also significant (P=0.01. Specific KRAS2 and APC mutations and loss of genes in the 1p34–36 region appear associated with aneuploidy suggesting that these events are not independent and may cooperate in inducing human sporadic colorectal adenomas. A cause effect relationship between gene mutations and aneuploidy remains, however, to be demonstrated.

  19. Xeroderma Pigmentosum: Low Prevalence of Germline XPA Mutations in a Brazilian XP Population

    Directory of Open Access Journals (Sweden)

    Karina Miranda Santiago

    2015-04-01

    Full Text Available Xeroderma pigmentosum (XP is a rare autosomal recessive disorder characterized by DNA repair defects that cause photophobia, sunlight-induced cancers, and neurodegeneration. Prevalence of germline mutations in the nucleotide excision repair gene XPA vary significantly in different populations. No Brazilian patients have been reported to carry a germline mutation in this gene. In this study, the germline mutational status of XPA was determined in Brazilian patients exhibiting major clinical features of XP syndrome. The study was conducted on 27 unrelated patients from select Brazilian families. A biallelic inactivating transition mutation c.619C>T (p.Arg207Ter was identified in only one patient with a history of neurological impairment and mild skin abnormalities. These findings suggest that XP syndrome is rarely associated with inherited disease-causing XPA mutations in the Brazilian population. Additionally, this report demonstrates the effectiveness of genotype-phenotype correlation as a valuable tool to guide direct genetic screening.

  20. Novel de novo BRCA2 mutation in a patient with a family history of breast cancer

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Bisgaard, Marie Luise; Jønson, Lars;

    2008-01-01

    exhibiting a ductal carcinoma at the age of 40. METHODS: Variations were identified by denaturing high performance liquid chromatography (dHPLC) and sequencing of the BRCA1 and BRCA2 genes. The effect of the mutation on splicing was examined by exon trapping in COS-7 cells and by RT-PCR on RNA isolated from...... whole blood. The paternity was determined by single nucleotide polymorphism (SNP) microarray analysis. Parental origin of the de novo mutation was determined by establishing mutation-SNP haplotypes by variant specific PCR, while de novo and mosaic status was investigated by sequencing of DNA from...... and synthesis of a truncated BRCA2 protein. The aberrant splicing was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. The mutation was not found in any of the patient's parents or in the mother's carcinoma, showing it is a de novo mutation. Variant specific PCR indicates...

  1. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling

    DEFF Research Database (Denmark)

    Larsen, Martin J; Kruse, Torben A; Tan, Qihua;

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants...... tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority...

  2. Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer

    OpenAIRE

    Sakai, Kazuko; Yoneshige, Azusa; Ito, Akihiko; UEDA Yoji; Kondo, Satoshi; Nobumasa, Hitoshi; Fujita, Yoshihiko; TOGASHI, YOSUKE; Terashima, Masato; Velasco, Marco A.; Tomida, Shuta; Nishio, Kazuto

    2015-01-01

    We compared the performance of the 3D-Gene® mutation assay (3D-Gene® KRAS mutation assay kit) with the Scorpion-ARMS (therascreen® KRAS RGQ PCR Kit) and Luminex (MEBGEN™ KRAS kit) assays for the detection of KRAS mutations in formalin-fixed, paraffin-embedded tissue samples from 150 patients diagnosed with colorectal cancer. DNA was extracted from the paraffin-embedded tissue samples with or without macrodissection under hematoxylin and eosin staining and the KRAS mutation status was independ...

  3. Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Grossmann, Vera; Kern, Wolfgang; Harbich, Stefan; Alpermann, Tamara; Jeromin, Sabine; Schnittger, Susanne; Haferlach, Claudia; Haferlach, Torsten; Kohlmann, Alexander

    2011-01-01

    The runt-related transcription factor 1, RUNX1, is crucial in the development of myeloid and lymphoid cell lineages and has been reported to be mutated in myeloid malignancies in approximately 30% of cases. In this study, the mutational status of RUNX1 was investigated in 128 acute lymphoblastic leukemia patients. We detected a mutation rate of 18.3% (13 of 71) in patients with T-cell acute lymphoblastic leukemia, 3.8% (2 of 52) in patients with B-cell acute lymphoblastic leukemia and no muta...

  4. Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Haslam, K

    2012-02-01

    BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

  5. Detection of the EGFR mutation in exhaled breath condensate from a heavy smoker with squamous cell carcinoma of the lung.

    Science.gov (United States)

    Zhang, Dan; Takigawa, Nagio; Ochi, Nobuaki; Tanimoto, Yasushi; Noujima, Daisuke; Chen, Yan Yan; Tanimoto, Mitsune; Kiura, Katsuyuki

    2011-09-01

    A 61-year-old male smoker (40 pack-years) presented with right chest pain. Computed tomography of the chest revealed a cavitary mass in the right lower lobe. A transbronchial biopsy showed squamous cell carcinoma. We examined epidermal growth factor receptor (EGFR) mutations in exhaled breath condensate (EBC). The DNA extracted from his EBC showed a deletion mutation in exon 19. Subsequently, the del E746-A750 mutation in exon 19 in a transbronchial tissue specimen was confirmed. Although he underwent whole-brain irradiation against multiple brain metastases, he had paralysis of the left side of the body and his performance status was 3. The patient was treated with gefitinib. He had marked tumor regression and no symptoms. Although only a small percentage of heavy smokers with squamous cell carcinoma harbor EGFR mutations, they probably benefit from EGFR-tyrosine kinase inhibitors. EGFR mutation status in the patients having such clinical features might be examined. PMID:21684624

  6. Minisequencing mitochondrial DNA pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Carracedo Ángel

    2008-04-01

    Full Text Available Abstract Background There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations. Methods We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease. Results We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain patients carrying haplogroup J lineages (Fisher's Exact test, P-value Conclusion We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories.

  7. HNPCC: Six new pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Epplen Joerg T

    2004-06-01

    Full Text Available Abstract Background Hereditary non-polyposis colorectal cancer (HNPCC is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR. HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6. Methods Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out. Results We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6 resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702], three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298] and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]. All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H. Conclusions HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.

  8. KRAS and BRAF Mutation Detection: Is Immunohistochemistry a Possible Alternative to Molecular Biology in Colorectal Cancer?

    Directory of Open Access Journals (Sweden)

    Nicolas Piton

    2015-01-01

    Full Text Available KRAS genotyping is mandatory in metastatic colorectal cancer treatment prior to undertaking antiepidermal growth factor receptor (EGFR monoclonal antibody therapy. BRAF V600E mutation is often present in colorectal carcinoma with CpG island methylator phenotype and microsatellite instability. Currently, KRAS and BRAF evaluation is based on molecular biology techniques such as SNaPshot or Sanger sequencing. As molecular testing is performed on formalin-fixed paraffin-embedded (FFPE samples, immunodetection would appear to be an attractive alternative for detecting mutations. Thus, our objective was to assess the validity of KRAS and BRAF immunodetection of mutations compared with the genotyping reference method in colorectal adenocarcinoma. KRAS and BRAF genotyping was assessed by SNaPshot. A rabbit anti-human KRAS polyclonal antibody was tested on 33 FFPE colorectal tumor samples with known KRAS status. Additionally, a mouse anti-human BRAF monoclonal antibody was tested on 30 FFPE tumor samples with known BRAF status. KRAS immunostaining demonstrated both poor sensitivity (27% and specificity (64% in detecting KRAS mutation. Conversely, BRAF immunohistochemistry showed perfect sensitivity (100% and specificity (100% in detecting V600E mutation. Although molecular biology remains the reference method for detecting KRAS mutation, immunohistochemistry could be an attractive method for detecting BRAF V600E mutation in colorectal cancer.

  9. KRAS and BRAF Mutation Detection: Is Immunohistochemistry a Possible Alternative to Molecular Biology in Colorectal Cancer?

    Science.gov (United States)

    Piton, Nicolas; Borrini, Francesco; Bolognese, Antonio; Lamy, Aude; Sabourin, Jean-Christophe

    2015-01-01

    KRAS genotyping is mandatory in metastatic colorectal cancer treatment prior to undertaking antiepidermal growth factor receptor (EGFR) monoclonal antibody therapy. BRAF V600E mutation is often present in colorectal carcinoma with CpG island methylator phenotype and microsatellite instability. Currently, KRAS and BRAF evaluation is based on molecular biology techniques such as SNaPshot or Sanger sequencing. As molecular testing is performed on formalin-fixed paraffin-embedded (FFPE) samples, immunodetection would appear to be an attractive alternative for detecting mutations. Thus, our objective was to assess the validity of KRAS and BRAF immunodetection of mutations compared with the genotyping reference method in colorectal adenocarcinoma. KRAS and BRAF genotyping was assessed by SNaPshot. A rabbit anti-human KRAS polyclonal antibody was tested on 33 FFPE colorectal tumor samples with known KRAS status. Additionally, a mouse anti-human BRAF monoclonal antibody was tested on 30 FFPE tumor samples with known BRAF status. KRAS immunostaining demonstrated both poor sensitivity (27%) and specificity (64%) in detecting KRAS mutation. Conversely, BRAF immunohistochemistry showed perfect sensitivity (100%) and specificity (100%) in detecting V600E mutation. Although molecular biology remains the reference method for detecting KRAS mutation, immunohistochemistry could be an attractive method for detecting BRAF V600E mutation in colorectal cancer.

  10. Effect of co-inheritance of β-thalassemia and hemochromatosis mutations on iron overload.

    Science.gov (United States)

    López-Escribano, Herminio; Ferragut, Joana F; Parera, Maria M; Guix, Pilar; Castro, José A; Ramon, M Misericòrdia; Picornell, Antònia

    2012-01-01

    Co-inheritance of mutations in the HFE gene underlying hereditary hemocromatosis (HH) may play a role in the variability of iron status in patients with β-thalassemia (β-thal) minor. Different studies have yielded conflicting results: some suggest iron overload might arise from the interaction of the β-thal trait with homozygosity or even heterozygosity for HFE mutations and others that it was unrelated to the HFE genotype. Because of the high frequency of HFE mutations in the Balearic Islands, where the β-thal trait is also moderately common, it is of interest to evaluate the effect of the co-inheritance of mutations in both genes on the severity of iron loading. A retrospective analysis of 142 individuals heterozygous for β-thal was performed to investigate the effect of HFE mutations on iron status of these patients. No significant differences were detected between β-thal carriers with and without HFE mutations. These results suggest that in the Balearic population the β-thal trait does not tend to be aggravated by the co-inheritance of HFE mutations.

  11. Radiation mutation breeding

    International Nuclear Information System (INIS)

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected

  12. Radiation mutation breeding

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek

    1998-04-01

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected.

  13. Mutation breeding by ion implantation

    Science.gov (United States)

    Yu, Zengliang; Deng, Jianguo; He, Jianjun; Huo, Yuping; Wu, Yuejin; Wang, Xuedong; Lui, Guifu

    1991-07-01

    Ion implantation as a new mutagenic method has been used in the rice breeding program since 1986, and for mutation breeding of other crops later. It has been shown, in principle and in practice, that this method has many outstanding advantages: lower damage rate; higher mutation rate and wider mutational spectrum. Many new lines of rice with higher yield rate; broader disease resistance; shorter growing period but higher quality have been bred from ion beam induced mutants. Some of these lines have been utilized for the intersubspecies hybridization. Several new lines of cotton, wheat and other crops are now in breeding. Some biophysical effects of ion implantation for crop seeds have been studied.

  14. Induction of mutations in wheat

    International Nuclear Information System (INIS)

    Studies on toxicity of various mutagenic factors including gamma radiation, X-rays and fast neutrons and their optimal doses for valuble mutation breeding of bread winter, spring and durum wheat have been carried out. Data on sublethal doses of mutagens and chromosome aberration frequency for different doses of mutagens have been collected. It is observed that the greater general frequency of visible mutations by a mutagen does not ensure the greater relative yield of valuable mutations. In the course of the investigations, about 90 valuable mutant forms and mutant hybrids are selected for further breeding studies. (M.G.B.)

  15. Mutations induced by ultraviolet light

    Energy Technology Data Exchange (ETDEWEB)

    Pfeifer, Gerd P. [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States)]. E-mail: gpfeifer@coh.org; You, Young-Hyun [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States); Besaratinia, Ahmad [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States)

    2005-04-01

    The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms

  16. Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing.

    Science.gov (United States)

    Sakai, Kazuko; Tsurutani, Junji; Yamanaka, Takeharu; Yoneshige, Azusa; Ito, Akihiko; Togashi, Yosuke; De Velasco, Marco A; Terashima, Masato; Fujita, Yoshihiko; Tomida, Shuta; Tamura, Takao; Nakagawa, Kazuhiko; Nishio, Kazuto

    2015-01-01

    Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (α = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.

  17. Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing.

    Directory of Open Access Journals (Sweden)

    Kazuko Sakai

    Full Text Available Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (α = 2 x 10(-5. The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100. KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100. DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.

  18. The Relationship of the Factor V Leiden Mutation and Pregnancy Outcomes for Mother and Fetus

    Science.gov (United States)

    Dizon-Townson, Donna; Miller, Connie; Sibai, Baha; Spong, Catherine Y.; Thom, Elizabeth; Wendel, George; Wenstrom, Katharine; Samuels, Philip; Cotroneo, Margaret A.; Moawad, Atef; Sorokin, Yoram; Meis, Paul; Miodovnik, Menachem; O’Sullivan, Mary J.; Conway, Deborah; Wapner, Ronald J.; Gabbe, Steven G.

    2013-01-01

    Objective We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. Methods Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. Results One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0–2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02–0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were

  19. Markov models for accumulating mutations

    CERN Document Server

    Beerenwinkel, Niko

    2007-01-01

    We introduce and analyze a waiting time model for the accumulation of genetic changes. The continuous time conjunctive Bayesian network is defined by a partially ordered set of mutations and by the rate of fixation of each mutation. The partial order encodes constraints on the order in which mutations can fixate in the population, shedding light on the mutational pathways underlying the evolutionary process. We study a censored version of the model and derive equations for an EM algorithm to perform maximum likelihood estimation of the model parameters. We also show how to select the maximum likelihood poset. The model is applied to genetic data from different cancers and from drug resistant HIV samples, indicating implications for diagnosis and treatment.

  20. Mutation breeding newsletter. No. 12

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  1. Plant improvement by induced mutations

    International Nuclear Information System (INIS)

    Genetic variability is required for the plant breeder to select better traits. Mutation induction by radiation and other mutagens is a means of altering genes and creating genetic variability for the breeder. A list is given of the number of mutant varieties of vegetables, fruits and ornamental flowers. Data given in the tables show that using induced mutations, 227 improved varieties of agricultural crops have been developed and released to farmers in 35 different countries. The IAEA has been involved in fostering mutation breeding since its foundation through training and direct research support. The Joint FAO/IAEA Division has published the Mutation Breeding Newsletter for plant breeders all over the world to keep abreast with developments in this field

  2. Dynamical Mutation of Dark Energy

    CERN Document Server

    Abramo, L R; Liberato, L; Rosenfeld, R

    2007-01-01

    We discuss the intriguing possibility that dark energy may change its equation of state in situations where large dark energy fluctuations are present. We show indications of this dynamical mutation in some generic models of dark energy.

  3. Mutation breeding newsletter. No. 4

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  4. Mutation breeding newsletter. No. 3

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  5. Mutation breeding newsletter. No. 11

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  6. Mutation breeding newsletter. No. 23

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  7. Mutation breeding newsletter. No. 30

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  8. Mutation breeding newsletter. No. 29

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  9. Mutation breeding newsletter. No. 26

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  10. Mutation breeding newsletter. No. 2

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  11. Mutation breeding newsletter. No. 8

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  12. Mutation breeding newsletter. No. 16

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  13. Mutation breeding newsletter. No. 32

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  14. Mutation breeding newsletter. No. 15

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  15. Mutation Breeding Newsletter. No. 37

    International Nuclear Information System (INIS)

    This newsletter contains a brief account of FAO/IAEA meetings held in 1990 on plant breeding involving the use of induced mutations. It also features a list of commercially available plant cultivars produced by such techniques. Refs and tabs

  16. Mutation breeding newsletter. No. 7

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  17. Mutation breeding newsletter. No. 5

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and rea search abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  18. Mutation breeding newsletter. No. 28

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  19. Mutation breeding newsletter. No. 17

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  20. Mutation breeding newsletter. No. 24

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  1. Mutation breeding newsletter. No. 10

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  2. Mutation breeding newsletter. No. 9

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  3. Mutation breeding newsletter. No. 14

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  4. Mutation breeding newsletter. No. 25

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  5. Mutation breeding newsletter. No. 27

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents reports and research abstracts on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  6. Mutation breeding newsletter. No. 22

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  7. Mutation breeding newsletter. No. 13

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  8. Mutation breeding newsletter. No. 18

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  9. Mutation breeding newsletter. No. 31

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  10. Mutation breeding newsletter. No. 36

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted

  11. Mutation breeding newsletter. No. 19

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents new reports on mutation breeding programs using radiation or chemical mutagenesis to improve productivity, introduce disease resistance or induce morphological changes in crop plants

  12. Mutation breeding newsletter. No. 34

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents abstracts and short communications of research results on radiation and chemical induced mutation breeding projects. Positive traits such as disease resistance and increased productivity are highlighted

  13. Mutation breeding newsletter. No. 44

    International Nuclear Information System (INIS)

    This issue of the Newsletter presents research reports on the role of radiation induced mutation and chemical mutagens in improving productivity, disease resistance; cold and salinity tolerance of various crops and ornamental plants

  14. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben

    2015-01-01

    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  15. PPARγ mutations, lipodystrophy and diabetes.

    Science.gov (United States)

    Astapova, Olga; Leff, Todd

    2014-11-01

    The focus of this review is the lipodystrophy syndrome caused by mutation in the PPARγ nuclear receptor - partial familial lipodystrophy FPLD3. To provide a broader context for how these mutations act to generate the clinical features of partial lipodystrophy we will review the basic biology of PPARγ and also survey the set PPARγ genetic variants that do not cause lipodystrophy, but are nonetheless associated with clinically related syndromes, specifically type 2 diabetes.

  16. Induced mutations in sorghum improvement

    International Nuclear Information System (INIS)

    A critical review of different aspects of mutagen sensitivity, considering the importance of such factors as genotypic constitution of the material, pre- and post-treatment modifications, type of mutagen and dose, techniques of handling the material and treatment procedures to maximize the induction of mutations together with the scope of induced mutations in sorghum improvement is presented. Hydrazine was found to be a more effective and efficient mutagen for inducing chlorophyll and viable mutations in sorghum than ethyl methanesulphonate, methyl methanesulphonate or γ-rays. Ethyl methane-sulphonate among the alkylating agents and nitroso methyl urea among nitroso compounds were the most potent mutagens. The efficient radiation dose was within the 20-35 kr range whereas 0.015M was the effective dosage for hydrazine and ethylmethane sulphonate. The combination treatments of various physical and chemical mutagens failed to yield significant increase in the recovery of mutations, while cysteine post-treatments of γ-irradiated and hydrazine-treated material reduced seedling injury, seed sterility and increased the recovery of viable mutations compared to single treatments. There is scope for induced mutations in solving some of the current problems of sorghum improvement such as, increasing the recombination potential of tropical X temperate crosses, improving the nutritional quality of grain and forage sorghums, diversification of male sterile cytoplasmic sources, better understanding of mechanism of apomixis and augmenting the levels of resistance to sorghum insects, pests and diseases. (author)

  17. Genome Destabilizing Mutator Alleles Drive Specific Mutational Trajectories in Saccharomyces cerevisiae

    Science.gov (United States)

    Stirling, Peter C.; Shen, Yaoqing; Corbett, Richard; Jones, Steven J. M.; Hieter, Philip

    2014-01-01

    In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13–Stn1–Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target sequence. Together our data suggest that specific genome-instability mutations are sufficient to drive discrete mutational signatures, some of which share properties with mutation patterns seen in tumors. Thus, in a population of cells, genome-instability mutations could influence clonal evolution by establishing discrete mutational trajectories for genomes. PMID:24336748

  18. Conformation-specific inhibitors of Raf kinases.

    Science.gov (United States)

    Wang, Xiaolun; Schleicher, Kristin

    2013-01-01

    Since the discovery linking B-Raf mutations to human tumors in 2002, significant advances in the development of Raf inhibitors have been made, leading to the recent approval of two Raf inhibitor drugs. This chapter includes a brief introduction to B-Raf as a validated target and focuses on the three different binding modes observed with Raf small-molecule inhibitors. These various binding modes lock the Raf kinase in different conformations that impact the toxicity profiles of the inhibitors. Possible solutions to mitigate the side effects caused by inhibitor-induced dimerization are also discussed.

  19. Adaptive mutations produce resistance to ciprofloxacin.

    OpenAIRE

    Riesenfeld, C; Everett, M.; Piddock, L J; Hall, B G

    1997-01-01

    Mutation to ciprofloxacin resistance continually occurred in nondividing Escherichia coli cells during a 7-day exposure to ciprofloxacin in agar, while no accumulation of rifampin resistance mutations was detected in those cells. We propose that the resistance mutations result from adaptive mutations, which preferentially produce phenotypes that promote growth in nondividing cells.

  20. The presence of two different infantile Tay-Sachs disease mutations in a Cajun population

    Energy Technology Data Exchange (ETDEWEB)

    McDowell, G.A.; Blitzer, M.G. (Univ. of Maryland School of Medicine, Baltimore, MD (United States)); Mules, E.H. (Kennedy Krieger Institute, Baltimore, MD (United States)); Fabacher, P. (Office of Public Health, Shreveport, LA (United States)); Shapira, E. (Tulane Univ. of School of Medicine, New Orleans, LA (United States))

    1992-11-01

    A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the [beta]-hexosaminidase A (Hex A) [alpha]-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the [alpha]-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families. 29 refs., 4 figs.

  1. Clinicopathologic Analysis of Angioimmunoblastic T-cell Lymphoma With or Without RHOA G17V Mutation Using Formalin-fixed Paraffin-embedded Sections.

    Science.gov (United States)

    Nagao, Ryoko; Kikuti, Yara Yukie; Carreras, Joaquim; Kikuchi, Tomoki; Miyaoka, Masashi; Matsushita, Hiromichi; Kojima, Minoru; Ando, Kiyoshi; Sakata-Yanagimoto, Mamiko; Chiba, Shigeru; Nakamura, Naoya

    2016-08-01

    Angioimmunoblastic T-cell lymphoma (AITL) is an infrequent subtype of peripheral T-cell lymphoma derived from follicular helper T cells. Recently, a somatic G17V RHOA gene mutation has been reported. In this article, we examined the RHOA G17V mutation in 18 cases of AITL by 3 different techniques of Sanger sequencing, fully automated SNP genotyping, and deep sequencing, using routine diagnostic formalin-fixed paraffin-embedded tissue. The RHOA G17V mutation was detected in 10 cases (56%). Among the 10 mutated cases, 8 cases were detected by all 3 methods. The status of RHOA mutation was subsequently compared with the clinicopathologic characteristics of AITL. RHOA-mutated AITL (10 cases) was clinically characterized by high serum IL-2R and a poor ECOG performance status. By immunohistochemistry, expression of CD10, PD-1, CXCL13, and CCR4 and a wide distribution of CD21(+) follicular dendritic cells were observed in RHOA-mutated cases. Among these, CCR4 expression and the CD21(+) network in RHOA-mutated AITL cases were more extensive than in the RHOA mutation-negative AITL cases (P<0.05). Thus, RHOA-mutated AITL cases are more characteristic of follicular helper T cells, and the presence of such a mutation is an important marker for AITL. PMID:27158755

  2. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing

    Directory of Open Access Journals (Sweden)

    Uta Francke

    2013-02-01

    -positive participants appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered.

  3. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing.

    Science.gov (United States)

    Francke, Uta; Dijamco, Cheri; Kiefer, Amy K; Eriksson, Nicholas; Moiseff, Bianca; Tung, Joyce Y; Mountain, Joanna L

    2013-01-01

    appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered. PMID:23638402

  4. Sodium ion channel mutations in glioblastoma patients correlate with shorter survival

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2011-02-01

    Full Text Available Abstract Background Glioblastoma Multiforme (GBM is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation. Results Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs. Conclusions These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.

  5. Routine implementation of EGFR mutation testing in clinical practice in Flanders: 'HERMES' project.

    Science.gov (United States)

    Janssens, A; De Droogh, E; Lefebure, A; Kockx, M; Pauwels, P; Germonpre, P; van Meerbeeck, J P

    2014-04-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the recommended first-line treatment in metastatic EGFR-mutation-positive non-small cell lung cancer (NSCLC) patients. Such a personalized treatment requires fast EGFR mutation testing. This study was performed to determine the turn around time (TAT) for EGFR mutation testing on tumour samples of NSCLC in the clinical care in the region of Antwerp (Belgium). The secondary aim was to determine the frequency of EGFR mutations in this Flemish population. Tumour tissue was prospectively obtained from lung cancer patients in participating hospitals and sent from the local pathology laboratory (lab) to two central laboratories (labs) where EGFR-mutation analysis was performed. Results were returned from the central labs to the clinicians and the local pathology lab. TAT was defined as the interval between the request from the oncologist and the result obtained by the oncologist. One hundred and seven specimens were analysed. The clinician got the result from the local lab in a median time of 10 days (3-37 days) and from the central lab in 9 days (3-29 days). We detected seven mutations (7%) in this study population, all occurring in tumours with an adenocarcinoma histology, four (57%) in men and five (71%) in (ex-)smokers. There were six exon 19 deletions and one L858R mutation. It is possible to implement EGFR-mutation testing with timely reporting of the EGFR-mutation status. EGFR-mutation occurs in 7% of Flemish patients with NSCLC. Patients with advanced non-squamous NSCLC should be tested for EGFR mutation regardless of their gender and smoking history. PMID:24724747

  6. Lack of mutation-histopathology correlation in a patient with Proteus syndrome.

    Science.gov (United States)

    Doucet, Meggie E; Bloomhardt, Hadley M; Moroz, Krzysztof; Lindhurst, Marjorie J; Biesecker, Leslie G

    2016-06-01

    Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth, and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17%, respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample whereas the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders. © 2016 Wiley Periodicals, Inc.

  7. Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer

    Science.gov (United States)

    Galardi, Francesca; Pestrin, Marta; Gabellini, Stefano; Simi, Lisa; Mancini, Irene; Vannucchi, Alessandro Maria; Pazzagli, Mario; Di Leo, Angelo; Pinzani, Pamela

    2016-01-01

    Circulating Tumor Cells (CTCs) represent a “liquid biopsy” of the tumor potentially allowing real-time monitoring of cancer biology and therapies in individual patients. The purpose of the study was to explore the applicability of a protocol for the molecular characterization of single CTCs by Next Generation Sequencing (NGS) in order to investigate cell heterogeneity and provide a tool for a personalized medicine approach. CTCs were enriched and enumerated by CellSearch in blood from four metastatic breast cancer patients and singularly isolated by DEPArray. Upon whole genome amplification 3–5 single CTCs per patient were analyzed by NGS for 50 cancer-related genes. We found 51 sequence variants in 25 genes. We observed inter- and intra-patient heterogeneity in the mutational status of CTCs. The highest number of somatic deleterious mutations was found in the gene TP53, whose mutation is associated with adverse prognosis in breast cancer. The discordance between the mutational status of the primary tumor and CTCs observed in 3 patients suggests that, in advanced stages of cancer, CTC characteristics are more closely linked to the dynamic modifications of the disease status. In one patient the mutational profiles of CTCs before and during treatment shared only few sequence variants. This study supports the applicability of a non-invasive approach based on the liquid biopsy in metastatic breast cancer patients which, in perspective, should allow investigating the clonal evolution of the tumor for the development of new therapeutic strategies in precision medicine. PMID:27034166

  8. Common Β- Thalassaemia Mutations in

    Directory of Open Access Journals (Sweden)

    P Azarfam

    2005-01-01

    Full Text Available Introduction: β –Thalassaemia was first explained by Thomas Cooly as Cooly’s anaemia in 1925. The β- thalassaemias are hereditary autosomal disorders with decreased or absent β-globin chain synthesis. The most common genetic defects in β-thalassaemias are caused by point mutations, micro deletions or insertions within the β-globin gene. Material and Methods: In this research , 142 blood samples (64 from childrens hospital of Tabriz , 15 samples from Shahid Gazi hospital of Tabriz , 18 from Urumia and 45 samples from Aliasghar hospital of Ardebil were taken from thalassaemic patients (who were previously diagnosed .Then 117 non-familial samples were selected . The DNA of the lymphocytes of blood samples was extracted by boiling and Proteinase K- SDS procedure, and mutations were detected by ARMS-PCR methods. Results: From the results obtained, eleven most common mutations,most of which were Mediterranean mutations were detected as follows; IVS-I-110(G-A, IVS-I-1(G-A ،IVS-I-5(G-C ,Frameshift Codon 44 (-C,( codon5(-CT,IVS-1-6(T-C, IVS-I-25(-25bp del ,Frameshift 8.9 (+G ,IVS-II-1(G-A ,Codon 39(C-T, Codon 30(G-C the mutations of the samples were defined. The results showed that Frameshift 8.9 (+G, IVS-I-110 (G-A ,IVS-II-I(G-A, IVS-I-5(G-C, IVS-I-1(G-A , Frameshift Codon 44(-C , codon5(-CT , IVS-1-6(T-C , IVS-I-25(-25bp del with a frequency of 29.9%, 25.47%,17.83%, 7.00%, 6.36% , 6.63% , 3.8% , 2.5% , 0.63% represented the most common mutations in North - west Iran. No mutations in Codon 39(C-T and Codon 30(G-C were detected. Cunclusion: The frequency of the same mutations in patients from North - West of Iran seems to be different as compared to other regions like Turkey, Pakistan, Lebanon and Fars province of Iran. The pattern of mutations in this region is more or less the same as in the Mediterranean region, but different from South west Asia and East Asia.

  9. Plant mutation reports. Vol. 1, No. 1, May 2006

    International Nuclear Information System (INIS)

    current status of induced mutations in rice germplasm enhancement, new variety development and functional genomics studies, and future perspectives of nuclear and related techniques in rice breeding and genetics. The Agency through RCA Project RAS/5/040 and National TC Projects VIE/5/014 and PAK/5/042, sponsored 15 participants. The host institute, the Institute of Radiation Breeding, National Institute of Agrobiological Resources, Japan, also invited and sponsored 5 Japanese participants. The participants presented their work on rice mutation breeding, new mutation techniques, biological basis of induced mutations, novel mutants for rice improvement and functional genomics research. Inside this issue, you will find the complete papers of some of the presentations. You will not only have an overview of the application of mutation techniques in rice breeding in these countries, but you will also be able to envision the future perspectives of nuclear techniques in rice improvement. We also included a few papers that were not presented in the meeting but are relevant to this theme and are beneficial for you to get a broader view. Based on my communications with these authors and my understanding of these papers, I got the following impressions on mutation techniques in rice improvement which I would like to share with you: (1) Mutation techniques can be successfully deployed even in institutes with limited infrastructure and laboratory facilities, a common situation in developing countries, which is a very important feature that made this technology widely accepted in almost all countries; (2) Mutation techniques have proven not only useful for improving agronomic traits, i.e., yield, plant height, growth duration, etc, but also for enhancing resistance to biotic stress such as disease and insect pests and tolerance to abiotic stress such as salinity and acidic soil; (3) Mutation techniques have also proven very useful in quality improvement, i.e. development of rice

  10. [Founder mutation in Lynch syndrome].

    Science.gov (United States)

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos

    2016-01-01

    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

  11. [Founder mutation in Lynch syndrome].

    Science.gov (United States)

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos

    2016-01-01

    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments. PMID:27295708

  12. Paternally Inherited IGF2 Mutation and Growth Restriction.

    Science.gov (United States)

    Begemann, Matthias; Zirn, Birgit; Santen, Gijs; Wirthgen, Elisa; Soellner, Lukas; Büttel, Hans-Martin; Schweizer, Roland; van Workum, Wilbert; Binder, Gerhard; Eggermann, Thomas

    2015-07-23

    In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.).

  13. Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development.

    NARCIS (Netherlands)

    Thunnissen, F.B.J.M.; Prinsen, C.; Hol, B.; Drift, M.A. van der; Vesin, A.; Brambilla, C.; Montuenga, L.; Field, J.K.

    2012-01-01

    BACKGROUND: In a European multicenter prospective study patients with lung cancer were interviewed for smoking history and biological samples centrally collected. The aim of this study was to compare KRAS mutation analysis with smoking status at the time of diagnosis. METHODS: A nested case-study wa

  14. Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines

    DEFF Research Database (Denmark)

    Liu, Ying; Bodmer, Walter F

    2006-01-01

    A comprehensive analysis of the TP53 gene and its protein status was carried out on a panel of 56 colorectal cancer cell lines. This analysis was based on a combination of denaturing HPLC mutation screening of all exons of the p53 gene, sequencing the cDNA, and assessing the function of the p53 p...

  15. DGKI Methylation Status Modulates the Prognostic Value of MGMT in Glioblastoma Patients Treated with Combined Radio-Chemotherapy with Temozolomide

    OpenAIRE

    Amandine Etcheverry; Marc Aubry; Ahmed Idbaih; Elodie Vauleon; Yannick Marie; Philippe Menei; Rachel Boniface; Dominique Figarella-Branger; Lucie Karayan-Tapon; Veronique Quillien; Marc Sanson; Marie de Tayrac; Jean-Yves Delattre; Jean Mosser

    2014-01-01

    BACKGROUND: Consistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors tha...

  16. Subclinical Inflammatory Status in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Alessio Cortelazzo

    2014-01-01

    Full Text Available Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR in stage II (i.e., “pseudo-autistic” RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions. Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P<0.0001 were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63. The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6 spots or negative (n=9 spots, and to a lesser extent as proteins involved in the immune system (n=2 spots, with some proteins having overlapping functions on metabolism (n=7 spots. The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

  17. Quantum dots immunofluorescence histochemical detection of EGFR gene mutations in the non-small cell lung cancers using mutation-specific antibodies

    Directory of Open Access Journals (Sweden)

    Qu YG

    2014-12-01

    Full Text Available Yan-Gang Qu,1 Qian Zhang,2 Qi Pan,3 Xian-Da Zhao,4 Yan-Hua Huang,2 Fu-Chun Chen,3 Hong-Lei Chen41Department of Pathology, The Central Hospital of Enshi Autonomous Prefecture, Enshi, 2Department of Molecular Pathology, Wuhan Nano Tumor Diagnosis Engineering Research Center, Wuhan, Hubei, People’s Republic of China; 3Department of Thoracosurgery, Traditional Chinese Medical Hospital of Wenling, Wenling, Zhejiang, People’s Republic of China; 4Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, People’s Republic of ChinaBackground: Epidermal growth factor receptor (EGFR mutation status plays an important role in therapeutic decision making for non-small cell lung cancer (NSCLC patients. Since EGFR mutation-specific antibodies (E746-A750del and L858R have been developed, EGFR mutation detection by immunohistochemistry (IHC is a suitable screening test. On this basis, we want to establish a new screening test, quantum dots immunofluorescence histochemistry (QDs-IHC, to assess EGFR gene mutation in NSCLC tissues, and we compared it to traditional IHC and amplification refractory mutation system (ARMS.Materials and methods: EGFR gene mutations were detected by QDs-IHC, IHC, and ADx-ARMS in 65 cases of NSCLC composed of 55 formalin-fixed, paraffin-embedded specimens and ten pleural effusion cell blocks, including 13 squamous cell carcinomas, two adenosquamous carcinomas, and 50 adenocarcinomas.Results: Positive rates of EGFR gene mutations detected by QDs-IHC, IHC, and ADx-ARMS were 40.0%, 36.9%, and 46.2%, respectively, in 65 cases of NSCLC patients. The sensitivity of QDs-IHC when detecting EGFR mutations, as compared to ADx-ARMS, was 86.7% (26/30; the specificity for both antibodies was 100.0% (26/26. IHC sensitivity was 80.0% (24/30 and the specificity was 92.31% (24/26. When detecting EGFR mutations, QDs-IHC and ADx-ARMS had perfect consistency (κ=0.882; P<0.01. Excellent agreement was observed

  18. Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP

    DEFF Research Database (Denmark)

    Peraldi, P; Frödin, M; Barnier, J V;

    1995-01-01

    In PC12 cells, cAMP stimulates the MAP kinase pathway by an unknown mechanism. Firstly, we examined the role of calcium ion mobilization and of protein kinase C in cAMP-stimulated MAP kinase activation. We show that cAMP stimulates p44mapk independently of these events. Secondly, we studied the r...

  19. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark

    DEFF Research Database (Denmark)

    Soegaard, M.; Kjaer, S.K.; Cox, M.;

    2008-01-01

    PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze...... the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors....... RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations...

  20. Plant Mutation Reports, Vol. 3, No. 1, July 2013

    International Nuclear Information System (INIS)

    your submissions of officially released mutant varieties to our Mutant Varieties Database (MVD). This database is unique and functions as a witness for the useful application of nuclear technology in food and agriculture. Currently the database lists more than 3200 released mutant varieties in more than 200 crop species and the number of plant species subject to mutagenesis also continues to rise. The MVD is currently being improved to facilitate submission of information and to provide more advanced search and data analysis tools. As to the current and final regular volume of PMR, I am happy that we can present an interesting mixture of two short notes on the development of new mutant varieties of rice in India, a review on the current status and trends in cassava mutation breeding and four research articles dealing with various topics in plant mutation. One of the articles addresses the characterization of various types of mutations in wheat as a resource for functional genomics, thus giving an example of the trend in broadening the use of mutation induction. Another article reports on the nature of molecular variation induced by gamma irradiation of barley as analysed by Amplified Fragment Length Polymorphisms (AFLPs) and Single Sequence Repeats (SSRs). This issue of PMR also gives a forum for results produced by a recently completed CRP on ''Molecular Tools for Quality Improvement in Vegetatively Propagated Crops Including Banana and Cassava''. Reports are included on the production of haploid tissue of the diploid Musa species M. acuminata cv. 'Matti' and on the analysis of carotenoid-protein content variation in pigmented cassava storage roots and its implication for traditional breeding strategies and use of induced mutations

  1. PROMISES FOR TREATING COLON CANCER PATIENTS WITH BRAF GENE MUTATION

    Directory of Open Access Journals (Sweden)

    M. Yu. Fedyanin

    2014-01-01

    Full Text Available Colon cancer represents a heterogenous disease group, which differ by cancerogenesis mechanisms, molecular alterations, prognosis and treatment possibilities. In modern clinical practice assessment of KRAS and NRAS genes status is already necessary in order to prescribe anti-EGFR treatment for metastatic disease. A separate poor prognosis group are patients with BRAF mutation. In this review we will focus on biological features of BRAF-mutant colorectal cancer, its epidemiology, clinical features on different stages, treatment choice and promising new treatment possibilities.

  2. Detection and Analysis of EGFR and KRAS Mutations 
in the Patients with Lung Squamous Cell Carcinomas

    Directory of Open Access Journals (Sweden)

    Hui ZHANG

    2015-10-01

    Full Text Available Background and objective Activating mutations in epidermal growth factor receptor (EGFR and KRAS are important markers in non-small cell lung cancer. However, EGFR and KRAS gene mutations in lung squamous cell carcinoma are rarely reported. The aim of this study was to analyze EGFR and KRAS gene mutation rate and their relationship with clinical features in patients with lung squamous cell carcinomas. Methods A total of 139 patients undergoing treatment for naïve lung squamous cell carcinomas with tumor tissue samples available for testing were recruited. EGFR and KRAS mutation statuses of the tumor samples were detected using a mutant enriched liquid chip. Results Of the 139 cases of lung squamous cell carcinoma, EGFR mutations were detected in 25 cases (18%, KRAS mutations were detected in 7 cases (5%, and the presence of both EGFR and KRAS mutations was detected in 1 case (0.7%. EGFR mutations occurred more often in females than in males (33.3% vs 16.5% and in patients that never smoked than in those who smoke (29.6% vs 16.1%. However, the difference did not reach statistical significance (P>0.05. No significant differences were observed in age, stage, and different biopsy type. KRAS mutations occurred more often in males than in females (5.5% vs 0%, but the difference did not reach statistical significance (P>0.05. No significant differences were observed in age, stage, different biopsy type, and smoking status (P>0.05. Conclusion EGFR and KRAS mutations were low in lung squamous cell carcinomas, and had no significant correlation with clinical features. Before using tyrosine kinase inhibitor targeted therapy, EGFR and KRAS mutations should be detected in patients with lung squamous cell carcinomas.

  3. Mutation Analysis of H3F3A and H3F3B as a Diagnostic Tool for Giant Cell Tumor of Bone and Chondroblastoma.

    Science.gov (United States)

    Cleven, Arjen H G; Höcker, Saskia; Briaire-de Bruijn, Inge; Szuhai, Karoly; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

    2015-11-01

    Specific H3F3A driver mutations and IDH2 mutations were recently described in giant cell tumor of bone (GCTB) and H3F3B driver mutations in chondroblastoma; these may be helpful as a diagnostic tool for giant cell-containing tumors of the bone. Using Sanger sequencing, we determined the frequency of H3F3A, H3F3B, IDH1, and IDH2 mutations in GCTBs (n=60), chondroblastomas (n=12), and other giant cell-containing tumors (n=24), including aneurysmal bone cyst, chondromyxoid fibroma, and telangiectatic osteosarcoma. To find an easy applicable marker for H3F3A mutation status, H3K36 trimethylation and ATRX expression were correlated with H3F3A mutations. In total, 69% of all GCTBs harbored an H3F3A (G34W/V) mutation compared with 0% of all other giant cell-containing tumors (Pchondroblastomas showed an H3F3B (K36M) mutation compared with 0% of other giant cell-containing tumors (Pchondroblastoma from other giant cell-containing tumors. Although H3K36 trimethylation and ATRX immunohistochemistry cannot be used as surrogate markers for H3F3A mutation status, mutations in H3F3A are associated with increased H3K36 trimethylation, suggesting that methylation at this residue may play a role in the etiology of the disease. PMID:26457357

  4. Mutation Analysis of H3F3A and H3F3B as a Diagnostic Tool for Giant Cell Tumor of Bone and Chondroblastoma.

    Science.gov (United States)

    Cleven, Arjen H G; Höcker, Saskia; Briaire-de Bruijn, Inge; Szuhai, Karoly; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

    2015-11-01

    Specific H3F3A driver mutations and IDH2 mutations were recently described in giant cell tumor of bone (GCTB) and H3F3B driver mutations in chondroblastoma; these may be helpful as a diagnostic tool for giant cell-containing tumors of the bone. Using Sanger sequencing, we determined the frequency of H3F3A, H3F3B, IDH1, and IDH2 mutations in GCTBs (n=60), chondroblastomas (n=12), and other giant cell-containing tumors (n=24), including aneurysmal bone cyst, chondromyxoid fibroma, and telangiectatic osteosarcoma. To find an easy applicable marker for H3F3A mutation status, H3K36 trimethylation and ATRX expression were correlated with H3F3A mutations. In total, 69% of all GCTBs harbored an H3F3A (G34W/V) mutation compared with 0% of all other giant cell-containing tumors (Pchondroblastomas showed an H3F3B (K36M) mutation compared with 0% of other giant cell-containing tumors (Pchondroblastoma from other giant cell-containing tumors. Although H3K36 trimethylation and ATRX immunohistochemistry cannot be used as surrogate markers for H3F3A mutation status, mutations in H3F3A are associated with increased H3K36 trimethylation, suggesting that methylation at this residue may play a role in the etiology of the disease.

  5. Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations

    Directory of Open Access Journals (Sweden)

    Vassos Neocleous

    2014-01-01

    Full Text Available Objectives: The objective was to seek evidence on the prevalence and consequences of heterozygous CYP21A2 mutations in girls, adolescent, and adult females with clinical manifestation of androgen excess. Patients and Methods: The study included 64 girls diagnosed with premature adrenarche (PA in childhood and 141 females with clinical hyperandrogenemia manifested in adolescence or adulthood. Direct DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to identify mutations in the CYP21A2 gene. Results: (1 Thirty-four patients were diagnosed with nonclassical-congenital adrenal hyperplasia (NC-CAH based on the 17-hydroxyprogesterone (17-OHP levels and the presence of two mutations in CYP21A2 and therefore were excluded from the study, 66 were found to be heterozygotes and finally 105 had no identifiable mutations. The most frequent mutations among the carriers were the mild p.Val281 Leu and p.Qln318stop. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281 Leu. (2 A notable increased allelic frequency for the known p.Asn493 Ser polymorphism was observed in the pool of females with hyperandrogenemia in whom no mutation was identified. (3 In girls, who presented early with PA, 26.6% were diagnosed with NC-CAH and carried two mutations, 28.7% were identified as heterozygotes 43.7% had no identifiable genetic defect in the translated region of the CYP21A2 gene. On the contrary, in the group of 141 females with late onset hyperandrogenemia, the presence of 2 mutations was detected in 12%, 1 mutation in 33.4% and no mutation in 54.6%. Conclusions: The carrier status for 21-OHD, may be an important factor in the variable phenotype of hyperandrogenism and may be a contributing factor for the early manifestation of the disease.

  6. Frameshift mutation of WISP3 gene and its regional heterogeneity in gastric and colorectal cancers.

    Science.gov (United States)

    Lee, Ju Hwa; Choi, Youn Jin; Je, Eun Mi; Kim, Ho Shik; Yoo, Nam Jin; Lee, Sug Hyung

    2016-04-01

    WISP3 is involved in many cancer-related processes including epithelial-mesenchymal transition, cell death, invasion, and metastasis and is considered a tumor suppressor. The aim of our study was to find whether WISP3 gene was mutated and expressionally altered in gastric (GC) and colorectal cancers (CRCs). WISP3 gene possesses a mononucleotide repeat in the coding sequence that could be mutated in cancers with high microsatellite instability (MSI-H). We analyzed 79 GCs and 156 CRCs, and found that GCs (8.8%) and CRCs (10.5%) with MSI-H, but not those with microsatellite stable/low MSI, harbored a frameshift mutation. We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the WISP3 mutation exhibited regional ITH in 25% of the CRCs. In immunohistochemistry, loss of WISP3 expression was identified in 24% of GCs and 21% of CRCs. The loss of expression was more common in those with WISP3 mutation than with wild-type WISP3 and those with MSI-H than with microsatellite stable/low MSI. Our data indicate that WISP3 harbored not only frameshift mutation but also mutational ITH and loss of expression, which together might play a role in tumorigenesis of GC and CRC with MSI-H by inhibiting tumor suppressor functions of WISP3. Our data also suggest that mutation analysis in multiregions is needed for a proper evaluation of mutation status in GC and CRC with MSI-H.

  7. In vitro resistance to interferon of hepatitis B virus with precore mutation

    Institute of Scientific and Technical Information of China (English)

    Yan Wang; Lai Wei; Dong Jiang; Xu Cong; Ran Fei; Jiang Xiao; Yu Wang

    2005-01-01

    AIM: Chronic hepatitis Bvirus (HBV) infection is predominantly treated with interferon alpha (IFN-α), which results in an efficient reduction of the viral load only in 20-40% of treated patients. Mutations at HBV precore prevail in different clinical status of HBV infection. The roles of precore mutation in the progression of chronic hepatitis and interferon sensitivity are still unknown. The aim of this study was to explore if there was any relationship between HBV precore mutation and sensitivity to interferon in vitro.METIODS: HBV replication-competent recombinant constructs with different patterns of precore mutations were developed. Then the recombinants were transiently transfected into hepatoma cell line (Huh7) by calcium phosphate transfection method. With or without IFN, viral products in culture medium were collected and quantified3 d after transfection.RESULTS: We obtained 4 recombinant constructs by orientation-cloning 1.2-fold-overlength HBV genome into pUC18 vector via the EcoRI and Hind Ⅲ and PCR mediated site-directed mutagenesis method. All the recombinants contained mutations within precore region. Huh7 cells transfected with recombinan ts secreted HBsAg and HBV particles into the cell culture medium, indicating that all the recombinants were replication-competent. By comparing the amount of HBV DNA in the medium, we found that HBV DNA in medium reflecting HBV replication efficiency was different in different recombinants. Recombinants containing precore mutation had fewer HBV DNAs in culture medium than wild type. This result showed that recombinants containing precore mutation had lower replication efficiency than wild type. HBV DNA was decreased in pUC18-HBV1.2-WT recombinants after IFN was added while others with precore mutations were not, indicating that HBV harboring precore mutation was less sensitive to IFN in cell culture system.CONCLUSION: These data indicate that HBV harboring precore mutation may be resistant to IFN in vitro.

  8. Correlation between 18F Fluorodeoxyglucose uptake and epidermal growth factor receptor mutations in advanced lung cancer

    International Nuclear Information System (INIS)

    Mutations in the epidermal growth factor receptor (EGFR)gene have been identified as potential targets for the treatment and prognostic factors for non small cell lung cancer (NSCLC). We assessed the correlation between fluorodeoxyglucose (FDG) uptake and EGFR mutations, as well as their prognostic implications. A total of 163 patients with pathologically confirmed NSCLC were enrolled (99 males and 64 females; median age, 60 years). All patients underwent FDG positron emission tomography before treatment, and genetic studies of EGFR mutations were performed. The maximum standardized uptake value (SUVmax)of the primary lung cancer was measured and normalized with regard to liver uptake. The SUVmax between the wild type and EGFR mutant groups was compared. Survival was evaluated according to SUVmax and EGFR mutation status. EGFR mutations were found in 57 patients (60.8%). The SUVmax tended to be higher in wild type than mutant tumors, but was not significantly different (11.1±5.7 vs. 9.8±4.4, P=0.103). The SUVmax was significantly lower in patients with an exon 19 mutation than in those with either an exon 21 mutation or wild type (P=0.003 and 0.009, respectively). The EGFR mutation showed prolonged overall survival (OS) compared to wild type tumors (P=0.004). There was no significant difference in survival according to SUVmax. Both OS and progression free survival of patients with a mutation in exon 19 were significant longer than in patients with wild type tumors. In patients with NSCLC, a mutation in exon 19 was associated with a lower SUVmax and is a reliable predictor for good survival

  9. Comparison of KRAS/BRAF mutations between primary tumors and serum in colorectal cancer: Biological and clinical implications.

    Science.gov (United States)

    Pu, Xingxiang; Pan, Zhizhong; Huang, Ying; Tian, Ying; Guo, Hongqiang; Wu, Lin; He, Xuexing; Chen, Xinggui; Zhang, Shaodan; Lin, Tongyu

    2013-01-01

    In colorectal cancer (CRC), KRAS and BRAF mutations in primary tumors are associated with resistance to anti-epidermal growth factor receptor (anti-EGFR)-based therapies. However, the correlation between KRAS/BRAF mutation in primary tumors and serum has not been well studied. To evaluate the degree of concordance of KRAS/BRAF mutations between the primary tumors and the matched serum samples in CRC, serum and tumor tissues were collected from 115 patients with CRC and KRAS/BRAF mutations were examined by nested polymerase chain reaction (PCR) and direct sequencing. BRAF mutations were present in 3.5% (4/115) of the primary tumor tissue samples and 0.87% (1/115) of the serum samples. In the 4 primary tumors with BRAF mutations, identical mutations were not observed in the corresponding serum samples (κ=-0.016). KRAS mutations were observed in 32.2% (37/115) of the primary tumors and 11.3% (13/115) of the serum samples. Of the 37 tumor cases with KRAS mutations, 9 had identical mutations in the corresponding serum sample, with a concordance rate of 24.3% (9/37). Discordance was observed in 32 (27.8%) patients. The concordance between KRAS mutations in the primary tumors and KRAS mutations in the matched serums was low (κ=0.231). The results of the present study suggest that the possibility of differences in the mutational status of KRAS/BRAF between primary tumors and matched serum samples should be considered when patients are selected for anti-EGFR-based therapies.

  10. TERT promoter mutations lead to high transcriptional activity under hypoxia and temozolomide treatment and predict poor prognosis in gliomas.

    Directory of Open Access Journals (Sweden)

    Chen Chen

    Full Text Available This study explored the effects of telomerase reverse transcriptase (TERT promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ treatment conditions, and investigated the status and prognostic value of these mutations in gliomas.The effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I-IV and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations.Mutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies.

  11. Induced mutation of Dendrobium orchid

    International Nuclear Information System (INIS)

    Dendrobiiim orchids serve as the main orchid cut flower export of Malaysia. The wide range of colour and forms presently available in the market are obtained through hybridisation. Induced mutation breeding program was initiated on a commercial variety Dendrobium 'Sonia Kai' to explore the possibilities of obtaining new colour and forms. Matured seeds from self pollination were cultured and irradiated at 35 Gy at the protocorm-like bodies (PLBS) stage. Selection of induced mutations was done after the first flowering of the plants regenerated from the irradiated protocorms. Results showed changes in flower colour, shape and size. Most of these chances are expressed in different combinations in the petals, sepals and lip of the flowers. Thus, resulting. in a very wide spectrum of mutations. Some of these chances are not stable. To date, mutants that showed stable characteristics changes are grouped into 11 categories based on flower colour and form. These results show that the combination of its vitro technique and induced mutation can be applied in orchid breeding to produce new interesting and attractive variety for the market

  12. Detection of frameshift mutations of RIZin gastric cancers with microsatellite instability

    Institute of Scientific and Technical Information of China (English)

    Kai-Feng Pan; You-Yong Lu; Wan-Guo Liu; Lian Zhang; Wei-Cheng You

    2004-01-01

    AIM: To study the frameshift mutations of the retinoblastomaprotein-interacting zinc finger gene RIZ in gastric cancer with microsatellite instability, and to identify two coding polyadenosine tracts of RIZ.METHODS: Frameshift mutations at (A)8 and (A)9 tracts of RIZwere detected in 70 human gastric cancer (HGC) specimens by DHPLC and DNA sequencing. Microsatelliteinstability (MSI) status was assessed by two mononucleotide markers, BAT26 and BAT25, by means of denaturing highperformance liquid chromatography (DHPLC).RESULTS: In 70 HGC samples, 8 (11.4%) were found positivefor instabilities at BAT26 and BAT25. In 7 of the 8 cases with instabilities at both BAT26 and BAT25 (MSI-H), 1 was unstable at BAT26 but stable at BAT25. Frameshift mutations were identified in 4 (57.1%) of the 7 samples with MSI-Hin the (A)9 tract of RIZ without mutations in the (A)8 tract.In contrast, frameshift mutations were found in neither of the polyadenosine tracts in 63 samples of MSI-L or MSI stable tumors. Pro704 LOH detection in 4 cases with frameshift mutations did not find LOH in these cases.CONCLUSION: Frameshift mutations of RIZ may play an important role in gastric cancers with MSI.

  13. Association between {sup 18}F-FDG avidity and the BRAF mutation in papillary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Suk Hyun; Han, Sang Won; Lee, Hyo Sang; Chae, Sun Young; Lee, Jong Jin; Song, Dong Eun; Ryu, Jin Sook [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2016-03-15

    The BRAF mutation, a potential prognostic factor in papillary thyroid carcinoma (PTC), is associated with a high expression of the glucose transporter gene. We investigated which clinicopathologic factors, including BRAF mutation status, influence {sup 18}F-fluoro-2-deoxyglucose ({sup 18}F-FDG) avidity. We retrospectively reviewed 55 patients who underwent BRAF analysis from biopsy-confirmed PTC and {sup 18}F-FDG positron emission tomography/computed tomography within 6 months before undergoing thyroid surgery from September 2008 to August 2014. Tumors were considered to be {sup 18}F-FDG avid if the uptake was greater than that of the liver. {sup 18}F-FDG uptake of PTCs was also analyzed semiquantitatively using SUV{sub max}. The association between {sup 18}F-FDG avidity and clinicopathologic variables (age, tumor size, perithyroidal extension, cervical lymph node status, and BRAF mutation status) was investigated. Twenty-nine (52.7 %) of 55 patients had {sup 18}F-FDG-avid PTCs. PTCs with the BRAF mutation showed higher {sup 18}F-FDG avidity (24/38, 63.2 %) than those without (5/17, 29.4 %). The BRAF mutation (p = 0.025) and tumor size (p = 0.003) were significantly associated with {sup 18}F-FDG avidity in univariate analysis, and the BRAF mutation status remained significant after adjusting for tumor size in multivariate analysis (p = 0.015). In the subgroup of tumor size ≥ 1 cm, the BRAF mutation was the only factor significantly associated with {sup 18}F-FDG avidity (p = 0.021). The mean SUV{sub max} of PTCs with the BRAF mutation was significantly higher than that of those without (4.89 ± 6.12 vs. 1.96 ± 1.10, p = 0.039). The BRAF mutation must be one of the most important factors influencing {sup 18}F-FDG avidity in PTCs, especially in those with a tumor size ≥ 1 cm.

  14. Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: Considerations from somatic mutations in microsatellite unstable (MSI gastrointestinal cancers

    Directory of Open Access Journals (Sweden)

    Elghalbzouri-Maghrani Elhaam

    2006-01-01

    Full Text Available Abstract Background The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI, somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. Results We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47% of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5–15 poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. Conclusion Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.

  15. Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma.

    Science.gov (United States)

    Jun, Sun-Young; Kim, Misung; Jin Gu, Mi; Kyung Bae, Young; Chang, Hee-Kyung; Sun Jung, Eun; Jang, Kee-Taek; Kim, Jihun; Yu, Eunsil; Woon Eom, Dae; Hong, Seung-Mo

    2016-04-01

    Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal

  16. Preoperative Assessment of TERT Promoter Mutation on Thyroid Core Needle Biopsies Supports Diagnosis of Malignancy and Addresses Surgical Strategy.

    Science.gov (United States)

    Crescenzi, A; Trimboli, P; Modica, D C; Taffon, C; Guidobaldi, L; Taccogna, S; Rainer, A; Trombetta, M; Papini, E; Zelano, G

    2016-03-01

    In the last decade, several molecular markers have been proposed to improve the diagnosis of thyroid nodules. Among these, mutations in the telomerase reverse transcriptase (TERT) promoter have been correlated to malignant tumors, characterized by highest recurrence and decreased patients' survival. This suggests an important role of TERT mutational analysis in the clinical diagnosis and management of thyroid cancer patients. The aim of the study was to demonstrate the adequacy of core needle biopsy (CNB) for the preoperative assessment of TERT mutational status, to reach a more accurate definition of malignancy and a more appropriate surgical planning. Indeed, CNB is gaining momentum for improving diagnosis of thyroid nodules deemed inconclusive by fine needle aspirate (FNA). The study included 50 patients submitted to CNB due to inconclusive FNA report. TERT mutational status was correlated with BRAF mutation, definitive histology, and post-operative TNM staging of the neoplasia. C228T mutation of the TERT promoter was reported in 10% of the papillary carcinomas (PTC) series. When compared with final histology, all cases harboring TERT mutation resulted as locally invasive PTCs. The prevalence of TERT mutated cases was 17.6% among locally advanced PTCs. TERT analysis on CNB allows the assessment of the pathological population on paraffin sections before DNA isolation, minimizing the risk of false negatives due to poor sampling that affects FNA, and gathering aggregate information about morphology and TERT mutational status. Data indicating a worse outcome of the tumor might be used to individualize treatment decision, surgical option, and follow-up design. PMID:25951319

  17. Tilting mutation of Brauer tree algebras

    CERN Document Server

    Aihara, T

    2010-01-01

    We define tilting mutations of symmetric algebras as the endomorphism algebras of Okuyama-Rickard complexes. For Brauer tree algebras, we give an explicit description of the change of Brauer trees under mutation.

  18. Prevalent mutations in fatty acid oxidation disorders

    DEFF Research Database (Denmark)

    Gregersen, N; Andresen, B S; Bross, P

    2000-01-01

    UNLABELLED: The mutational spectrum in a given disease-associated gene is often comprised of a large number of different mutations, of which a single or a few are present in a large proportion of diseased individuals. Such prevalent mutations are known in four genes of the fatty acid oxidation...... carrying the prevalent 985A > G mutation are at risk of developing life-threatening attacks. In SCAD/ethylmalonic aciduria, on the other hand, the presence of the prevalent susceptibility variations, 625A and 511T, in the SCAD gene seems to require additional genetic and cellular factors to be present...... in order to result in a phenotype. For the prevalent mutations in the LCHAD and CPT II genes further data are needed to evaluate the penetrance and risk of manifest disease when carrying these mutations. CONCLUSION: Assessment of the prevalence of a prevalent mutation in the mutation spectrum...

  19. Identifying driver mutations in sequenced cancer genomes

    DEFF Research Database (Denmark)

    Raphael, Benjamin J; Dobson, Jason R; Oesper, Layla;

    2014-01-01

    High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise......, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA...... sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein...

  20. Manual on mutation breeding. 2. ed.

    International Nuclear Information System (INIS)

    The manual is a compilation of work done on the use of induced mutations in plant breeding, and presents general methods and techniques in this field. The use of chemical mutagens and ionizing radiations (X-rays, gamma rays, α- and β-particles, protons, neutrons) are described as well as the effects of these mutagens. The different types of mutations achieved can be divided into genome mutations, chromosome mutations and extra nuclear mutations. Separate chapters deal with mutation techniques in breeding seed-propagated species and asexually propagated plants (examples of development of cultivars given). Plant characters which can be improved by mutation breeding include yield, ripening time, growth habit, disease resistance and tolerance to environmental factors (temperature, salinity etc.). The use of mutagens for some specific plant breeding problems is discussed and attention is also paid to somatic cell genetics in connection with induced mutations. The manual contains a comprehensive bibliography (60 p. references) and a subject index

  1. USCIS My Case Status

    Data.gov (United States)

    Department of Homeland Security — USCIS provide a way for the public who applied for U.S. citizenship to check the status of their application online. To view the status of a case, the application...

  2. Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer

    International Nuclear Information System (INIS)

    The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population. We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test, with significance level of 0.05. In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation. The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in

  3. Developing Herbicide-Tolerant Crops from Mutations

    International Nuclear Information System (INIS)

    Several herbicide-tolerant crops have been developed and commercialized from herbicide-tolerant mutants obtained through chemical mutagenesis followed by herbicide selection or direct herbicide selection of spontaneous mutations. All mutations used in commercial herbicide-tolerant crops are derived from a single nucleotide substitution of genes that encode enzymes or proteins targeted by herbicides. The alleles of all commercial herbicide-tolerant mutations are incompletely-dominant except for the triazine-tolerant mutation. (author)

  4. Tracking Down Mutations Cell by Cell.

    Science.gov (United States)

    Kosik, Kenneth S

    2016-03-16

    Using somatic cell nuclear transfer, Hazen et al. (2016) examined clonally expanded single neurons for mutations and found ∼100 mutations from a variety of classes. Post-mitotic mutations in individual neurons represent an exploratory direction for finding fundamental origins of neurodegeneration. PMID:26985720

  5. Studies of human mutation rates: Progress report

    International Nuclear Information System (INIS)

    Progress was recorded between January 1 and July 1, 1987 on a project entitled ''Studies of Human Mutation Rates''. Studies underway include methodology for studying mutation at the DNA level, algorithms for automated analyses of two-dimensional polyacrylamide DNA gels, theoretical and applied population genetics, and studies of mutation frequency in A-bomb survivors

  6. BRAF Mutation is Associated with Improved Local Control of Melanoma Brain Metastases Treated with Gamma Knife Radiosurgery

    Directory of Open Access Journals (Sweden)

    Ian S Gallaher

    2016-05-01

    Full Text Available Objectives: Evidence has implicated a possible role of tumor mutation status on local control (LC with radiotherapy. BRAF is a proto-oncogene that is mutated in approximately 50% of patients with melanoma. We sought to analyze the influence of BRAF status on LC of melanoma brain metastases following Gamma Knife radiosurgery (GK. Methods: Among 125 patients treated with GK for melanoma brain metastases at our institution between 2006 and 2015, we identified 19 patients with 69 evaluable metastases whose BRAF mutation status was known and follow-up imaging was available. LC of individual metastases was compared based on BRAF mutation status using statistical techniques to control for measurements of multiple metastases within each patient. CNS progression was defined as either local failure or development of new lesions. Results: Of the 69 metastases, BRAF was mutated in 30, and wild-type in 39. With a median follow-up of 30 months for all patients and a median follow-up of 5.5 months for treated lesions, one-year LC was significantly better among metastases with mutated vs. wild-type BRAF (69% vs. 34%, RR = 0.3, 95% CI = 0.1-0.7, p = 0.01. BRAF mutation was found to be a significant predictor of LC after SRS in both univariate (RR=0.3, [95% CI 0.1-0.7, p = 0.01] and multivariate (RR=0.2, [95% CI 0.1-0.7, p = 0.01] analyses. There was also a trend towards improved CNS progression free survival (PFS at one year (26% vs. 0%, p=0.06, favoring BRAF-mutated patients. Conclusions: In this retrospective study, melanoma brain metastases treated with GK had significantly improved local control for patients with BRAF mutation vs. wild-type. Our data suggest that BRAF mutation may sensitize tumors to radiosurgery, and that BRAF wild-type tumors may be more radioresistant. Results: Of the 69 metastases, BRAF was mutated in 30, and wild-type in 39. With a median follow-up of 30 months for all patients and a median follow-up of 5.5 months for treated lesions

  7. Citrus Improvement Using Mutation Techniques

    International Nuclear Information System (INIS)

    Citrus cultivar improvement is hampered by several biological factors inherent to most citrus species. Facultative apomixis, self and cross-incompatibility, long juvenility period, and high heterozygosis are some of the vast arrays of impediments faced by citrus breeders in conventional hybridization. Since oranges and grapefruits are highly polyembryonic, the production of enough numbers of zygotic offspring for selection of superior genotypes of these species is basically impossible; hence, most commercially important cultivars of these species have originated through natural or induced mutation. Star Ruby, a deep-red-fleshed grapefruit, was developed by irradiation of Hudson grapefruit seeds with thermal neutrons. Unlike Hudson, which contains over 50 seeds per fruit, Star Ruby is nearly seedless. Hensz irradiated buds of Ruby Red grapefruit with thermal neutrons and a tree that originated from one of the buds produced fruits three times redder than Ruby Red. It was named A and I-1-48. Ten trees were propagated from A and I -1-48, and out of one of the trees, a budsport mutation was found producing fruits five times redder than Ruby Red. Called Rio Red, it is currently the variety of choice for Texas and is known worldwide for its sweetness, red flesh and beautiful blush. Currently, 37 years after A and I -1-48 was first propagated, the trees are still producing several budsport mutations. So far, in the 2007/2008 season, more than 100 new mutations were obtained from a 100-tree block. In the mandarin group, the existence of several monoembryonic cultivars facilitates conventional breeding, but still, induced mutation is part of most mandarin breeding programmes, and proprietary, new seedless cultivars have been produced in the US, Italy, Israel and elsewhere. Seedless mandarins produced by the University of California Riverside include Dayse, Fairchild, Encore, and Nova. The USDA-ARS, U.S. Horticultural Research Laboratory in Florida released a seedless

  8. Heuristic status polling

    Science.gov (United States)

    Archer, Charles J.; Blocksome, Michael A.; Heidelberger, Philip; Kumar, Sameer; Parker, Jeffrey J.; Ratterman, Joseph D.

    2011-06-07

    Methods, compute nodes, and computer program products are provided for heuristic status polling of a component in a computing system. Embodiments include receiving, by a polling module from a requesting application, a status request requesting status of a component; determining, by the polling module, whether an activity history for the component satisfies heuristic polling criteria; polling, by the polling module, the component for status if the activity history for the component satisfies the heuristic polling criteria; and not polling, by the polling module, the component for status if the activity history for the component does not satisfy the heuristic criteria.

  9. CDH1 germline mutation in hereditary gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Hai-Dan Wang; Jun Ren; Lian Zhang

    2004-01-01

    This paper provides a bird's-eye view both in preclinical and clinical aspects of E-cadherin germline gene (CDH1)in gastric cancer patients and their families. E-cadherin,a product of CDH1 gene, belonging to the functionally related trans-membrane glycoprotein family, is responsible for the Ca2+-dependent cell-cell adhesion mechanism and contributes to dissociation followed by acquisition of cell motility, which usually occurs in the first step of cancer invasion and metastasis. CDH1 gene germline mutation is common in many types of carcinoma,and occurs very frequent in hereditary gastric carcinoma (HGC) patients and their families. Recently, more and more researches support that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. So it is of great value to clarify its mechanisms both for understanding HGC pathogenesis and for clinical therapy, especially in China, where there are a high risk population of gastric cancer and a high HGC incidence rate. In this paper, recent researches on CDH1 gene mutation, especially its role in tumor genesis and progress of HGC, are reviewed, and advances in evaluation of its mutation status for HGC diagnosis, therapy and prognosis,are also discussed briefly.

  10. Value of {sup 18}F-FDG uptake on PET/CT and CEA level to predict epidermal growth factor receptor mutations in pulmonary adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ko, Kai-Hsiung; Hsu, Hsian-He; Chang, Wei-Chou; Hsu, Yi-Chih; Chang, Tsun-Hou [Tri-Service General Hospital and National Defense Medical Center, Department of Radiology, Taipei 114 (China); Huang, Tsai-Wang; Chang, Hung [Tri-Service General Hospital and National Defense Medical Center, Department of Thoracic Surgery, Taipei (China); Gao, Hong-Wei [Tri-Service General Hospital and National Defense Medical Center, Department of Pathology, Taipei (China); Shen, Daniel H.Y. [Tri-Service General Hospital and National Defense Medical Center, Department of Nuclear medicine, Taipei (China); Chu, Chi-Ming [Institute of Public Health, National Defense Medical Center and University, Section of Health Informatics, Taipei (China); Ho, Ching-Liang [Tri-Service General Hospital and National Defense Medical Center, Division of Hematology-Oncology, Department of Internal Medicine, Taipei (China)

    2014-10-15

    The identification of the mutation status of the epidermal growth factor receptor (EGFR) is important for the optimization of treatment in patients with pulmonary adenocarcinoma. The acquisition of adequate tissues for EGFR mutational analysis is sometimes not feasible, especially in advanced-stage patients. The aim of this study was to predict EGFR mutation status in patients with pulmonary adenocarcinoma based on {sup 18}F-fluorodeoxyglucose (FDG) uptake and imaging features in positron emission tomography/computed tomography (PET/CT), as well as on the serum carcinoembryonic antigen (CEA) level. We retrospectively reviewed 132 pulmonary adenocarcinoma patients who underwent EGFR mutation testing, pretreatment FDG PET/CT and serum CEA analysis. The associations between EGFR mutations and patient characteristics, maximal standard uptake value (SUVmax) of primary tumors, serum CEA level and CT imaging features were analyzed. Receiver-operating characteristic (ROC) curve analysis was performed to quantify the predictive value of these factors. EGFR mutations were identified in 69 patients (52.2 %). Patients with SUVmax ≥6 (p = 0.002) and CEA level ≥5 (p = 0.013) were more likely to have EGFR mutations. The CT characteristics of larger tumors (≥3 cm) (p = 0.023) and tumors with a nonspiculated margin (p = 0.026) were also associated with EGFR mutations. Multivariate analysis showed that higher SUVmax and CEA level, never smoking and a nonspiculated tumor margin were the most significant predictors of EGFR mutation. The combined use of these four criteria yielded a higher area under the ROC curve (0.82), suggesting a good discrimination. The combined evaluation of FDG uptake, CEA level, smoking status and tumor margins may be helpful in predicting EGFR mutation status in patients with pulmonary adenocarcinoma, especially when the tumor sample is inadequate for genetic analysis or genetic testing is not available. Further large-scale prospective studies are

  11. APC and K-ras gene mutation in aberrant crypt foci of human colon

    Institute of Scientific and Technical Information of China (English)

    Ping Yuan; Meng Hong Sun; Jin Sheng Zhang; Xiong Zeng Zhu; Da Ren Shi

    2001-01-01

    AIM To study the genetic alteration in ACF andto define the possibility that ACF may be a veryearly morphological lesion with molecularchanges, and to explore the relationshipbetween ACF and colorectal adenoma evencarcinoma.METHODS DNA from 35 CRC, 15 adenomas, 34ACF and 10 normal mucus was isolated by meansof microdissection. Direct gene sequencing of K-ras gene including codon 12, 13 and 61 as well asthe mutation cluster region (MCR) of APC genewas performed.RESULTS K-ras gene mutation frequency inACF, adenoma and carcinoma was 17.6% (6/34), 13.3% (2/ 15), and 14.3% (5/ 35)respectively, showing no difference ( P > 0.05)in K-fas gene mutation among three pathologicprocedures. The K-ras gene mutation inadenoma, carcinoma and 4 ACF restricted incodon 12 (GGT→GAT), but the other 2 mutationsfrom ACF located in codon 13 (GGC→GAC). K-res gene mutation was found more frequently inolder patients and patients with polypoidcancer. No mutation in codon 61 was found in thethree tissue types. Mutation rate of APO gene inadenoma and carcinoma was 22.9% (8/35) and26.7% (4/ 15), which was higher than ACF(2.9%) (P < 0.05). APC gene mutation incarcinoma was not correlated with age ofpatients, location, size and differentiation oftumor.CONCLUSION ACF might be a very earlymorphological lesion in the tumorogenesis ofcolorectal tumor. The morphological feature andgene mutation status was different in ACF andadenoma. ACF is possibly putative"microadenoma" that might be the precursor ofadenoma. In addition, the development of asubgroup of colorectal carcinomas mightundergo a way of "normal epithelium→ ACF→carcinomas".

  12. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials.

    Directory of Open Access Journals (Sweden)

    Christine M Lovly

    Full Text Available PURPOSE: Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1 potentially relevant to existing and emerging targeted therapies specifically in melanoma. METHODS: The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis and can be performed rapidly with high sensitivity (requiring 5-10% mutant allele frequency and minimal amounts of DNA (10-20 nanograms. The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab. RESULTS: Directing this test to a single disease, 90 of 150 (60% melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43% patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials. CONCLUSION: We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease.

  13. Tailoring the metabolism against mutations

    Science.gov (United States)

    Gulbahce, Natali; Motter, Adilson E.; Almaas, Eivind; Barabasi, Albert Laszlo

    2008-03-01

    In the post-genomic era, organisms can be modelled at the whole-cell level in silico via steady state methods to describe their metabolic capabilities. We use two such methods, Flux Balance Analysis and Minimization of Metabolic Adjustment to explore the behavior of cells (of E. coli and S. cerevisiae) after severe mutations. We propose experimentally feasible ways of modifying the underlying biochemical reaction network of a mutant cell such that cell functionality, in particular growth rate, is significantly improved.

  14. Mutation breeding newsletter. No. 41

    International Nuclear Information System (INIS)

    This newsletter contains short descriptions of research methods for the use of radiation to induce mutations and facilitate plant breeding. This method is used to develop species of plants that can survive in harsh climates and thus provide a food supply for humans and animals. Some of the mutants discussed include a salt tolerant barley, a disease resistant shrub, a cold tolerant chickpea, a highly productive Canavalia virosa and productive tomato. Refs, figs and tabs

  15. Induced mutations in sesame breeding

    International Nuclear Information System (INIS)

    The scope of induced mutations in sesame (Sesamum indicum L.) breeding is reviewed. So far in Egypt, India, Iraq, Rep. of Korea, and Sri Lanka, 14 officially released varieties have been developed through induced mutations: 12 directly and 2 through cross breeding (one using the 'dt45' induced mutant from Israel). For another variety released in China there are no details. The induced mutations approach was adopted primarily in order to obtain genetic variability that was not available in the germplasm collection. The mutagens commonly applied have been gamma rays, EMS and sodium azide. Sesame seeds can withstand high mutagen doses, and there are genotypic differences in sensitivity between varieties. The mutants induced in the above named countries and others include better yield, improved seed retention, determinate habit, modified plant architecture and size, more uniform and shorter maturation period, earliness, resistance to diseases, genic male sterility, seed coat color, higher oil content and modified fatty acids composition. Some of the induced mutants have already given rise to improved varieties, the breeding value of other mutants is now being assessed and still others can serve as useful markers in genetic studies and breeding programmes. (author)

  16. LHON: Mitochondrial Mutations and More.

    Science.gov (United States)

    Kirches, E

    2011-03-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the 'primary LHON mutations' to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.

  17. Identification of Novel Mutations in FAH Gene and Prenatal Diagnosis of Tyrosinemia in Indian Family

    Directory of Open Access Journals (Sweden)

    Jayesh J. Sheth

    2012-01-01

    Full Text Available Carrier of tyrosinemia type I was diagnosed by sequencing FAH (fumarylacetoacetate hydrolase gene. It leads to the identification of heterozygous status for both c.648C>G (p.Ile216Met and c.1159G>A (p.Gly387Arg mutations in exons 8 and 13, respectively, in the parents. The experimental program PolyPhen, SIFT, and MT predicts former missense point mutation as “benign” that creates a potential donor splice site and later one as “probably damaging” which disrupts secondary structure of protein.

  18. Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants

    Science.gov (United States)

    Ardighieri, Laura; Zeppernick, Felix; Hannibal, Charlotte G; Vang, Russell; Cope, Leslie; Junge, Jette; Kjaer, Susanne K; Kurman, Robert J; Shih, Ie-Ming

    2014-01-01

    There is debate as to whether peritoneal implants associated with serous borderline tumours/atypical proliferative serous tumours (SBT/APSTs) of the ovary are derived from the primary ovarian tumour or arise independently in the peritoneum. We analysed 57 SBT/APSTs from 45 patients with advanced-stage disease identified from a nation-wide tumour registry in Denmark. Mutational analysis for hotspots in KRAS and BRAF was successful in 55 APSTs and demonstrated KRAS mutations in 34 (61.8%) and BRAF mutations in eight (14.5%). Mutational analysis was successful in 56 peritoneal implants and revealed KRAS mutations in 34 (60.7%) and BRAF mutations in seven (12.5%). Mutational analysis could not be performed in two primary tumours and in nine implants, either because DNA amplification failed or because there was insufficient tissue for mutational analysis. For these specimens we performed VE1 immunohistochemistry, which was shown to be a specific and sensitive surrogate marker for a V600E BRAF mutation. VE1 staining was positive in one of two APSTs and seven of nine implants. Thus, among 63 implants for which mutation status was known (either by direct mutational analysis or by VE1 immunohistochemistry), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations, of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST–implant pairs and identical BRAF mutations in 14 (100%) of 14 SBT/APST–implant pairs. Wild-type KRAS and BRAF (at the loci investigated) were found in 11 (100%) of 11 SBT/APST–implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST–implant (non-invasive and invasive) pairs (p < 0.00001). This study provides cogent evidence that the vast majority of peritoneal implants, non-invasive and invasive, harbour the identical KRAS or BRAF mutations that are present in the associated SBT/APST, supporting the view that peritoneal implants are derived from the primary ovarian tumour. PMID:24307542

  19. Antiproliferative Effect of Rottlerin on Sk-Mel-28 Melanoma Cells.

    Science.gov (United States)

    Daveri, Elena; Valacchi, Giuseppe; Romagnoli, Roberta; Maellaro, Emilia; Maioli, Emanuela

    2015-01-01

    Melanoma is the most aggressive and chemoresistant form of skin cancer. Mutated, constitutively active B-RAF is believed to play a crucial role, although the selective B-RAF inhibition has shown poor clinical success, since phenomena of resistance usually occur, likely arising from additional genetic aberrations, such as loss of function of p53 and PTEN, overexpression of cyclin D1, hyperactivation of NF-κB, and downregulation of p21/Cip1. Since all of them are present in the Sk-Mel-28 melanoma cells, this cell line could be an ideal, albeit hard to study, model to develop new therapeutic strategies. In the current study, we tested the cytostatic action of Rottlerin on Sk-Mel-28 melanoma cells, on the basis of the known Rottlerin effects on the main proliferative signaling pathways. We presented evidence that the drug inhibits cell growth by an Akt- and p21/Cip1-independent mechanism, involving the dual inhibition of ERK and NF-κB and downregulation of cyclin D1. In addition, we found that Rottlerin increases ERK phosphorylation, but, surprisingly, this resulted in decreased ERK activity. Pull-down experiments, using Rottlerin-CNBr-conjugated Sepharose beads, revealed that Rottlerin binds to ERK, independently from its phosphorylation status. This direct interaction could in part explain the paradoxical blockage of ERK downstream signaling and growth arrest. We would like to dedicate this paper to the memory of our friend and colleague, prematurely deceased, Claudia Torricelli, who actively contributed to this project. PMID:26161122

  20. Mutation induction by ion beams in plants

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Atsushi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    2001-03-01

    The effect of ion beams such as C, He, and Ne ions was investigated on the mutation induction in plants with the expectation that ion beams of high linear energy transfer (LET) can frequently produce large DNA alternation such as inversion, translocation and large deletion rather than point mutation. Mutation frequency was investigated using Arabidopsis visible phenotype loci and was 8 to 33 fold higher for 220 MeV carbon ions than for electrons. Mutation spectrum was investigated on the flower color of chrysanthemum cv to find that flower mutants induced by ion beams show complex and stripe types rather than single color. Polymerase chain reaction analysis was performed to investigate DNA alteration of mutations. In conclusion, the characteristics of ion beams for the mutation induction are 1) high frequency, 2) broad mutation spectrum, and 3) novel mutants. (S. Ohno)

  1. Androgen receptor gene mutation, rearrangement, polymorphism.

    Science.gov (United States)

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

    2013-09-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  2. EGFR Mutations in Surgically Resected Fresh Specimens from 697 Consecutive Chinese Patients with Non-Small Cell Lung Cancer and Their Relationships with Clinical Features

    Directory of Open Access Journals (Sweden)

    Yuanyang Lai

    2013-12-01

    Full Text Available We aimed to reveal the true status of epidermal growth factor receptor (EGFR mutations in Chinese patients with non-small cell lung cancer (NSCLC after lung resections. EGFR mutations of surgically resected fresh tumor samples from 697 Chinese NSCLC patients were analyzed by Amplification Refractory Mutation System (ARMS. Correlations between EGFR mutation hotspots and clinical features were also explored. Of the 697 NSCLC patients, 235 (33.7% patients had tyrosine kinase inhibitor (TKIs sensitive EGFR mutations in 41 (14.5% of the 282 squamous carcinomas, 155 (52.9% of the 293 adenocarcinomas, 34 (39.5% of the 86 adenosquamous carcinomas, one (9.1% of the 11 large-cell carcinomas, 2 (11.1% of the 18 sarcomatoid carcinomas, and 2 (28.6% of the 7 mucoepidermoid carcinomas. TKIs sensitive EGFR mutations were more frequently found in female patients (p < 0.001, non-smokers (p = 0.047 and adenocarcinomas (p < 0.001. The rates of exon 19 deletion mutation (19-del, exon 21 L858R point mutation (L858R, exon 21 L861Q point mutation (L861Q, exon 18 G719X point mutations (G719X, including G719C, G719S, G719A were 43.4%, 48.1%, 1.7% and 6.8%, respectively. Exon 20 T790M point mutation (T790M was detected in 3 squamous carcinomas and 3 adenocarcinomas and exon 20 insertion mutation (20-ins was detected in 2 patients with adenocarcinoma. Our results show the rates of EGFR mutations are higher in all types of NSCLC in Chinese patients. 19-del and L858R are two of the more frequent mutations. EGFR mutation detection should be performed as a routine postoperative examination in Chinese NSCLC patients.

  3. LDA-SVM-Based EGFR Mutation Model for NSCLC Brain Metastases

    Science.gov (United States)

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-01-01

    Abstract Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non–small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this

  4. LDA-SVM-based EGFR mutation model for NSCLC brain metastases: an observational study.

    Science.gov (United States)

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-02-01

    Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non-small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of

  5. Mutation analysis of GJB2 gene and prenatal diagnosis in a non-syndromic deafness family

    Directory of Open Access Journals (Sweden)

    Xiao-hua CHEN

    2014-08-01

    Full Text Available Objective To identify the pathogenic gene in a non-syndromic deafness family, provide an accurate genetic consultation and early intervention for deaf family to reduce the incidence of congenital deafness. Methods Mutation analysis was carried out by polymerase chain reaction followed by DNA sequencing of coding region of GJB2 gene. The fetal DNA was extracted from the amniotic fluid cells by amniocentesis at 20 weeks during pregnancy. The genotype of the fetus was characterized for predicting the status of hearing. Results Complex heterozygous mutations 235delC and 176-191del16bp were detected in the proband of the family, heterozygous mutation 176-191del16bp was detected in the father, and 235delC was detected in the mother. Fetus carried 235delC heterozygous mutation inherited from his mother. Conclusions The proband's hearing loss is resulted from the complex heterozygous mutations 235delC and 176-191del16bp in GJB2 gene. Fetus is a heterozygous mutation 235delC carrier. Prenatal diagnosis for deafness assisted by genetic test can provide efficient guidance about offspring's hearing condition, and prevent another deaf-mute member from birth. DOI: 10.11855/j.issn.0577-7402.2014.07.09

  6. Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Rachinger Andrea

    2008-10-01

    Full Text Available Abstract Background In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas. Methods We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750 in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1 were quantified in 62 cancer tissues by real-time RT-PCR. Results Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy. Conclusion In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

  7. Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

    LENUS (Irish Health Repository)

    Geranmayeh, Fatemeh

    2010-04-01

    Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.

  8. An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ying Yu; Xu Ma; Bin-Bin Wang; Zhong-Cheng Xin; Tao Liu; Ke Ma; Jian Jiang; Xiang Fang; Li-Hua Yu; Yi-Feng Peng

    2012-01-01

    Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe,and excess iron is associated with the impairment of spermatogenesis.The aim of this study is to investigate the association between three mutations (C282Y,H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population.Two groups of Chinese men were recruited:444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility.The HFEgene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.The experimental results demonstrated that no C282Y or S65C mutations were detected.Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801,95% confidence interval=0.452-1.421,X2=0.577,P=0.448).The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH),follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896,P=0.404 and P=0.05,respectively).Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction.

  9. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring

  10. How the leopard hides its spots: ASIP mutations and melanism in wild cats.

    Directory of Open Access Journals (Sweden)

    Alexsandra Schneider

    Full Text Available The occurrence of melanism (darkening of the background coloration is documented in 13 felid species, in some cases reaching high frequencies at the population level. Recent analyses have indicated that it arose multiple times in the Felidae, with three different species exhibiting unique mutations associated with this trait. The causative mutations in the remaining species have so far not been identified, precluding a broader assessment of the evolutionary dynamics of melanism in the Felidae. Among these, the leopard (Panthera pardus is a particularly important target for research, given the iconic status of the 'black panther' and the extremely high frequency of melanism observed in some Asian populations. Another felid species from the same region, the Asian golden cat (Pardofelis temminckii, also exhibits frequent records of melanism in some areas. We have sequenced the coding region of the Agouti Signaling Protein (ASIP gene in multiple leopard and Asian golden cat individuals, and identified distinct mutations strongly associated with melanism in each of them. The single nucleotide polymorphism (SNP detected among the P. pardus individuals was caused by a nonsense mutation predicted to completely ablate ASIP function. A different SNP was identified in P. temminckii, causing a predicted amino acid change that should also induce loss of function. Our results reveal two additional cases of species-specific mutations implicated in melanism in the Felidae, and indicate that ASIP mutations may play an important role in naturally-occurring coloration polymorphism.

  11. High frequency and reduced penetrance of LRRK2 G2019S mutation among Parkinson's disease patients in Cantabria (Spain).

    Science.gov (United States)

    Sierra, María; González-Aramburu, Isabel; Sánchez-Juan, Pascual; Sánchez-Quintana, Coro; Polo, José Miguel; Berciano, José; Combarros, Onofre; Infante, Jon

    2011-11-01

    The frequency and penetrance of the LRRK2 G2019S mutation varies considerably in different Parkinson disease (PD) populations. This information is essential both for clinical purposes and genetic counseling. The objective of this study was to estimate the prevalence and penetrance of the G2019S mutation of the LRRK2 gene in a small region in northern Spain (Cantabria). The G2019S mutation was tested in 367 consecutive patients with PD attended as outpatients in a tertiary Hospital in Northern Spain, and 126 at-risk family members of probands were also investigated for G2019S mutation and disease status. The gene penetrance was estimated in terms of cumulative age-specific incidence of PD by the Kaplan-Meier method. Thirty-two PD patients (8.7%) carried the G2019S mutation. Penetrance estimation of the G2019S mutation was 2% at 50 years, 12% at 60 years, 26% at 70 years, and 47% at 80 years. The frequency of the G2019S mutation of the LRRK2 gene in PD patients from Cantabria is among the highest reported so far after North African Arabs and Ashkenazi Jews. At the age of 80 years only one-half of G2019S mutation carriers manifest motor symptoms of PD. PMID:21954089

  12. Clinicopathological characteristics associated with BRAF(K601E) and BRAF(L597) mutations in melanoma.

    Science.gov (United States)

    Voskoboynik, Mark; Mar, Victoria; Mailer, Sonia; Colebatch, Andrew; Fennessy, Anne; Logan, Aleksandra; Hewitt, Chelsee; Cebon, Jonathon; Kelly, John; McArthur, Grant

    2016-03-01

    BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors. PMID:26643848

  13. Detection of TP53 mutation, loss of heterozygosity and DNA content in fine-needle aspirates of breast carcinoma.

    Science.gov (United States)

    Lavarino, C.; Corletto, V.; Mezzelani, A.; Della Torre, G.; Bartoli, C.; Riva, C.; Pierotti, M. A.; Rilke, F.; Pilotti, S.

    1998-01-01

    Recent preclinical and clinical data suggest that TP53 status and TP53 mutations may be important in determining tumour aggressiveness and therapy response. In this study we investigate the feasibility of a structural and quantitative analysis of TP53 on fine-needle aspiration (FNA) material obtained from 31 consecutive female patients with breast carcinoma, enrolled in a primary chemotherapy protocol. Tumours were screened for p53 protein overexpression and TP53 mutations (exons 5-8) using immunocytochemistry, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing analyses, and finally using fluorescence in situ hybridization (FISH) analysis. Positive nuclear staining was identified in six cases whereas mutations were detected in nine. Although the immunoreactive pattern fitted fully with the characterized TP53 mutation type, the considerable number of null p53 mutations (i.e. four) coupled with the lack of information regarding the localization of TP53 mutations make immunocytochemistry an inadequate indicator of TP53 function deregulation. Combining molecular and FISH analyses, we detected three cases with TP53 deletion and one case with deletion and mutation. Finally, DNA static-image analysis performed on 29 cases showed aneuploidy in 26 cases, which included all TP53-mutated cases. The present results show that FNA may assist clinical decisions by allowing the evaluation of a variety of biological parameters relevant for prognosis and treatment planning. Images Figure 1 PMID:9459157

  14. Evaluation of CFTR gene mutations in Adana

    Directory of Open Access Journals (Sweden)

    Ozlem Goruroglu Ozturk

    2013-04-01

    Full Text Available ABSTRACT Objective: Cystic fibrosis is the most common autosomal recessive inherited disorder seen in the white populations. It develops in result of mutations of cystic fibrosis transmembrane regulator (CFTR gene. Rate of these mutations vary in different geographical regions. In this study, we aimed to determine the frequency of CFTR gene mutations in Adana. Methods: DNA samples of 63 subjects (21 women, 42 men who were diagnosed as cystic fibrosis at Balcali Hospital of Cukurova University, were studied for 19 different CFTR mutations by the strip assay method which is based on reverse hybridization. Results: In cystic fibrosis diagnosed patients, 19 mutations were observed of which 9 were homozygous and 10 were heterozygous. ∆F508 frequency was found as 11.9%, and rate of homozygous was found as 66.7%. Mutation frequencies of W1282X and N1303K were found as 2.40% and 4.80% respectively and rate of homozygous mutations were 50% for both. I148T mutation frequency was found as 3.20% and all were heterozygous. For the whole 19 mutations, frequency of mutation in 63 subjects was 22.3%. Conclusion: Detection of CFTR gene mutations by the strip assay method by reverse hybridization is an easy, fast and informative method. However, due to improvability of the common mutations in probable cystic fibrosis patients because of heterogenity in this region, it is still a major problem and does not exclude cystic fibrosis diagnosis. But this problematic issue can be overcome by evaluating the whole exons of CFTR mutations by advanced molecular tecniques. Key words: CFTR, cystic fibrosis, molecular diagnosis, reverse hibridisation [Cukurova Med J 2013; 38(2.000: 202-208

  15. Service Level Status

    CERN Multimedia

    Lopienski, S

    2007-01-01

    Nowadays, IT departments provide, and people use, computing services of an increasingly heterogeneous nature. There is thus a growing need for a status display that groups these different services and reports status and availability in a uniform way. The Service Level Status (SLS) system addresses these needs by providing a web-based display that dynamically shows availability, basic information and statistics about various IT services, as well as the dependencies between them.

  16. Status and the brain.

    OpenAIRE

    Utevsky, Amanda V.; Platt, Michael L.

    2014-01-01

    Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one's own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan ...

  17. Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas

    Directory of Open Access Journals (Sweden)

    Hagen Per

    2006-03-01

    Full Text Available Abstract Background The association between colorectal cancer (CRC and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC gene has been reported to have a "gatekeeper" function in the colonic mucosa. Methods To evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas and 334 controls. All tumors were sequenced in the mutation cluster region (MCR of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin. Results The mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and "ever smoking" OR = 1.73 (95% CI 0.83–3.58. For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and "duration of smoking > 30 years", yielded a statistically significant OR = 2.86 (1.06–7.7. When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to "ever smoking", with an OR = 3.97 (1.26–12.51. For CRC cases without APC mutation "duration of smoking > 30 years", yielded a statistically significant OR = 4.06 (1.20–13.7. The smoking parameter "starting smoking ≥ 40 years ago" was only associated with CRC cases with APC mutations, OR = 2.0 (0.34–11.95. A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73–6.86. Conclusion Our data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation

  18. Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas

    International Nuclear Information System (INIS)

    The association between colorectal cancer (CRC) and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC) gene has been reported to have a 'gatekeeper' function in the colonic mucosa. To evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas) and 334 controls. All tumors were sequenced in the mutation cluster region (MCR) of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin. The mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and 'ever smoking' OR = 1.73 (95% CI 0.83–3.58). For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and 'duration of smoking > 30 years', yielded a statistically significant OR = 2.86 (1.06–7.7). When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to 'ever smoking', with an OR = 3.97 (1.26–12.51). For CRC cases without APC mutation 'duration of smoking > 30 years', yielded a statistically significant OR = 4.06 (1.20–13.7). The smoking parameter 'starting smoking ≥ 40 years ago' was only associated with CRC cases with APC mutations, OR = 2.0 (0.34–11.95). A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73–6.86). Our data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation

  19. SIS - Status Determination

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Status Determination dataset within the Species Information System (SIS) contains information related to overfishing, overfished, and approaching overfished...

  20. Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms

    Science.gov (United States)

    Yonal-Hindilerden, Ipek; Daglar-Aday, Aynur; Akadam-Teker, Basak; Yilmaz, Ceylan; Nalcaci, Meliha; Yavuz, Akif Selim; Sargin, Deniz

    2015-01-01

    Background Despite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs), a significant proportion of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs. Methods About 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF. Results A total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS) was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival. Conclusion We conclude that ASXL1 mutations are molecular predictors of short OS in PMF. PMID:26082670

  1. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

    Science.gov (United States)

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A.; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N.; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R.; Weitzel, Jeffrey N.

    2014-01-01

    Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer

  2. Macronodular Adrenal Hyperplasia due to Mutations in an Armadillo Repeat Containing 5 (ARMC5) Gene: A Clinical and Genetic Investigation

    Science.gov (United States)

    Faucz, Fabio R.; Zilbermint, Mihail; Lodish, Maya B.; Szarek, Eva; Trivellin, Giampaolo; Sinaii, Ninet; Berthon, Annabel; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Bertherat, Jerome

    2014-01-01

    Context: Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH). Objective: We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared. Methods: Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed. Results: Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002). Conclusions: ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families. PMID:24601692

  3. Common Β- Thalassaemia Mutations in

    OpenAIRE

    P Azarfam; M Aminbakhsh; M. Asgharzadeh; AA Hossainpour; MA Hossainpour-Faizi; N Pouladi

    2005-01-01

    Introduction: β –Thalassaemia was first explained by Thomas Cooly as Cooly’s anaemia in 1925. The β- thalassaemias are hereditary autosomal disorders with decreased or absent β-globin chain synthesis. The most common genetic defects in β-thalassaemias are caused by point mutations, micro deletions or insertions within the β-globin gene. Material and Methods: In this research , 142 blood samples (64 from childrens hospital of Tabriz , 15 samples from Shahid Gazi hospital of Tabriz , 18 from Ur...

  4. Lattices, graphs, and Conway mutation

    CERN Document Server

    Greene, Joshua Evan

    2011-01-01

    The d-invariant of an integral, positive definite lattice L records the minimal norm of a characteristic covector in each equivalence class mod 2L. We prove that the 2-isomorphism type of a connected graph is determined by the d-invariant of its lattice of integral cuts (or flows). As an application, we prove that a reduced, alternating link diagram is determined up to mutation by the Heegaard Floer homology of the link's branched double-cover. Thus, alternating links with homeomorphic branched double-covers are mutants.

  5. Insulin gene mutations and diabetes

    OpenAIRE

    Nishi, Masahiro; Nanjo, Kishio

    2011-01-01

    Abstract Some mutations of the insulin gene cause hyperinsulinemia or hyperproinsulinemia. Replacement of biologically important amino acid leads to defective receptor binding, longer half‐life and hyperinsulinemia. Three mutant insulins have been identified: (i) insulin Chicago (F49L or PheB25Leu); (ii) insulin Los Angeles (F48S or PheB24Ser); (iii) and insulin Wakayama (V92L or ValA3Leu). Replacement of amino acid is necessary for proinsulin processing results in hyperproinsulinemia. Four t...

  6. Induced mutations for crop improvement

    International Nuclear Information System (INIS)

    Mutation induction has become an established tool in plant breeding to supplement existing germ plasma and to improve cultivars in certain specific traits. Hundreds of improved varieties have been released to farmers for many different crop species, demonstrating the economic value of the technology. Limitations arise mainly from the large mutagenized populations to be screened and from the unsatisfactory selection methods. Both limitations may be eased to some extent by advances in techniques of plant in-vitro culture. (author). Refs, 1 fig., 7 tabs

  7. Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond.

    Science.gov (United States)

    Rosenquist, Richard; Rosenwald, Andreas; Du, Ming-Qing; Gaidano, Gianluca; Groenen, Patricia; Wotherspoon, Andrew; Ghia, Paolo; Gaulard, Philippe; Campo, Elias; Stamatopoulos, Kostas

    2016-09-01

    Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management. In selected entities, a predominantly mutated gene is identified in almost all cases (e.g. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma and hairy-cell leukemia), while for the vast majority of lymphomas a quite diverse mutation pattern is observed, with a limited number of frequently mutated genes followed by a seemingly endless tail of genes with mutations at a low frequency. Herein, the European Expert Group on NGS-based Diagnostics in Lymphomas (EGNL) summarizes the current status of this ever-evolving field, and, based on the present evidence level, segregates mutations into the following categories: i) immediate impact on treatment decisions, ii) diagnostic impact, iii) prognostic impact, iv) potential clinical impact in the near future, or v) should only be considered for research purposes. In the coming years, coordinated efforts aiming to apply targeted next-generation sequencing in large patient series will be needed in order to elucidate if a particular gene mutation will have an immediate impact on the lymphoma classification, and ultimately aid clinical decision making. PMID:27582569

  8. Epidermal Growth Factor Receptor Activating Mutations in Squamous Histology of Lung Cancer Patients of Southern Bulgaria

    Directory of Open Access Journals (Sweden)

    Genova Silvia N.

    2015-12-01

    Full Text Available There is only limited data on the prevalence of epidermal growth factor receptor (EGFR activating mutations in squamous cell carcinomas and adenosquamous carcinomas of the lung in patients of the Southern Bulgarian region and the efficacy of EGFR tyrosine kinase inhibitors. AIM: Previous reports for Bulgarian population showed high incidence of EGFR mutations in the squamous cell carcinomas, so we set the goal to investigate their frequency in Southern Bulgaria, after precise immunohistochemical verification of lung cancers. MATERIALS AND METHODS: Two hundred and thirty-six lung carcinomas were included in this prospective study. All biopsies were initially analysed with p63, TTF1, Napsin A, CK7, CK34βE12, synaptophysin, CK20 and CDX2. Two hundred and twenty-five non-small cell lung carcinomas were studied with real-time PCR technology to assess the status of the EGFR gene. RESULTS: We detected 132 adenocarcinomas (58.7%, 89 squamous cell carcinomas (39.2%, 4 adenosquamous carcinomas (1.8%, 9 large cell neuroendocrine carcinomas (3.8% and 2 metastatic colorectal adenocarcinomas (0.8%. Activating mutations in the EGF receptor had 3 out of 89 squamous cell carcinomas (3.37%. We have established mutations in L858R, deletion in exon 19 and rare mutation in S7681. One out of four adenosquamous carcinomas had a point mutation in the L858R (25%. CONCLUSIONS: The frequency of EGFR mutations we found in lung squamous cell carcinomas in a Southern Bulgarian region is lower than that in European countries. Ethnic diversity in the region does not play role of an independent predictive factor in terms of mutation frequency.

  9. Clinicopathologic findings and BRAF mutation in cutaneous melanoma in young adults.

    Science.gov (United States)

    Estrozi, Bruna; Machado, Juliana; Rodriguez, Rubens; Bacchi, Carlos E

    2014-01-01

    Cutaneous melanoma in young patients is rare with increasing incidence. It is not clear whether the etiology and clinical outcome are similar to cutaneous melanoma in the elderly. Mutations in BRAF gene in patients with cutaneous melanoma, in general, range in frequency from 20% to 80%; however, the status and clinical significance of BRAF mutations in the young population have not been evaluated. We investigated 132 cases of primary cutaneous melanoma in patients aged between 18 and 30 years with emphasis on clinical characteristics, pathologic features, and molecular evaluation of mutation in the BRAF gene (BRAF(V600E)). It was predominantly seen in female individuals (61.4%), trunk was the most common site of involvement (40.4%), and superficially spreading melanoma was the predominant histologic type (79.5%). Mutation in BRAF(V600E) was analyzed successfully in 93 cases using an RT-PCR. The BRAF(V600E) mutation was identified in 38.7% (36/93) and was associated with vertical growth phase (P=0.01) and mild inflammatory infiltrate (P=0.02). No case of melanoma with regression phenomenon presented with BRAF(V600E) mutation (P<0.05). There was no significant association between BRAF(V600E) mutation and sex, histologic type, the Clark level, the Breslow index, solar elastosis, angiolymphatic and perineural invasion, satellitosis, and coexisting nevus. As in melanomas in older patients, these results probably indicate that BRAF mutation may not be the only key factor in melanoma tumorigenesis, and that there should be multiple alternative genetic pathways related to melanoma.

  10. PIK3CA mutation detection in metastatic biliary cancer using cell-free DNA

    Science.gov (United States)

    Deng, Shibing; Lee, Sujin; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Mao, Mao; Heo, Jin Seok; Kwon, Wooil; Jang, Kee-Taek; Lee, Jeeyun; Park, Joon Oh

    2015-01-01

    PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers. PMID:26498688

  11. Mutation, Witten Index, and Quiver Invariant

    CERN Document Server

    Kim, Heeyeon; Yi, Piljin

    2015-01-01

    We explore Seiberg-like dualities, or mutations, for ${\\cal N}=4$ quiver quantum mechanics in the context of wall-crossing. In contrast to higher dimensions, the 1d Seiberg-duality must be performed with much care. With fixed Fayet-Iliopoulos constants, at most two nodes can be mutated, one left and the other right, mapping a chamber of a quiver into a chamber of a mutated quiver. We delineate this complex pattern for triangle quivers and show how the Witten indices are preserved under such finely chosen mutations. On the other hand, the quiver invariants, or wall-crossing-safe part of supersymmetric spectra, mutate more straightforwardly, whereby a quiver is mapped to a quiver. The mutation rule that preserves the quiver invariant is different from the usual one, however, which we explore and confirm numerically.

  12. Is The Ribosome Targeted By Adaptive Mutations

    DEFF Research Database (Denmark)

    Jimenez Fernandez, Alicia; Molin, Søren; Johansen, Helle Krogh

    2015-01-01

    degree of evolutionary conservation of the cellular MMSM tend to support this view. However, under certain selective conditions the machinery itself may be targeted by adaptive mutations, which result in fitness-increasing phenotypic changes. Here we investigate and characterize the role of ribosomal...... mutations in adaptive evolution. Methods: Several mutations in ribosomal genes have been identified in the genome analysis of nearly 700 Pseudomonas aeruginosa isolates from infected cystic fibrosis patients. Among these mutations we have repeatedly identified insertions, deletions and substitutions...... in specific ribosomal genes. The bacterial phenotypes of the mutated strains will be investigated. Results: Preliminary assays show that mutant strains have reduced growth rate and an altered antibiotic resistance pattern. The selection for mutations in ribosomal protein genes is partly explainable...

  13. How mutation affects evolutionary games on graphs.

    Science.gov (United States)

    Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E; Nowak, Martin A

    2012-04-21

    Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration.

  14. Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations.

    Science.gov (United States)

    Alibakhshi, Reza; Moradi, Keyvan; Mohebbi, Zahra; Ghadiri, Keyghobad

    2014-03-01

    Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a mutation in the phenylalanine hydroxylase (PAH) gene. Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. This study was designed to investigate the status of molecular defects in the PAH gene and their association with polymorphisms in Kurdish patients with PKU in the Kermanshah province, western Iran. The study was conducted on 27 unrelated patients with PKU over a 2-year period (from 2010 to 2012). All 13 exons plus exon-intron boundaries of the PAH gene were analyzed and we identified 15 different mutations, including two novel mutations, in 51 of the 54 mutant alleles (diagnostic efficiency of 94.4 %). IVS4 + 1G > C (c.441 + 1G > C) and IVS7 - 5 T > C (c.843 - 5 T > C) are novel mutations that have not been reported in the academic literature or the PAH locus database ( http://www.pahdb.mcgill.ca ); therefore, they may be specific to the Kurdish population. IVS2 + 5G > C and IVS9 + 5G > A were the two most prevalent mutations in our sample, with frequencies of 26 % and 17 %, respectively. The second most common mutations were p.R261X, IVS10 - 11G > A, p.K363 > Nfs and IVS7 - 5 T > C, with each showing a relative frequency of 7.4 %. All other detected mutations, including p.F55 > Lfs, p.R176X, p.R243Q, p.V230I, p.R243X, p.R261Q, IVS8 - 7A > G and p.E390G had frequencies of less than 4 %. The present study showed that there is a distinct difference in the characteristics of PAH mutations between the Kermanshah province and other parts of Iran, suggesting that Kermanshah may have a unique population distribution of PAH gene mutations. Iran lies on the route of major ancient movements of the Caucasian people toward the Mediterranean basin, and Kermanshah has previously been called the gateway to Asia. Most of the mutations identified in this study are common in the Mediterranean region. Therefore, our findings are consistent with the historical and

  15. Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in sporadic intestinal adenocarcinoma.

    Science.gov (United States)

    Hartman, Douglas J; Binion, David; Regueiro, Miguel; Schraut, Wolfgang; Bahary, Nathan; Sun, Weijing; Nikiforova, Marina; Pai, Reetesh K

    2014-08-01

    The underlying molecular alterations in chronic idiopathic inflammatory bowel disease-associated intestinal adenocarcinoma remain largely unknown. Somatic IDH mutations are often seen in gliomas and myeloid leukemia but have also been recently reported in a subset of other neoplasms. We analyzed a series of intestinal adenocarcinomas with (n=23) and without (n=39) associated chronic idiopathic inflammatory bowel disease treated at our institution for IDH1 and IDH2 mutations and correlated the clinicopathologic findings with mutation status. Compared with intestinal adenocarcinomas not associated with inflammatory bowel disease, adenocarcinomas associated with inflammatory bowel disease more frequently demonstrated IDH mutations (13% vs. 0%, P=0.047). All IDH mutations were identified in IDH1 and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1 mutations were frequently (66%) associated with concurrent KRAS mutations (p.G12D, c.35G>A). IDH1-mutated intestinal adenocarcinomas were seen in the setting of both Crohn disease and ulcerative colitis and were located in both the ileum and colon. Compared with IDH1-negative inflammatory bowel disease-associated adenocarcinoma, IDH1-positive adenocarcinomas more frequently demonstrated tubuloglandular histology (100% vs. 25%, P=0.032) and were more frequently associated with precursor lesions exhibiting serrated morphology (66% vs. 6%, P=0.034). IDH1 mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1 mutations are occasionally identified in inflammatory bowel disease-associated intestinal adenocarcinoma but not in intestinal adenocarcinoma not associated with inflammatory bowel disease. In addition, IDH1-mutated intestinal adenocarcinoma is associated with a characteristic low-grade tubuloglandular histology and often harbors concurrent KRAS mutations. Identification of patients

  16. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome.

    Science.gov (United States)

    Mian, Syed A; Smith, Alexander E; Kulasekararaj, Austin G; Kizilors, Aytug; Mohamedali, Azim M; Lea, Nicholas C; Mitsopoulos, Konstantinos; Ford, Kevin; Nasser, Erick; Seidl, Thomas; Mufti, Ghulam J

    2013-07-01

    The recent identification of acquired mutations in key components of the spliceosome machinery strongly implicates abnormalities of mRNA splicing in the pathogenesis of myelodysplastic syndromes. However, questions remain as to how these aberrations functionally combine with the growing list of mutations in genes involved in epigenetic modification and cell signaling/transcription regulation identified in these diseases. In this study, amplicon sequencing was used to perform a mutation screen in 154 myelodysplastic syndrome patients using a 22-gene panel, including commonly mutated spliceosome components (SF3B1, SRSF2, U2AF1, ZRSR2), and a further 18 genes known to be mutated in myeloid cancers. Sequencing of the 22-gene panel revealed that 76% (n=117) of the patients had mutations in at least one of the genes, with 38% (n=59) having splicing gene mutations and 49% (n=75) patients harboring more than one gene mutation. Interestingly, single and specific epigenetic modifier mutations tended to coexist with SF3B1 and SRSF2 mutations (P<0.03). Furthermore, mutations in SF3B1 and SRSF2 were mutually exclusive to TP53 mutations both at diagnosis and at the time of disease transformation. Moreover, mutations in FLT3, NRAS, RUNX1, CCBL and C-KIT were more likely to co-occur with splicing factor mutations generally (P<0.02), and SRSF2 mutants in particular (P<0.003) and were significantly associated with disease transformation (P<0.02). SF3B1 and TP53 mutations had varying impacts on overall survival with hazard ratios of 0.2 (P<0.03, 95% CI, 0.1-0.8) and 2.1 (P<0.04, 95% CI, 1.1-4.4), respectively. Moreover, patients with splicing factor mutations alone had a better overall survival than those with epigenetic modifier mutations, or cell signaling/transcription regulator mutations with and without coexisting mutations of splicing factor genes, with worsening prognosis (P<0.001). These findings suggest that splicing factor mutations are maintained throughout disease

  17. The Mutational Robustness of Influenza A Virus

    Science.gov (United States)

    McCrone, John T.; Lauring, Adam S.

    2016-01-01

    A virus’ mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  18. The Mutational Robustness of Influenza A Virus.

    Science.gov (United States)

    Visher, Elisa; Whitefield, Shawn E; McCrone, John T; Fitzsimmons, William; Lauring, Adam S

    2016-08-01

    A virus' mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  19. Evaluation of CFTR gene mutations in Adana

    OpenAIRE

    Ozlem Goruroglu Ozturk; Filiz Kibar; Esin Damla Ziyanoglu Karacor; Salih Cetiner; Gulhan Sahin; Akgun Yaman

    2013-01-01

    ABSTRACT Objective: Cystic fibrosis is the most common autosomal recessive inherited disorder seen in the white populations. It develops in result of mutations of cystic fibrosis transmembrane regulator (CFTR) gene. Rate of these mutations vary in different geographical regions. In this study, we aimed to determine the frequency of CFTR gene mutations in Adana. Methods: DNA samples of 63 subjects (21 women, 42 men) who were diagnosed as cystic fibrosis at Balcali Hospital of Cukurova Universi...

  20. Evaluation of CFTR gene mutations in Adana

    OpenAIRE

    Öztürk, Özlem Görüroğlu; Filiz KIBAR; Karaçor, Esin Damla Ziyanoğlu; Çetiner, Salih; Şahin, Gülhan; Yaman, Akgün

    2013-01-01

    ABSTRACT Objective: Cystic fibrosis is the most common autosomal recessive inherited disorder seen in the white populations. It develops in result of mutations of cystic fibrosis transmembrane regulator (CFTR) gene. Rate of these mutations vary in different geographical regions. In this study, we aimed to determine the frequency of CFTR gene mutations in Adana. Methods: DNA samples of 63 subjects (21 women, 42 men) who were diagnosed as cystic fibrosis at Balcalı Hospital of Çukurova Unive...

  1. Telomerase mutations in smokers with severe emphysema

    OpenAIRE

    Stanley, Susan E.; Chen, Julian J. L.; Podlevsky, Joshua D.; Alder, Jonathan K; Hansel, Nadia N.; Rasika A Mathias; Qi, Xiaodong; Rafaels, Nicholas M.; Wise, Robert A.; Silverman, Edwin K.; Kathleen C. Barnes; Armanios, Mary

    2014-01-01

    Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This p...

  2. RELN mutations in autism spectrum disorder

    OpenAIRE

    Lammert, Dawn B.; Howell, Brian W.

    2016-01-01

    RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia, accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum dis...

  3. Prevalence of the B Type Raf Kinase V600E Mutation in Cytologically Indeterminate Thyroid Nodules: Correlation with Ultrasonographic and Pathologic Features

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chae Hyun; Choi, Yoon Jung; Choi, Seon Hyeong; Rho, Myong Ho Kook Shin Ho; Chung, Eun Chul [Dept. of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul (Korea, Republic of); Chae, Seoung Wan; Kim, Dong Hoon; Sohn, Jin Hee [Dept. of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul (Korea, Republic of); Yun, Ji Sup [Dept. of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul (Korea, Republic of)

    2012-01-15

    To study the prevalence of B type Raf kinase (BRAF) mutations, and to evaluate the ultrasonographic and clinicopathological features associated with thyroid cytology of indeterminate nodules. We assessed the presence or absence of BRAF mutation in 44 specimens from patients with cytologically indeterminate thyroid nodules according to two consecutive preoperative fine needle aspiration cytology procedures. In 9 specimens, the test for BRAF mutation was not possible due to scant cellularity. DNA was extracted from the atypical cells and then analyzed for the BRAF V600E mutation by pyrosequencing. The ultrasonographic and clinicopathological features of the patients were characterized according to their mutation status. The BRAF V600E mutation was present in 17 (48.6%) of 35 patients with indeterminate cytology results and in 17 (54.8%) of the 31 patients with papillary thyroid cancer (PTC). Twenty two of 35 cytologically indeterminate nodules had calcifications, and among them 14 cases were proven to be positive for BRAF V600E mutations. Extrathyroid extension was significantly more frequent in the presence of the BRAF V600E mutation (p = 0.027), while tumor size, lympho-vascular invasion, or lymph node metastasis were not associated with the mutation. Screening for BRAF V600E mutations in conjunction with cytology may increase the diagnostic accuracy for PTC with indeterminate cytology results.

  4. Precise Detection of IDH1/2 and BRAF Hotspot Mutations in Clinical Glioma Tissues by a Differential Calculus Analysis of High-Resolution Melting Data.

    Science.gov (United States)

    Hatae, Ryusuke; Hata, Nobuhiro; Yoshimoto, Koji; Kuga, Daisuke; Akagi, Yojiro; Murata, Hideki; Suzuki, Satoshi O; Mizoguchi, Masahiro; Iihara, Koji

    2016-01-01

    High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1R132 and IDH2R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAFV600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2R172 and BRAFV600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments.

  5. Precise Detection of IDH1/2 and BRAF Hotspot Mutations in Clinical Glioma Tissues by a Differential Calculus Analysis of High-Resolution Melting Data.

    Science.gov (United States)

    Hatae, Ryusuke; Hata, Nobuhiro; Yoshimoto, Koji; Kuga, Daisuke; Akagi, Yojiro; Murata, Hideki; Suzuki, Satoshi O; Mizoguchi, Masahiro; Iihara, Koji

    2016-01-01

    High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1R132 and IDH2R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAFV600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2R172 and BRAFV600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments. PMID:27529619

  6. Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events

    DEFF Research Database (Denmark)

    Serizawa, Reza R; Ralfkiaer, Ulrik; Steven, Kenneth;

    2011-01-01

    screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We...

  7. Prevalence of BRCA1 and BRCA2 Germline Mutations in Breast Cancer Women of Multiple Ethnic Region in Northwest China

    NARCIS (Netherlands)

    Ou, Jianghua; Wu, Tao; Sijmons, Rolf; Ni, Duo; Xu, Wenting; Upur, Halmurat

    2013-01-01

    Purpose: The aim of this study is to further understand the status of BRCA1 and BRCA2 mutation among Chinese high-risk breast cancer patients in multiple-ethnic regions of China. Methods: A total of 79 blood samples of high-risk breast cancer patients from Xinjiang Uyghur autonomous region were anal

  8. Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit

    DEFF Research Database (Denmark)

    Nagirnaja, Liina; Venclovas, Česlovas; Rull, Kristiina;

    2012-01-01

    CG by applying a combination of in silico (sequence and structure analysis, molecular dynamics) and in vitro (co-immunoprecipitation, immuno- and bioassays) approaches. The carrier status of each mutation was determined for 1086 North-Europeans [655 patients with recurrent miscarriage (RM)/431 healthy controls......) and was inherited by two of seven studied live born children. The mutation caused ~50% of secreted β-subunits to acquire an alternative conformation, but did not affect its biological activity. For the CGB8 p.Arg8Trp (rs72556341) substitution, the applied in vitro methods revealed no alterations in the assembly...... of intact hCG as also supported by an in silico analysis. In summary, the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCGβ genes CGB5 and CGB8....

  9. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

    DEFF Research Database (Denmark)

    Høgh, Julie Kaae; Hellgren, Lars; Jungersted, JM;

    2010-01-01

    chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). Results: In the......Background: Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now......, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. Methods: A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer...

  10. Identification of weak points prone for mutation in ferredoxin of Trichomonas vaginalis

    Directory of Open Access Journals (Sweden)

    Wiwanitkit V

    2008-01-01

    Full Text Available Trichomonas vaginalis , the causative agent for human trichomoniasis, is a problematic sexually transmitted disease mainly in women. At present, metronidazole-resistant trichomoniasis is an infrequent but challenging problem with no universally successful treatment. Genetic mutation is believed to be an important factor leading to increasing drug resistance. Understanding the mutation status will help to design accurate strategies of therapy against mutant strains of T. vaginalis . The author performed a bioinformatic analysis to determine positions that tend to comply peptide motifs in the amino acid sequence of ferridoxin of T. vaginalis . Based on this study, the weak linkages in the studied protein can be identified and can be useful information for prediction of possible new mutations that can lead to drug resistance. In addition, the results from this study can be good information for further research on the diagnosis for mutants and new effective drug development.

  11. Identification of weak points prone for mutation in ferredoxin of Trichomonas vaginalis.

    Science.gov (United States)

    Wiwanitkit, V

    2008-01-01

    Trichomonas vaginalis, the causative agent for human trichomoniasis, is a problematic sexually transmitted disease mainly in women. At present, metronidazole-resistant trichomoniasis is an infrequent but challenging problem with no universally successful treatment. Genetic mutation is believed to be an important factor leading to increasing drug resistance. Understanding the mutation status will help to design accurate strategies of therapy against mutant strains of T. vaginalis. The author performed a bioinformatic analysis to determine positions that tend to comply peptide motifs in the amino acid sequence of ferredoxin of T. vaginalis. Based on this study, the weak linkages in the studied protein can be identified and can be useful information for prediction of possible new mutations that can lead to drug resistance. In addition, the results from this study can be good information for further research on the diagnosis for mutants and new effective drug development. PMID:18445954

  12. A novel EDA gene mutation in a Spanish family with X-linked hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Cañueto, J; Zafra-Cobo, M I; Ciria, S; Unamuno, P; González-Sarmiento, R

    2011-11-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by abnormal development of the hair, teeth, and sweat glands. It is caused by mutations in the EDA gene, which maps to the X chromosome and encodes a protein called ectodysplasin-A, a member of the tumor necrosis factor-related ligand family. Affected males typically exhibit all the typical features of HED, but heterozygous carriers may show mild to moderate clinical manifestations. We describe the case of a Spanish family in which a novel heterozygous c.733_734insGA mutation at the EDA gene was identified. It was located in exon 5 and consisted of a frame-shift mutation at codon 245, which gave rise to an abnormal protein with a premature stop codon after 35 residues. Genetic analyses in families with XLHED are useful for checking carrier status, but they also provide information for genetic counseling and prenatal diagnosis. PMID:21696697

  13. Tumor suppressors status in cancer cell line Encyclopedia.

    Science.gov (United States)

    Sonkin, Dmitriy; Hassan, Mehedi; Murphy, Denis J; Tatarinova, Tatiana V

    2013-08-01

    Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor-promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss of function mutation, copy number (CN) loss, or loss of heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional "status". This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research.

  14. Methods for detection of ataxia telangiectasia mutations

    Science.gov (United States)

    Gatti, Richard A.

    2005-10-04

    The present invention is directed to a method of screening large, complex, polyexonic eukaryotic genes such as the ATM gene for mutations and polymorphisms by an improved version of single strand conformation polymorphism (SSCP) electrophoresis that allows electrophoresis of two or three amplified segments in a single lane. The present invention also is directed to new mutations and polymorphisms in the ATM gene that are useful in performing more accurate screening of human DNA samples for mutations and in distinguishing mutations from polymorphisms, thereby improving the efficiency of automated screening methods.

  15. Mutation direction by irradiation in rice

    International Nuclear Information System (INIS)

    The mutation directions of rice were studied. The results indicated that the mutation directions of rice induced by 14C were invert correlation to their genetic backgrounds of tested rice varieties, i.e. early mature and short stem varieties produced later mature and higher stem mutation; late mature and high stem varieties produced earlier mature and shorter stem mutation; the varieties of middle maturity and height produced both direction mutations of earlier and later maturity or shorter and higher stem. The mutation directions induced by 14C were also related to treated doses and stages. Frequency of earlier maturity mutation by protons treatment were higher than those induced by other mutagens. Frequency of later maturity by γ-rays were higher than those induced by other mutagens. Frequency of short stem mutation by synchronous irradiation (soft X-rays) were higher than those induced by other mutagens. Frequency of beneficial mutation induced by proton treatment were higher than those induced by γ-rays

  16. Novel PORCN mutations in focal dermal hypoplasia.

    Science.gov (United States)

    Froyen, G; Govaerts, K; Van Esch, H; Verbeeck, J; Tuomi, M-L; Heikkilä, H; Torniainen, S; Devriendt, K; Fryns, J-P; Marynen, P; Järvelä, I; Ala-Mello, S

    2009-12-01

    Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

  17. Optimal Mutation Rates in Dynamic Environments

    CERN Document Server

    Nilsson, M; Nilsson, Martin; Snoad, Nigel

    2000-01-01

    In this paper we study the evolution of the mutation rate for simple organisms in dynamic environments. A model with multiple fitness coding loci tracking a moving fitness peak is developed and an analytical expression for the optimal mutation rate is derived. Surprisingly it turns out that the optimal mutation rate per genome is approximately independent of genome length, something that also has been observed in nature. Simulations confirm the theoretical predictions. We also suggest an explanation for the difference in mutation frequency between RNA and DNA based organisms.

  18. The mutational spectrum in Waardenburg syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Read, A.P.; Tassabehji, M.; Liu, X.Z. [and others

    1994-09-01

    101 individuals or families with Waardenburg syndrome (WS) or related abnormalities have been screened for mutations in the PAX3 gene. PAX3 mutations were seen in 19 of 35 individuals or families with features of Type I Waardenburg syndrome. None of the 47 Type 2 WS families showed any PAX3 mutation, nor did any of 19 individuals with other neural crest syndromes or pigmentary disturbances. PAX3 mutations included substitutions of highly conserved amino acids, splice site mutations, nonsense mutations and frameshifting deletions or insertions. One patient (with Type 1 WS, mental retardation and growth retardation) had a chromosomal deletion of 7-8 Mb encompassing the PAX3 gene. Mutations were seen in each of exons 2-6, with a concentration in the 5{prime} part of the paired box (exon 2) and the 3{prime} part of the homeobox (exon 6). There was no evident relation between the molecular change and the clinical manifestations in mutation carriers. We conclude that PAX3 dosage effects very specifically produce dystopia canthorum, the distinguishing feature of Type 1 WS, and variably produce the other features of Type 1 WS depending on genetic background or chance events. Two of the Type 2 families showed linkage to markers from 3p14, the location of the MITF gene. MITF encodes a basic helix-loop-helix-zipper protein which is the homologue of the mouse microphthalmia gene product. It is likely that mutations in MITF cause some but not all Type 2 WS.

  19. Status of APEmille

    CERN Document Server

    Bartoloni, A; Cabibbo, Nicola; Calvayrac, F; Della Morte, M; De Pietri, R; De Riso, P; Carlo, F D; Renzo, F D; Errico, W; Frezzotti, R; Giorgino, T; Heitger, J; Lonardo, A; Loukianov, M; Magazzù, G; Micheli, J; Morénas, V; Paschedag, N; Pène, O; Petronzio, Roberto; Pleiter, D; Rapuano, F; Rolf, J; Rossetti, D; Sartori, L; Simma, H; Schifano, F; Torelli, M; Tripiccione, R; Vicini, P; Wegner, P

    2002-01-01

    This paper presents the status of the APEmille project, which is essentially completed, as far as machine development and construction is concerned. Several large installations of APEmille are in use for physics production runs leading to many new results presented at this conference. This paper briefly summarizes the APEmille architecture, reviews the status of the installations and presents some performance figures for physics codes.

  20. Status epilepticus in adults.

    Science.gov (United States)

    Betjemann, John P; Lowenstein, Daniel H

    2015-06-01

    Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

  1. Frequency of telomerase reverse transcripter promoter mutations in desmoplastic melanoma subtypes: analyses of 76 cases.

    Science.gov (United States)

    Yang, Shi; Leone, Dominick; Frydenlund, Noah; Hoang, Mai; Deng, April; Hernandez-Perez, Marier; Biswas, Asok; Singh, Rajendra; Yaar, Ron; Mahalingam, Meera

    2016-08-01

    Estimates of the frequency of telomerase reverse transcripter (TERT) mutations in desmoplastic melanoma (DM) are limited. DM is categorized into subtypes, pure and mixed, differing in prognosis, suggesting genetic heterogeneity. Given this, our aims were to determine the incidence of TERT promoter mutations in DM subtypes and to evaluate its relationship with established histopathologic prognosticators, BRAF and RETp status, and neurofibromin protein expression. Of the archival annotated samples retrieved, 76 cases of DM (48 pure and 28 mixed) fulfilled the criteria for inclusion. PCR amplification of the TERT promoter region was performed on DNA extracted from formalin-fixed paraffin-embedded tissue using primers5'-GCCGATTCGACCTCTCTCC-3' (forward) and 5'-CAGCGCTGCCTGAAACTC-3' (reverse). For each case, appropriate C>T mutations were identified on the electropherograms. Univariate analysis using χ-test was carried out to identify potential confounders; a nested case-control study of demographic, clinical, histopathological, and genetic determinants was carried out using multiple logistic regression. Significant differences in TERT promoter mutation frequencies were noted in the subtypes (mixed vs. pure; 15/28, 54% vs. 11/48, 23%, respectively, P=0.0066). After adjusting for potential confounding, multivariate analyses indicated a three-fold increase in the odds of the TERT mutation for those with the mixed subtype compared with the pure subtype (P=0.04, adjusted odds ratio =3.32). No other significant associations were noted (sex/junctional component/Breslow depth/ulceration/mitoses/host response/RETp, BRAF status, and neurofibromin protein expression). Our findings, the largest to date investigating TERT promoter mutations in DM, support the hypothesis that the subtypes have distinct genetic drivers and underscore the relevance of telomere integrity in the etiopathogenesis of the mixed variant. PMID:27244099

  2. Aneuploidy vs. gene mutation hypothesis of cancer: Recent study claims mutation but is found to support aneuploidy

    OpenAIRE

    Li, Ruhong; Sonik, Arvind; Stindl, Reinhard; Rasnick, David; Duesberg, Peter

    2000-01-01

    For nearly a century, cancer has been blamed on somatic mutation. But it is still unclear whether this mutation is aneuploidy, an abnormal balance of chromosomes, or gene mutation. Despite enormous efforts, the currently popular gene mutation hypothesis has failed to identify cancer-specific mutations with transforming function and cannot explain why cancer occurs only many months to decades after mutation by carcinogens and why solid cancers are aneuploid, although conventional mutation does...

  3. Epidemiology of doublet/multiplet mutations in lung cancers: evidence that a subset arises by chronocoordinate events.

    Directory of Open Access Journals (Sweden)

    Zhenbin Chen

    Full Text Available BACKGROUND: Evidence strongly suggests that spontaneous doublet mutations in normal mouse tissues generally arise from chronocoordinate events. These chronocoordinate mutations sometimes reflect "mutation showers", which are multiple chronocoordinate mutations spanning many kilobases. However, little is known about mutagenesis of doublet and multiplet mutations (domuplets in human cancer. Lung cancer accounts for about 25% of all cancer deaths. Herein, we analyze the epidemiology of domuplets in the EGFR and TP53 genes in lung cancer. The EGFR gene is an oncogene in which doublets are generally driver plus driver mutations, while the TP53 gene is a tumor suppressor gene with a more typical situation in which doublets derive from a driver and passenger mutation. METHODOLOGY/PRINCIPAL FINDINGS: EGFR mutations identified by sequencing were collected from 66 published papers and our updated EGFR mutation database (www.egfr.org. TP53 mutations were collected from IARC version 12 (www-p53.iarc.fr. For EGFR and TP53 doublets, no clearly significant differences in race, ethnicity, gender and smoking status were observed. Doublets in the EGFR and TP53 genes in human lung cancer are elevated about eight- and three-fold, respectively, relative to spontaneous doublets in mouse (6% and 2.3% versus 0.7%. CONCLUSIONS/SIGNIFICANCE: Although no one characteristic is definitive, the aggregate properties of doublet and multiplet mutations in lung cancer are consistent with a subset derived from chronocoordinate events in the EGFR gene: i the eight frameshift doublets (present in 0.5% of all patients with EGFR mutations are clustered and produce a net in-frame change; ii about 32% of doublets are very closely spaced (< or =30 nt; and iii multiplets contain two or more closely spaced mutations. TP53 mutations in lung cancer are very closely spaced (< or =30 nt in 33% of doublets, and multiplets generally contain two or more very closely spaced mutations. Work in

  4. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA ...

  5. Mutation specific functions of EGFR result in a mutation-specific downstream pathway activation

    NARCIS (Netherlands)

    L. Eraslan-Erdem (Lale); Y. Gao; N.K. Kloosterhof (Nanne); Y. Atlasi (Yaser); J.A.A. Demmers (Jeroen); A. Sacchetti (Andrea); J.M. Kros (Johan); P.A.E. Sillevis Smitt (Peter); J.G.J.V. Aerts (Joachim); P.J. French (Pim)

    2015-01-01

    markdownabstractBackground: Epidermal growth factor receptor (EGFR) is frequently mutated in various types of cancer. Although all oncogenic mutations are considered activating, different tumour types have different mutation spectra. It is possible that functional differences underlie this tumour-ty

  6. The prevalence and prognostic significance of KRAS mutation subtypes in lung adenocarcinomas from Chinese populations

    Directory of Open Access Journals (Sweden)

    Zheng DF

    2016-02-01

    Full Text Available Difan Zheng,1,2,* Rui Wang,1,2,* Yang Zhang,1,2 Yunjian Pan,1,2 Xinghua Cheng,3 Chao Cheng,1,2 Shanbo Zheng,1,2 Hang Li,1,2 Ranxia Gong,1,2 Yuan Li,2,4 Xuxia Shen,2,4 Yihua Sun,1,2 Haiquan Chen1–3,51Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, 3Shanghai Chest Hospital, Shanghai Jiao Tong University, 4Department of Pathology, Fudan University Shanghai Cancer Center, 5Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workBackground: We performed this retrospective study to identify the prevalence of KRAS mutation in Chinese populations and make a comprehensive investigation of the clinicopathological features of KRAS mutation in these patients.Patients and methods: Patients from 2007 to 2013 diagnosed with primary lung adenocarcinoma who received a radical resection were examined for KRAS, EGFR, HER2, BRAF mutations, and ALK, RET, and ROS1 fusions. Clinicopathological features, including sex, age, tumor–lymph node–metastasis stage, tumor differentiation, smoking status, histological subtypes, and survival information were analyzed.Result: KRAS mutation was detected in 113 of 1,368 patients. Nine different subtypes of KRAS mutation were identified in codon 12, codon 13, and codon 61. KRAS mutation was more frequently found in male patients and former/current smoker patients. Tumors with KRAS mutation had poorer differentiation. Invasive mucinous adenocarcinoma predominant and solid predominant subtypes were more frequent in KRAS mutant patients. No statistical significance was found in relapse-free survival or overall survival between patients with KRAS mutation and patients with other mutations.Conclusion: In Chinese populations, we identified KRAS mutation in 8.3% (113/1,368 of the patients with lung adenocarcinoma. KRAS mutation defines a molecular subset of

  7. Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability.

    Science.gov (United States)

    Choi, Youn Jin; Oh, Hye Rim; Choi, Mi Ryoung; Gwak, Min; An, Chang Hyeok; Chung, Yeun Jun; Yoo, Nam Jin; Lee, Sug Hyung

    2014-08-01

    Histone methyltransferase (HMT), which catalyzes a histone methylation, is frequently altered in cancers at mutation and expression levels. The aims of this study were to explore whether SETD1B, SETDB2, and SETD2, SET domain-containing HMT genes, are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). In a public database, we found that SETD1B, SETDB2, and SETD2 had mononucleotide repeats in coding sequences that might be mutation targets in cancers with microsatellite instability (MSI). We analyzed the mutations in 76 GCs and 93 CRCs and found SETD1B (38.7% of GC and 35.6% of CRC with high MSI [MSI-H]), SETDB2 (11.1% of CRC with MSI-H), and SETD2 frameshift mutations (6.7% of CRC with MSI-H). These mutations were not found in stable MSI/low MSI. In addition, we analyzed intratumoral heterogeneity (ITH) of SETD1B mutation in 6 CRCs and found that 2 CRCs harbored regional ITH of SETD1B. We also analyzed SETD1B expression in GC and CRC by immunohistochemistry. Loss of SETD1B expression was identified in 15% to 55% of the GC and CRC with respect to the MSI status. Of note, the loss of expression was more common in those with SETD1B mutations than those with wild-type SETD1B. We identified alterations of SET domain-containing HMT at various levels (frameshift mutations, genetic ITH, and expression loss), which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our data suggest that mutation analysis in multiple regions is needed for a better evaluation of mutation status in CRC with MSI-H.

  8. Rice breeding with induced mutations

    International Nuclear Information System (INIS)

    The Joint FAO/IAEA Division of Atomic Energy in Food and Agriculture decided in 1964 to organize a co-ordinated research programme on the use of induced mutations in rice breeding. The programme was organized within the framework of activities of the International Rice Commission. This is a report of the Third Co-ordination Meeting of the participants, which was held in Taipei, 5-9 June 1967. As the projects, which together make up the co-ordinated programme, are at different stages of progress, the report contains a variety of papers including completed studies, field and progress reports, and highlights of the discussions with some additional recommendations prepared by the participants. Refs, figs and tabs

  9. Studies of human mutation rates

    Energy Technology Data Exchange (ETDEWEB)

    Neel, J.V.

    1990-01-01

    November 1989, marked the beginning of a new three-year cycle of DOE grant support, in connection with which the program underwent a major reorganization. This document presents the progress on the three objectives of the present program which are: to isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; to develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of mutations in the parents of the individual whose DNA is being examined; and, to continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level.

  10. Correlation between {sup 18}F Fluorodeoxyglucose uptake and epidermal growth factor receptor mutations in advanced lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Jung; Cho, Byoung Chul; Jeong, Youg Hyu; Seo, Hyo Jung; Kim, Hyun Jeong; Cho, Arthur; Lee, Jae Hoon; Yun, Mi Jin; Jeon, Tae Joo; Lee, Jong Doo; Kang, Won Jun [Yonsei Univ., Health System, Seoul (Korea, Republic of)

    2012-09-15

    Mutations in the epidermal growth factor receptor (EGFR)gene have been identified as potential targets for the treatment and prognostic factors for non small cell lung cancer (NSCLC). We assessed the correlation between fluorodeoxyglucose (FDG) uptake and EGFR mutations, as well as their prognostic implications. A total of 163 patients with pathologically confirmed NSCLC were enrolled (99 males and 64 females; median age, 60 years). All patients underwent FDG positron emission tomography before treatment, and genetic studies of EGFR mutations were performed. The maximum standardized uptake value (SUVmax)of the primary lung cancer was measured and normalized with regard to liver uptake. The SUVmax between the wild type and EGFR mutant groups was compared. Survival was evaluated according to SUVmax and EGFR mutation status. EGFR mutations were found in 57 patients (60.8%). The SUVmax tended to be higher in wild type than mutant tumors, but was not significantly different (11.1{+-}5.7 vs. 9.8{+-}4.4, P=0.103). The SUVmax was significantly lower in patients with an exon 19 mutation than in those with either an exon 21 mutation or wild type (P=0.003 and 0.009, respectively). The EGFR mutation showed prolonged overall survival (OS) compared to wild type tumors (P=0.004). There was no significant difference in survival according to SUVmax. Both OS and progression free survival of patients with a mutation in exon 19 were significant longer than in patients with wild type tumors. In patients with NSCLC, a mutation in exon 19 was associated with a lower SUVmax and is a reliable predictor for good survival.

  11. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases.

    Science.gov (United States)

    Koczkowska, Magdalena; Zuk, Monika; Gorczynski, Adam; Ratajska, Magdalena; Lewandowska, Marzena; Biernat, Wojciech; Limon, Janusz; Wasag, Bartosz

    2016-07-01

    The overall prevalence of germline BRCA1/2 mutations is estimated between 11% and 15% of all ovarian cancers. Individuals with germline BRCA1/2 alterations treated with the PARP1 inhibitors (iPARP1) tend to respond better than patients with wild-type BRCA1/2. Additionally, also somatic BRCA1/2 alterations induce the sensitivity to iPARP1. Therefore, the detection of both germline and somatic BRCA1/2 mutations is required for effective iPARP1 treatment. The aim of this study was to identify the frequency and spectrum of germline and somatic BRCA1/2 alterations in a group of Polish patients with ovarian serous carcinoma. In total, 100 formalin-fixed paraffin-embedded (FFPE) ovarian serous carcinoma tissues were enrolled to the study. Mutational analysis of BRCA1/2 genes was performed by using next-generation sequencing. The presence of pathogenic variants was confirmed by Sanger sequencing. In addition, to confirm the germline or somatic status of the mutation, the nonneoplastic tissue was analyzed by bidirectional Sanger sequencing. In total, 27 (28% of patient samples) mutations (20 in BRCA1 and 7 in BRCA2) were identified. For 22 of 27 patients, nonneoplastic cells were available and sequencing revealed the somatic character of two BRCA1 (2/16; 12.5%) and two BRCA2 (2/6; 33%) mutations. Notably, we identified six novel frameshift or nonsense BRCA1/2 mutations. The heterogeneity of the detected mutations confirms the necessity of simultaneous analysis of BRCA1/2 genes in all patients diagnosed with serous ovarian carcinoma. Moreover, the use of tumor tissue for mutational analysis allowed the detection of both somatic and germline BRCA1/2 mutations. PMID:27167707

  12. GJC2 Missense Mutations Cause Human Lymphedema

    OpenAIRE

    Ferrell, Robert E; Baty, Catherine J.; Kimak, Mark A.; Karlsson, Jenny M; Lawrence, Elizabeth C.; Franke-Snyder, Marlise; Meriney, Stephen D.; Feingold, Eleanor; Finegold, David N.

    2010-01-01

    Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in mainta...

  13. Mutation update for the PORCN gene

    DEFF Research Database (Denmark)

    Lombardi, Maria Paola; Bulk, Saskia; Celli, Jacopo;

    2011-01-01

    , the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all...

  14. Finite mutation classes of coloured quivers

    CERN Document Server

    Torkildsen, Hermund André

    2010-01-01

    We consider the general notion of coloured quiver mutation and show that the mutation class of a coloured quiver $Q$, arising from an $m$-cluster tilting object associated with $H$, is finite if and only if $H$ is of finite or tame representation type, or it has at most 2 simples. This generalizes a result known for 1-cluster categories.

  15. Silting mutation for self-injective algebras

    CERN Document Server

    Aihara, Takuma

    2010-01-01

    We study `silting mutaion' for self-injective algebras. In particular we focus on `tilting mutation' and show that iterated irreducible `silting mutation' transitively act on the set of silting objects for representation-finite symmetric algebras. Moreover we give some sufficient conditions for `Bongartz-type Lemma' on silting objects.

  16. Model for Mutation in Bacterial Populations

    Science.gov (United States)

    Donangelo, R.; Fort, H.

    2002-07-01

    We describe the evolution of E. coli populations through a Bak-Sneppen-type model which incorporates random mutations. We show that, for a value of the mutation level which coincides with the one estimated from experiments, this model reproduces the measures of mean fitness relative to that of a common ancestor, performed for over 10 000 bacterial generations.

  17. A model for mutation in bacterial populations

    OpenAIRE

    Donangelo, R.; Fort, H.

    2002-01-01

    We describe the evolution of $E.coli$ populations through a Bak-Sneppen type model which incorporates random mutations. We show that, for a value of the mutation level which coincides with the one estimated from experiments, this model reproduces the measures of mean fitness relative to that of a common ancestor, performed for over 10,000 bacterial generations.

  18. Mutation Breeding in Root and Tuber Crops

    International Nuclear Information System (INIS)

    Proceeded by a few general considerations about problems and results of mutation breeding in vegetatively propagated plants a review is given of the results of mutation breeding programs up to new in the different (tropical) root and tuber crops (cassava, sweet potato, yam, potato and others). (author)

  19. The mutation rate to Huntington's chorea

    OpenAIRE

    Shaw, Michael; Caro, Adrian

    1982-01-01

    The problems of estimating the mutation rate to Huntington's chorea, or the proportion of new mutants among all sufferers, are discussed. The available survey data are reviewed. The prevalence of sporadic phenotypes, which include new mutations, is probably less than 2·5%. New mutants probably make up around 0·1% or less of all sufferers.

  20. De novo mutations in epileptic encephalopathies.

    Science.gov (United States)

    Allen, Andrew S; Berkovic, Samuel F; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E; Epstein, Michael P; Glauser, Tracy; Goldstein, David B; Han, Yujun; Heinzen, Erin L; Hitomi, Yuki; Howell, Katherine B; Johnson, Michael R; Kuzniecky, Ruben; Lowenstein, Daniel H; Lu, Yi-Fan; Madou, Maura R Z; Marson, Anthony G; Mefford, Heather C; Esmaeeli Nieh, Sahar; O'Brien, Terence J; Ottman, Ruth; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K; Scheffer, Ingrid E; Sherr, Elliott H; Yuskaitis, Christopher J; Abou-Khalil, Bassel; Alldredge, Brian K; Bautista, Jocelyn F; Berkovic, Samuel F; Boro, Alex; Cascino, Gregory D; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P; Fiol, Miguel; Fountain, Nathan B; French, Jacqueline; Friedman, Daniel; Geller, Eric B; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R; Hayward, Jean; Helmers, Sandra L; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E; Knowlton, Robert C; Kossoff, Eric H; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H; McGuire, Shannon M; Motika, Paul V; Novotny, Edward J; Ottman, Ruth; Paolicchi, Juliann M; Parent, Jack M; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E; Shellhaas, Renée A; Sherr, Elliott H; Shih, Jerry J; Singh, Rani; Sirven, Joseph; Smith, Michael C; Sullivan, Joseph; Lin Thio, Liu; Venkat, Anu; Vining, Eileen P G; Von Allmen, Gretchen K; Weisenberg, Judith L; Widdess-Walsh, Peter; Winawer, Melodie R

    2013-09-12

    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders. PMID:23934111

  1. KIT mutation analysis in mast cell neoplasms

    DEFF Research Database (Denmark)

    Arock, M; Sotlar, K; Akin, C;

    2015-01-01

    Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutat...

  2. Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer

    International Nuclear Information System (INIS)

    Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease. Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples. EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression. Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series

  3. Validation of Deleterious Mutations in Vorderwald Cattle.

    Science.gov (United States)

    Reinartz, Sina; Distl, Ottmar

    2016-01-01

    In Montbéliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbéliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbéliarde bulls through artificial insemination, inbreeding on Montbéliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbéliarde as well as Vorderwald x Montbéliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbéliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible

  4. Latex allergy and filaggrin null mutations

    DEFF Research Database (Denmark)

    Carlsen, Berit C; Meldgaard, Michael; Hamann, Dathan;

    2011-01-01

    Objectives Natural rubber latex (NRL) contains over 200 proteins of which 13 have been identified as allergens and the cause of type I latex allergy. Health care workers share a high occupational risk for developing latex allergy. Filaggrin null mutations increase the risk of type I sensitizations...... to aeroallergens and it is possible that filaggrin null mutations also increase the risk of latex allergy. The aim of this paper was to examine the association between filaggrin null mutations and type I latex allergy. Methods Twenty latex allergic and 24 non-latex allergic dentists and dental assistants......, occupationally exposed to latex, were genotyped for filaggrin null mutations R501X and 2282del4. Latex allergy was determined by a positive reaction or a historical positive reaction to a skin prick test with NRL. Results 41 individuals were successfully genotyped. Three individuals were filaggrin mutation...

  5. Hypomyelinating Leukodystrophy due to HSPD1 Mutations

    DEFF Research Database (Denmark)

    Schioldan Kusk, Maria; Damgaard, Bodil; Risom, Lotte;

    2016-01-01

    The hypomyelinating leukodystrophies (HMLs) encompass the X-linked Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations and known as the classical form of HML as well as Pelizaeus-Merzbacher-like disease (PMLD) (Online Mendelian Inheritance in Man [OMIM] 608804 and OMIM 260600) due to GJC2...... mutations. In addition, mutations in at least 10 other genes are known to cause HMLs. In 2008, an Israeli family with clinical and neuroimaging findings similar to those found in PMD was reported. The patients were found to have a homozygous missense mutation in HSPD1, encoding the mitochondrial heat......-shock protein 60 (Hsp60), and the disorder was defined as the autosomal recessive mitochondrial Hsp60 chaperonopathy (MitCHAP-60) disease. We here report the first case of this severe neurodegenerative disease since it was first described. Given the fact that the families carried the same mutation our patient...

  6. OPTIMISED RANDOM MUTATIONS FOR EVOLUTIONARY ALGORITHMS

    Directory of Open Access Journals (Sweden)

    Sean McGerty

    2014-07-01

    Full Text Available To demonstrate our approaches we will use Sudoku puzzles, which are an excellent test bed for evolutionary algorithms. The puzzles are accessible enough for people to enjoy. However the more complex puzzles require thousands of iterations before an evolutionary algorithm finds a solution. If we were attempting to compare evolutionary algorithms we could count their iterations to solution as an indicator of relative efficiency. Evolutionary algorithms however include a process of random mutation for solution candidates. We will show that by improving the random mutation behaviours we were able to solve problems with minimal evolutionary optimisation. Experiments demonstrated the random mutation was at times more effective at solving the harder problems than the evolutionary algorithms. This implies that the quality of random mutation may have a significant impact on the performance of evolutionary algorithms with Sudoku puzzles. Additionally this random mutation may hold promise for reuse in hybrid evolutionary algorithm behaviours.

  7. Mutation Rates of STR Systems in Danes

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Bøttcher, Susanne Gammelgaard; Christensen, Susanne;

    Danish paternity cases in the period 1999 to 2005 were investigated regarding mutation rates in STR loci. STR-typing was performed by the Applied Biosystems AmplfStr Profiler Plus kit in the period 1999 to early 2005, hereafter named the PP9, and by Applied Biosystems AmplfStr Identifier kit...... for the rest of 2005, hereafter named the IDFL. All cases with one to four genetic inconsistencies were manually inspected by two forensic geneticists and statistically analyzed by five statisticians. We found no significant effect of kits and no interaction of kits and STRA loci, but differences in mutation...... rates on different STR loci. In the cases where mutations had occured, we found no interaction between kits, STRA loci or sexes. However, we found differences in the mutation rates between the sexes, meaning that the differences in male and female mutation rates can be assumed constant over STR loci...

  8. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene

    International Nuclear Information System (INIS)

    Additional mutations in the cystic fibrosis (CF) gene were identified in the regions corresponding to the two putative nucleotide (ATP)-binding folds (NBFs) of the predicted polypeptide. The patient cohort included 46 Canadian CF families with well-characterized DNA marker haplotypes spanning the disease locus and several other families from Israel. Eleven mutations were found in the first NBF, 2 were found in the second NBF, but none was found in the R-domain. Seven of the mutations were of the missense type affecting some of the highly conserved amino acid residues in the first NBF; 3 were nonsense mutations; 2 would probably affect mRNA splicing; 2 corresponded to small deletions, including another 3-base-pair deletion different from the major mutation (δF508), which could account for 70% of the CF chromosomes in the population. Nine of these mutations accounted for 12 of the 31 non-δF508 CF chromosomes in the Canadian families. The highly heterogeneous nature of the remaining CF mutations provides important insights into the structure and function of the protein, but it also suggests that DNA-based genetic screening for CF carrier status will not be straightforward

  9. Detection of BRAF mutation in Chinese tumor patients using a highly sensitive antibody immunohistochemistry assay

    Science.gov (United States)

    Qiu, Tian; Lu, Haizhen; Guo, Lei; Huang, Wenting; Ling, Yun; Shan, Ling; Li, Wenbin; Ying, Jianming; Lv, Ning

    2015-03-01

    BRAF mutations can be found in various solid tumors. But accurate and reliable screening for BRAF mutation that is compatible for clinical application is not yet available. In this study, we used an automated immunohistochemistry (IHC) staining coupled with mouse monoclonal anti-BRAF V600E (VE1) primary antibody to screen the BRAF V600E mutation in 779 tumor cases, including 611 colorectal carcinomas (CRC), 127 papillary thyroid carcinomas (PTC) and 41 malignant melanomas. Among the 779 cases, 150 cases were positive for BRAF (V600E) staining, including 38 (of 611, 6%) CRCs, 102 (of 127, 80%) PTCs and 10 (of 41, 24%) malignant melanomas. Sanger sequencing and real-time PCR confirmed the sensitivity and specificity of IHC staining for the V600E mutation are 100% and 99%, respectively. Therefore, our study demonstrates that the fully automated IHC is a reliable tool to determine BRAF mutation status in CRC, PTC and melanoma and can be used for routine clinical screen.

  10. Correlation of p53 gene mutation and expression of P53 protein in cholangiocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Fang Liu; Hao Zhang; Shi-Guang Zhu; Xian-Ting Zhou; Hai-Long Su; Zheng Xu; Shao-Jun Li

    2006-01-01

    AIM: To characterize the tumor suppressor gene p53 mutations and study the correlation of p53 gene mutation and the expression of P53 protein in cholangiocarcinoma.METHODS: A total of 36 unselected, frozen samples of cholangiocarcinoma were collected. p53 gene status(exon 5-8) and P53 protein were examined by automated sequencing and immunohistochemical staining, combined with the clinical parameters of patients.RESULTS: p53 gene mutations were found in 22 of 36 (61.1%) patients. Nineteen of 36 (52.8%) patients were positive for P53 protein expression. There were significant differences in extent of differentiation and invasion between the positive and negative expression of P53 protein. However, there were no significant differences in pathologic parameters between the mutations and non-mutations.CONCLUSION: The alterations of the p53 gene evaluated by DNA sequence analysis is relatively accurate. Expression of P53 protein could not act as an independent index to estimate the prognosis of cholangiocarcinoma.

  11. Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi.

    Science.gov (United States)

    Yélamos, Oriol; Merkel, Emily A; Sholl, Lauren Meldi; Zhang, Bin; Amin, Sapna M; Lee, Christina Y; Guitart, Gerta E; Yang, Jingyi; Wenzel, Alexander T; Bunick, Christopher G; Yazdan, Pedram; Choi, Jaehyuk; Gerami, Pedram

    2016-09-01

    Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN.

  12. Mutational specificity of γ-rays

    International Nuclear Information System (INIS)

    The aim of the study described in this thesis was to get more information on the mutagenic properties of radiation-induced DNA modifications and the possible mechanisms involved in radiation-induced mutagenesis, principally by investigating the kinds of mutations by DNA sequence analysis. The mutations were analyzed after γ-irradiation of recombinant bacteriophage M13 and plasmide pUC DNA in diluted aqueous solutions, followed by transfection or transformation to E. coli cells, in which the damaged DNA molecules are repaired and replicated. Error-prone repair, misrepair or bypass of lesions during replication may lead to the introduction of mutations. Both the M13 and the plasmid DNA used in our mutation studies contain a mutation target sequence, which makes an easy selection and sequence analysis of mutant DNA molecules possible. Under the radiation conditions used, e.g. irradiation of diluted aqueous DNA solutions, only DNA damage occurs introduced by the water derived OH* and H* radicals and the hydrated electrons. By using different gas conditions during irradiation the relative yields of these reaction species can be manipulated, which opens up the opportunity to determine their effects separately. The mutation spectrum obtained in double-stranded (ds) M13DNA after irradiation under oxic conditions and the mutation spectrum obtained under the same conditions and in the same mutation target but cloned in plasmid DNA, are described. The mutation specificity under anoxic conditions in ds M13DNA is given. Results obtained after irradiation of ds M13DNA under N2 conditions are discussed together with experiments with single-stranded DNA. Similarities and differences between radiation-induced mutation spectra obtained by other groups and those presented in this thesis are discussed. (author). 155 refs.; 134 figs.; 16 tabs

  13. Mutations affecting gyrase in Haemophilus influenzae

    Energy Technology Data Exchange (ETDEWEB)

    Setlow, J.K.; Cabrera-Juarez, E.; Albritton, W.L.; Spikes, D.; Mutschler, A.

    1985-11-01

    Mutants separately resistant to novobiocin, coumermycin, nalidixic acid, and oxolinic acid contained gyrase activity as measured in vitro that was resistant to the antibiotics, indicating that the mutations represented structural alterations of the enzyme. One Novr mutant contained an altered B subunit of the enzyme, as judged by the ability of a plasmid, pNov1, containing the mutation to complement a temperature-sensitive gyrase B mutation in Escherichia coli and to cause novobiocin resistance in that strain. Three other Novr mutations did not confer antibiotic resistance to the gyrase but appeared to increase the amount of active enzyme in the cell. One of these, novB1, could only act in cis, whereas a new mutation, novC, could act in trans. An RNA polymerase mutation partially substituted for the novB1 mutation, suggesting that novB1 may be a mutation in a promoter region for the B subunit gene. Growth responses of strains containing various combinations of mutations on plasmids or on the chromosome indicated that low-level resistance to novobiocin or coumermycin may have resulted from multiple copies of wild-type genes coding for the gyrase B subunit, whereas high-level resistance required a structural change in the gyrase B gene and was also dependent on alteration in a regulatory region. When there was mismatch at the novB locus, with the novB1 mutation either on a plasmid or the chromosome, and the corresponding wild-type gene present in trans, chromosome to plasmid recombination during transformation was much higher than when the genes matched, probably because plasmid to chromosome recombination, eliminating the plasmid, was inhibited by the mismatch.

  14. Software Mutational Robustness: Bridging The Gap Between Mutation Testing and Evolutionary Biology

    CERN Document Server

    Schulte, Eric; Fast, Ethan; Forrest, Stephanie; Weimer, Westley

    2012-01-01

    In the mutation testing paradigm, test suite quality is measured by its ability to detect variant programs generated through application of random changes to an original program. In evolutionary biology however, neutral mutations that leave fitness unchanged are considered to be beneficial---improving the system's robustness and ability to discover evolutionary improvements. In this paper, we generate a population of variant programs from an original program by applying lightweight random mutations. We adopt biological terminology and refer to undetected variants as neutral, and the percentage of all variants that are neutral as mutational robustness. Although they are related to equivalent mutants in mutation testing, which are viewed as problematic, we show positive properties of neutral variants which are easily generated and can be used to protect software against unknown defects. Even when mutations are restricted to statements executed by the test suit, we find that mutational robustness is high: 36.75%...

  15. NAIP Status Maps Gallery

    Data.gov (United States)

    Farm Service Agency, Department of Agriculture — NAIP Status Maps Gallery. These maps illustrate what aerial imagery collection is planned, whats been collected, when it is available and how it is available. These...

  16. Aleutian Goose Status Report

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This 1995-96 status report includes the most recent observations of Aleutian Canada geese populations wintering in the El Sobrante and East San Francisco Bay areas...

  17. Deadline Compliance Status Reports

    Data.gov (United States)

    Department of Housing and Urban Development — These monthly Deadline Compliance Status Reports assist Participating Jurisdictions and HUD Field Offices in monitoring compliance with the 2-year commitment and...

  18. Topical report review status

    International Nuclear Information System (INIS)

    A Topical Report Review Status is scheduled to be published semi-annually. The primary purpose of this document is to provide periodic progress reports of on-going topical report reviews, to identify those topical reports for which the Nuclear Regulatory Commission (NRC) staff review has been completed and, to the extent practicable, to provide NRC management with sufficient information regarding the conduct of the topical report program to permit taking whatever actions deemed necessary or appropriate. This document is also intended to be a source of information to NRC Licensing Project Managers and other NRC personnel regarding the status of topical reports which may be referenced in applications for which they have responsibility. This status report is published primarily for internal NRC use in managing the topical report program, but is also used by NRC to advise the industry of report review status

  19. Partial motor status epilepticus

    OpenAIRE

    Gilberto Rebello de Mattos; José C. Rollemberg Filho

    1992-01-01

    We report the case of a young female patient with photosensitive primary epilepsy who presented partial motor status epilepticus provoked by the act of shutting the eyes. Clinical, EEG and neuroimage data are presented and discussed.

  20. Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

    Directory of Open Access Journals (Sweden)

    Rasic Milic V.

    2014-12-01

    Full Text Available Duchenne muscular dystrophy (DMD is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation- dependent probe amplification (MLPA, polymerase chain reaction (PCR] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale. In 37 patients with an estimated full scale intelligence quotient (FSIQ, six (16.22% had borderline intelligence (70mutations when boundaries were set at exons 30 and 45. However, FSIQ was statistically significantly associated with mutation location when we assumed their functional consequence on dystrophin isoforms and when mutations in the 5’-untranslated region (5’UTR of Dp140 (exons 45-50 were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients.

  1. Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

    Science.gov (United States)

    Milic Rasic, V; Vojinovic, D; Pesovic, J; Mijalkovic, G; Lukic, V; Mladenovic, J; Kosac, A; Novakovic, I; Maksimovic, N; Romac, S; Todorovic, S; Savic Pavicevic, D

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70mutations when boundaries were set at exons 30 and 45. However, FSIQ was statistically significantly associated with mutation location when we assumed their functional consequence on dystrophin isoforms and when mutations in the 5′-untranslated region (5′UTR) of Dp140 (exons 45–50) were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients. PMID:25937795

  2. Five novel mutations of GALNS in Korean patients with mucopolysaccharidosis IVA.

    Science.gov (United States)

    Park, Hyung-Doo; Ko, Ah-Ra; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Jong-Won; Cho, Sung Yoon; Kim, Se Hwa; Park, Sung Won; Sohn, Young Bae; Jin, Dong-Kyu

    2013-03-01

    Mucopolysaccharidosis IVA (MPS IVA; OMIM #253000) is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme involved in the catabolism of keratan and chondroitin sulfate. In this study, we examined biochemical and genetic data from 6 Korean patients presenting with classic MPS IVA by measuring GALNS activity in peripheral blood leukocytes and skin fibroblasts. We initially identified Korean patients with MPS IVA by clinical, biochemical, and genetic analyses. We performed PCR-direct sequencing to identify molecular defects of the GALNS gene in patients and assessed the mutational statuses of family members as well as 50 healthy unrelated subjects. In silico analyses were performed to check for novel mutations. The mean age of the six female patients was 8.0 ± 5.2 years (range: 2-17 years), and were all found to have severe reductions of GALNS enzyme. A total of 12 mutant alleles were identified, corresponding to 7 different mutations. Five novel mutations were c.218A>G (p.Y73C), c.451C>A (p.P151T), c.725C>G (p.S242C), c.752G>A (p.R251Q), and c.1000C>T (p.Q334X). Two other mutations were c.1156C>T (p.R386C) and c.1243-1G>A. Two mutations, c.451C>A and c.1000C>T, accounted for 58% of all mutations in this sample.

  3. Laminin gene LAMB4 is somatically mutated and expressionally altered in gastric and colorectal cancers.

    Science.gov (United States)

    Choi, Mi Ryoung; An, Chang Hyeok; Yoo, Nam Jin; Lee, Sug Hyung

    2015-01-01

    Laminins are important in tumor invasion and metastasis as well as in maintenance of normal epithelial cell structures. However, mutation status of laminin chain-encoding genes remains unknown in cancers. Aim of this study was to explore whether laminin chain genes are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). In a public database, we found that laminin chain genes LAMA1, LAMA3, LAMB1 and LAMB4 had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the genes in 88 GC and 139 CRC [high MSI (MSI-H) or stable MSI/low MSI (MSS/MSI-L)] by single strand conformation polymorphism analysis and DNA sequencing. In the present study, we found LAMB4 (11.8% of GC and 7.6% of CRC with MSI-H), LAMA3 (2.9% of GC and 2.5 of CRC with MSI-H), LAMA1 (5.9% of GC with MSI-H) and LAMB1 frameshift mutations (1.3% of CRC with MSI-H). These mutations were not found in MSS/MSI-L (0/114). We also analyzed LAMB4 expression in GC and CRC by immunohistochemistry. Loss of LAMB4 expression was identified in 17-32% of the GC and CRC. Of note, the loss expression was more common in the cancers with LAMB4 mutation or those with MSI-H. Our data show that frameshift mutations of LAMA1, LAMA3, LAMB1 and LAMB4, and loss of LAMB4 may be features of GC and CRC with MSI-H. PMID:25257191

  4. Increased oxidative damage in carriers of the germline TP53 p.R337H mutation.

    Directory of Open Access Journals (Sweden)

    Gabriel S Macedo

    Full Text Available Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS and Li-Fraumeni-like (LFL Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H. The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17 and non-carriers (NC, n = 17. We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively. Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20±0.71, C = 160.5±0.88, P<0.0001. Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.

  5. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    International Nuclear Information System (INIS)

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations

  6. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, Charlene; Zhang, Junran, E-mail: Junran.zhang@case.edu

    2015-10-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.

  7. STATUS GIZI DAN STATUS KESEHATAN SUKU BADUY

    Directory of Open Access Journals (Sweden)

    Faisal Anwar

    2012-03-01

    Full Text Available 800x600 Normal 0 false false false IN X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Calibri","sans-serif"; mso-bidi-font-family:"Times New Roman";} The objectives of the study were: (1 To analyze the socio-economic and demographic characteristics of Baduy people; (2 To analyze the health status and nutritional status of Baduy people and its influential factors. This research is an explorative and descriptive study on the socio-cultural aspects of food system. The data were collected through a direct interview and discussion with respondents as well as a direct observation at the location of respondents. A sample size of 338 households was drawn from the population. To obtain the data on the cultural aspects, history and  socio aspect of food, in-depth interviews was conducted with 19 key persons. The study was last for 12 months. In Outer Baduy, the factors significantly related to nutritional status are age, number of household size, income, nutritional knowledge, and wife’s ability to read. In Moslem Baduy, only age and income are related to the nutritional status of children. In Moslem Baduy and the Outer Baduy, the correlation between age and W/A or W/H is similar: namely, the higher the age, the lower would the Z-score for the W/A or W/H. The income is significantly correlated to the child nutritional status according to Z-score for W/A with a high correlation coefficient, that is, 0.61. This means that the higher the income, the higher would be the Z-score value for the W/A.  The distribution of adults according to BMI classification in Outer Baduy it shows that 12.7% husbands and 17.6% wives are thin (wasted, while the

  8. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer

    Science.gov (United States)

    Ellis, Matthew J; Lin, Li; Crowder, Robert; Tao, Yu; Hoog, Jeremy; Snider, Jacqueline; Davies, Sherri; DeSchryver, Katherine; Evans, Dean B; Steinseifer, Jutta; Bandaru, Raj; Liu, WeiHua; Gardner, Humphrey; Semiglazov, Vladimir; Watson, Mark; Hunt, Kelly; Olson, John; Baselga, José

    2010-01-01

    Background Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in ~30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Methods Exon 9 (helical domain - HD) and Exon 20 (kinase domain- KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials. Interactions with clinical, pathological and biomarker response parameters were examined. Results A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected (N=235 P=<0.05), but not with treatment-induced changes in Ki67-based proliferation index (N=418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log rank P=0.02) in the P024 trial (N=153). The favorable prognostic effect was maintained in a multivariable analysis (N=125) that included the preoperative prognostic index (PEPI), an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9–105 P=0.01). Conclusion PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA kinase domain mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained. PMID:19844788

  9. Status of ADSW 2005

    DEFF Research Database (Denmark)

    Hartmann, H.; Ahring, Birgitte Kiær

    2006-01-01

    The status of the recent developments in anaerobic digestion of solid waste (ADSW) is outlined on the basis of a selection of papers presented at the 4(th) International Symposium on ADSW 2005.......The status of the recent developments in anaerobic digestion of solid waste (ADSW) is outlined on the basis of a selection of papers presented at the 4(th) International Symposium on ADSW 2005....

  10. STATUS EPILEPTICUS: A REVIEW

    Directory of Open Access Journals (Sweden)

    B. Adibeik

    2009-01-01

    Full Text Available ObjectiveStatus Epilepticus (SE has been described as a series of major motor seizure without recovery of consciousness between seizures.SE is a medical emergency that requires prompt diagnosis and appropriate treatment.In this article we shall conclude history, epidemiology, etiology, risk factors, thebest management as well as the prognosis of the condition.Keywords:Status Epilepticus (SE, adults, children, neonates.

  11. Status of numerical relativity

    Indian Academy of Sciences (India)

    Masaru Shibata

    2004-10-01

    I describe the current status of numerical relativity from my personal point of view. Here, I focus mainly on explaining the numerical implementations necessary for simulating general relativistic phenomena such as the merger of compact binaries and stellar collapse, emphasizing the well-developed current status of such implementations that enable simulations for several astrophysical phenomena. Some of our latest results for simulation of binary neutron star mergers are briefly presented.

  12. Economic Aspects of Using Induced Mutations in Plant Breeding

    International Nuclear Information System (INIS)

    Economic aspects of mutation plant breeding are considered in relation to basic principles of mutation induction and selection, when to use mutations in plant breeding programmes and mutation breeding strategies. The following basic principles of mutation plant breeding are outlined: - A imitation is induced in a single cell and expressed in the progeny from that cell. - Expression of a mutation is influenced by its genetic nature and the breeding system of the organism. - The mutation frequency determines the number of cell progenies that have to be examined to detect a particular mutant. - Random mutations in quantitatively inherited characters generally result in an increase in variance and a shift in the mean. Mutation rates for various types of mutations have been estimated and population sizes for mutation plant breeding experiments calculated. Based upon these principles the potential for using induced mutations in plant breeding and some breeding strategies are outlined. (author)

  13. EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases

    International Nuclear Information System (INIS)

    The presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) is associated with increased radiosensitivity in vitro. However, the results from clinical studies regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. We retrospectively analyzed our NSCLC patients who had been regularly followed up by imaging studies after irradiation for brain metastases, and investigated the impact of EGFR mutations on radiotherapy (RT). Forty-three patients with brain metastases treated with RT, together with EGFR mutation status, demographics, smoking history, performance status, recursive partitioning analysis (RPA) class, tumor characteristics, and treatment modalities, were included. Radiological images were taken at 1 to 3 months after RT, and 3 to 6 months thereafter. Radiographic response was evaluated by RECIST criteria version 1.1 according to the intracranial images before and after RT. Log-rank test and Cox regression model were used to correlate EGFR mutation status and other clinical features with intracranial radiological progression-free survival (RPFS) and overall survival (OS). The median follow-up duration was 15 months. Patients with mutant EGFR had higher response rates to brain RT than those with wild-type EGFR (80% vs. 46%; p = 0.037). Logistic regression analysis showed that EGFR mutation status is the only predictor for treatment response (p = 0.032). The median intracranial RPFS was 18 months (95% CI = 8.33-27.68 months). In Cox regression analysis, mutant EGFR (p = 0.025) and lower RPA class (p = 0.026) were associated with longer intracranial RPFS. EGFR mutation status (p = 0.061) and performance status (p = 0.076) had a trend to predict OS. Mutant EGFR in NSCLC patients is an independent prognostic factor for better treatment response and longer intracranial RPFS following RT for brain metastases

  14. EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases

    Science.gov (United States)

    2012-01-01

    Background The presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) is associated with increased radiosensitivity in vitro. However, the results from clinical studies regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. We retrospectively analyzed our NSCLC patients who had been regularly followed up by imaging studies after irradiation for brain metastases, and investigated the impact of EGFR mutations on radiotherapy (RT). Methods Forty-three patients with brain metastases treated with RT, together with EGFR mutation status, demographics, smoking history, performance status, recursive partitioning analysis (RPA) class, tumor characteristics, and treatment modalities, were included. Radiological images were taken at 1 to 3 months after RT, and 3 to 6 months thereafter. Radiographic response was evaluated by RECIST criteria version 1.1 according to the intracranial images before and after RT. Log-rank test and Cox regression model were used to correlate EGFR mutation status and other clinical features with intracranial radiological progression-free survival (RPFS) and overall survival (OS). Results The median follow-up duration was 15 months. Patients with mutant EGFR had higher response rates to brain RT than those with wild-type EGFR (80% vs. 46%; p = 0.037). Logistic regression analysis showed that EGFR mutation status is the only predictor for treatment response (p = 0.032). The median intracranial RPFS was 18 months (95% CI = 8.33-27.68 months). In Cox regression analysis, mutant EGFR (p = 0.025) and lower RPA class (p = 0.026) were associated with longer intracranial RPFS. EGFR mutation status (p = 0.061) and performance status (p = 0.076) had a trend to predict OS. Conclusions Mutant EGFR in NSCLC patients is an independent prognostic factor for better treatment response and longer intracranial RPFS following RT for brain metastases. PMID:23110940

  15. Low prevalence of K-RAS, EGF-R and BRAF mutations in sinonasal adenocarcinomas. Implications for anti-EGFR treatments.

    Science.gov (United States)

    Franchi, Alessandro; Innocenti, Duccio Rossi Degli; Palomba, Annarita; Miligi, Lucia; Paiar, Fabiola; Franzese, Ciro; Santucci, Marco

    2014-07-01

    We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR (p = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies.

  16. Experience of BRCA1/2 mutation-negative young women from families with hereditary breast and ovarian cancer: a qualitative study

    OpenAIRE

    Macrae, Lynn; de Souza, Alicia Navarro; Loiselle, Carmen G.; Wong, Nora

    2013-01-01

    Background Little is known about the experience of young women who become aware of their parent’s BRCA1 or BRCA2 (BRCA) mutation status as adolescents or young adults. There is also currently a gap in the literature pertaining to those who are found to be negative for their familial mutation. We aimed to investigate the experience of these mutation-negative young women from hereditary breast and ovarian cancer (HBOC) families. Methods Using a semi-structured questionnaire we interviewed 8 wom...

  17. SOX10 mutations mimic isolated hearing loss.

    Science.gov (United States)

    Pingault, V; Faubert, E; Baral, V; Gherbi, S; Loundon, N; Couloigner, V; Denoyelle, F; Noël-Pétroff, N; Ducou Le Pointe, H; Elmaleh-Bergès, M; Bondurand, N; Marlin, S

    2015-10-01

    Ninety genes have been identified to date that are involved in non-syndromic hearing loss, and more than 300 different forms of syndromic hearing impairment have been described. Mutations in SOX10, one of the genes contributing to syndromic hearing loss, induce a large range of phenotypes, including several subtypes of Waardenburg syndrome and Kallmann syndrome with deafness. In addition, rare mutations have been identified in patients with isolated signs of these diseases. We used the recent characterization of temporal bone imaging aspects in patients with SOX10 mutations to identify possible patients with isolated hearing loss due to SOX10 mutation. We selected 21 patients with isolated deafness and temporal bone morphological defects for mutational screening. We identified two SOX10 mutations and found that both resulted in a non-functional protein in vitro. Re-evaluation of the two affected patients showed that both had previously undiagnosed olfactory defects. Diagnosis of anosmia or hyposmia in young children is challenging, and particularly in the absence of magnetic resonance imaging (MRI), SOX10 mutations can mimic non-syndromic hearing impairment. MRI should complete temporal bones computed tomographic scan in the management of congenital deafness as it can detect brain anomalies, cochlear nerve defects, and olfactory bulb malformation in addition to inner ear malformations. PMID:25256313

  18. Inherited cardiomyopathies caused by troponin mutations

    Institute of Scientific and Technical Information of China (English)

    Qun-Wei Lu; Xiao-Yan Wu; Sachio Morimoto

    2013-01-01

    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.

  19. New mutations in CMT 1 and HNPP

    Energy Technology Data Exchange (ETDEWEB)

    Vandenberghe, A.; Boucherat, M. [Faculty of Pharmacy, Lyon (France); Bonnebouche, C. [Hopital de l`Antiquaille, Lyon (France)] [and others

    1994-09-01

    The majority of mutations in CMT 1 (Charcot-Marie-Tooth disease type 1) are due to a duplication of a 1.5 Mb fragment from chromosome 17 containing the PMP22 myelin gene. In addition, micromutations are found in the genes for PMP22 and myelin Po. We collected data from over one hundred families with a duplication in 17p11.2. In about 10% of these families, a de novo mutation was observed. All parents were clinically examined as normal and correct paternity was confirmed. Some families were informative for polymorphic probes located in the duplicated region, and we could deduce a majority of new mutations to be from paternal origin. HNPP (hereditary neuropathy with liability to pressure palsies) is believed to be the reciprocal product of an unequal crossing over underlying the CMT 1 mutation and is due to a deletion of the 1.5 Mb fragment. One new HNPP mutation was found among 7 deleted HNPP families. This mutation is of paternal origin. Clinically assigned CMT 1 patients without a duplication are screened for micromutations applying the SSCP technique. In one family, a de novo mutation was found in the gene for Po.

  20. Significance of duon mutations in cancer genomes

    Science.gov (United States)

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; de, Subhajyoti

    2016-06-01

    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.

  1. Predicting Resistance Mutations Using Protein Design Algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Frey, K.; Georgiev, I; Donald, B; Anderson, A

    2010-01-01

    Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K*, to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance.

  2. Mutational robustness of gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Aalt D J van Dijk

    Full Text Available Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive. In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence.

  3. Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity

    Institute of Scientific and Technical Information of China (English)

    GUAN Min-Xin

    2006-01-01

    The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U - A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.

  4. Roles of DNA mutation in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumors.

    Science.gov (United States)

    Qiu, Hengbin; Lin, Deigui

    2016-07-01

    The Breast cancer 1, early onset gene (BRCA1) is known to be significantly associated with human familial breast cancer and is identified to play an important role in canine mammary tumors. Here, genetic variations in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumor samples, 15 each of benign and malignant against 10 normal canine mammary tissue samples, were analyzed using the direct sequencing method. The results indicated two point mutations each in the coding region of canine BRCA1 in one benign mammary tumor sample (4702G >T and 4765G >T) and in one malignant canine mammary tumor sample (3619A >G and 4006G >A). No mutations were detected in the normal canine mammary tissue samples. The 4702G >T mutation was found to terminate further translation. The physical effect of the 4765G >T mutation was found to be the repalacement of the glutamate residue with glutamine. The physical effect of the 3619A >G mutation was found to be the replacement of the threonine residue with alanine, and that of mutation 4006G >A was the replacement of the valine residue with isoleucine in the BRCA1 protein. Bisulfite sequencing detected methylated CpG sites in one canine malignant mammary tumor sample. In conclusion, the present study elucidated the mutational status of the BRCA1 coding region and methylation status of the 5' flanking region of BRCA1 in canine mammary tumors. PMID:26888582

  5. Association between FAT1 mutation and overall survival in patients with human papillomavirus–negative head and neck squamous cell carcinoma

    Science.gov (United States)

    Kim, Ki Tae; Kim, Bo‐Sung

    2016-01-01

    Abstract Background The purpose of this study was to characterize the mutation profile of FAT atypical cadherin 1 (FAT1) and determine the prognostic significance of FAT1 mutation for overall survival in patients with human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC). Methods Data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) data portals and used as discovery and validation sets. FAT1 mutational status was determined in 234 and 37 patients with HPV‐negative HNSCC, respectively, and overall survival analysis was performed. For comparison, HPV‐positive patients were also analyzed for overall survival. Results Most of the identified nonsynonymous somatic FAT1 mutations were loss‐of‐function mutations. FAT1 mutation was significantly associated with better overall survival in HPV‐negative patients from both the TCGA cohort (p = .026) and the ICGC cohort (p = .047), but not in HPV‐positive patients. Conclusion FAT1 mutational status is a strong independent prognostic factor in patients with HPV‐negative HNSCC. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E2021–E2029, 2016 PMID:26876381

  6. Screening for EGFR Mutations in Patients with Head and Neck Cancer Treated with Gefitinib on a Compassionate-Use Program: A Hellenic Cooperative Oncology Group Study

    Directory of Open Access Journals (Sweden)

    Samuel Murray

    2010-01-01

    Full Text Available Background and Aim. EGFR is commonly expressed in cancers of the head and neck (H and N, and anti-EGFR agents have demonstrated improvements in outcomes (TTP and OS. The aim of this study was to determine EGFR gene status in H and N cancer patients treated with gefitinib and to correlate mutational status with clinico-pathological data and response. Patients and Methods. Patients with histologically confirmed H and N cancer having failed prior treatment for advanced disease entered this compassionate-use-program. Nineteen patients received gefitinib. EGFR expression was assessed by IHC, gene copy number by FISH, and mutation analysis was conducted for EGFR (18-21, KRAS, BRAF (V600E, and HER-2 exon 20. An additional TKI naive cohort of 73 patients was also screened. Results. Mutations were detected in 6/19 patients (3× EGFR, 1× KRAS, and 2× HER2-exon 20. There were no significant differences in TTP or OS for patients with somatic EGFR mutations. No BRAF mutations were detected. Conclusions. The incidence of EGFR mutations in H and N cancer in this study was 5.3%. No statistically relevant correlations between mutation or gene gain and response or survival were observed. Due to the limited number of patients and low incidence of genetic aberrations in the genes analyzed, additional studies are warranted.

  7. BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy.

    Directory of Open Access Journals (Sweden)

    Diana Meckbach

    Full Text Available BACKGROUND: The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial. PATIENTS AND METHODS: We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options. RESULTS: No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001. The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001 and an elevated serum LDH (hazard ratio 2.5; p<0.001 were the only factors, which independently predicted survival. CONCLUSIONS: No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy.

  8. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics.

    Science.gov (United States)

    Akiyama, M

    2010-03-01

    Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype-phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.

  9. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer.

    Science.gov (United States)

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L

    2016-01-01

    The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID:26590264

  10. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations.

    Science.gov (United States)

    Sampieri, Katia; Hadjistilianou, Theodora; Mari, Francesca; Speciale, Caterina; Mencarelli, Maria Antonietta; Cetta, Francesco; Manoukian, Siranoush; Peissel, Bernard; Giachino, Daniela; Pasini, Barbara; Acquaviva, Antonio; Caporossi, Aldo; Frezzotti, Renato; Renieri, Alessandra; Bruttini, Mirella

    2006-01-01

    Retinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splice-site mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

  11. Studies of human mutation rates

    Energy Technology Data Exchange (ETDEWEB)

    Neel, J.V.

    1991-07-15

    The three objectives of the program are: To isolate by the technique of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), proteins of special interest because of the relative mutability of the corresponding gene, establish the identity of the protein, and, for selected proteins, move to a characterization of the corresponding gene; To develop a more efficient approach, based on 2-D PAGE, for the detection of variants in DNA, with special reference to the identification of a variant in a child not present in either parent of the child (i.e., a mutation); and, To continue an effective interface with the genetic studies on the children of atomic bomb survivors in Japan, with reference to both the planning and implementation of new studies at the molecular level. For administrative purposes, the program is subdivided into four sections, each under the direction of one of the four co-PIs; the progress during the past year will be summarized in accordance with this sectional structure. 1 tab.

  12. Particle Swarm Optimization with Adaptive Mutation

    Institute of Scientific and Technical Information of China (English)

    LU Zhen-su; HOU Zhi-rong; DU Juan

    2006-01-01

    A new adaptive mutation particle swarm optimizer,which is based on the variance of the population's fitness,is presented in this paper.During the rtmning time,the mutation probability for the current best particle is determined by two factors:the variance of the population's fitness and the current optimal solution.The ability of particle swarm optimization (PSO) algorithm to break away from the local optimum is greatly improved by the mutation.The experimental results show that the new algorithm not only has great advantage of convergence property over genetic algorithm and PSO,but can also avoid the premature convergence problem effectively.

  13. Novel pathogenic mutations in the glucocerebrosidase locus.

    Science.gov (United States)

    Duran, Raquel; McNeill, Alisdair; Mehta, Atul; Hughes, Derralyn; Cox, Timothy; Deegan, Patrick; Schapira, Anthony H V; Hardy, John

    2012-08-01

    To determine the frequency of mutations responsible for Gaucher's disease, we systematically sequenced the GBA1 gene as part of a molecular characterization of 73 adult patients in the United Kingdom. Five hitherto unknown pathogenic variants were identified, one of which is a splice site change; the others are novel missense mutations. Given that GBA1 gene mutations are an important risk factor for the development of Parkinson's disease, we contend that a complete analysis and molecular characterization of both the known and novel GBA1 variants will be needed before the biochemical processes underlying this genetic association can be fully understood. PMID:22658918

  14. Pharmacogenomics: mapping monogenic mutations to direct therapy.

    Science.gov (United States)

    Taylor, Palmer

    2012-07-01

    The molecular mapping of mutations that underlie congenital disorders of monogenic origin can result in both a broader understanding of the molecular basis of the disorder and novel therapeutic insights. Indeed, genotyping patients and then replicating the behavior of the mutant gene products in well-defined biochemical or electrophysiological systems will allow tailoring of therapy to be mutation- and protein sequence-dependent. In this issue of the JCI, Shen and colleagues describe such an approach that identified novel mutations in the α subunit of the nicotinic receptor linked to myasthenia gravis. PMID:22728931

  15. Optimal Mutation Rates on Static Fitness Landscpes

    CERN Document Server

    Nilsson, M

    2000-01-01

    We study the evolution of mutation rates for an asexual population living on a static fitness landscape, consisting of multiple peaks forming an evolutionary staircase. The optimal mutation rate is found by maximizing the diffusion towards higher fitness. Surprisingly the optimal genomic copying fidelity is given by Q = e^(-1/ln(n)) (where n is the genome length), independent of all other parameters in the model. Simulations confirm this theoretical result. We also discuss the relation between the optimal mutation rate on static and dynamic fitness landscapes.

  16. Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2.

    Directory of Open Access Journals (Sweden)

    Jung-Sik Kim

    2016-02-01

    Full Text Available Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 mutation. We find that many mutant STAG2 proteins retain their ability to interact with cohesin; however, the presence of mutant STAG2 resulted in a reduction in the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Using AAV-mediated gene targeting, we then introduced nine tumor-derived mutations into the endogenous allele of STAG2 in cultured human cells. While all nonsense mutations led to defects in sister chromatid cohesion and a subset induced anaphase defects, missense mutations behaved like wild-type in these assays. Furthermore, only one of nine tumor-derived mutations tested induced overt alterations in chromosome counts. These data indicate that not all tumor-derived STAG2 mutations confer defects in cohesion, chromosome segregation, and ploidy, suggesting that there are likely to be other functional effects of STAG2 inactivation in human cancer cells that are relevant to cancer pathogenesis.

  17. Clinical Characteristics and Outcomes of Lung Cancer Patients 
with EGFR Mutations in Exons 19 and 21

    Directory of Open Access Journals (Sweden)

    Renwang LIU

    2014-11-01

    cancer patients with EGFR exon 21 mutations, the patients with EGFR exon 19 mutations were younger, and their primary tumors were more likely to occur in the right lung. There were no significant differences between the lung cancer patients with exon 19 and 21 mutations for overall survival, gender, smoking status, histopathology, level of differentiation, and disease stage.

  18. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jie Jin

    Full Text Available Recent genomic sequencing efforts have identified a number of recurrent mutations in myelodysplastic syndromes (MDS that may contribute to disease progression and overall survival, including mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2.Pretreatment bone marrow (BM samples were acquired from mononuclear cells in 146 adult patients with de novo MDS from January 2006 to June 2013. Polymerase chain reaction (PCR and direct sequencing were performed on exon 4 of IDH1/2 genes and mutation status was correlated with overall survival (OS and leukemia-free survival (LFS. We then performed a meta-analysis combining previously published and current studies to explore the effect of IDH mutations on OS and LFS in MDS.In our study, somatic mutations of either IDH gene were discovered in 11 MDS patients (7.53% and were significantly correlated with poorer OS (P = 0.007. IDH mutations were specifically associated with a poorer OS in the intermediate-1 risk group by the International Prognostic Scoring System (IPSS (P = 0.039. In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023. We identified six previous studies of IDH mutations in MDS. A meta-analysis of these studies included 111 MDS patients IDH mutations and 1671 MDS patients with wild-type IDH1/2. The hazard ratios (HRs of OS and LFS for patients with IDH mutations were 1.62 (95% CI, 1.27-2.09 and 2.21 (95% CI, 1.48-3.30, respectively.The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS. Identification of IDH mutations may be pivotal for better risk stratification in MDS patients and improving IPSS score. Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

  19. Multiple mutations and mutation combinations in the sodium channel of permethrin resistant mosquitoes, Culex quinquefasciatus

    Science.gov (United States)

    Li, Ting; Zhang, Lee; Reid, William R.; Xu, Qiang; Dong, Ke; Liu, Nannan

    2012-10-01

    A previous study identified 3 nonsynonymous and 6 synonymous mutations in the entire mosquito sodium channel of Culex quinquefasciatus, the prevalence of which were strongly correlated with levels of resistance and increased dramatically following insecticide selection. However, it is unclear whether this is unique to this specific resistant population or is a common mechanism in field mosquito populations in response to insecticide pressure. The current study therefore further characterized these mutations and their combinations in other field and permethrin selected Culex mosquitoes, finding that the co-existence of all 9 mutations was indeed correlated with the high levels of permethrin resistance in mosquitoes. Comparison of mutation combinations revealed several common mutation combinations presented across different field and permethrin selected populations in response to high levels of insecticide resistance, demonstrating that the co-existence of multiple mutations is a common event in response to insecticide resistance across different Cx. quinquefasciatus mosquito populations.

  20. Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine.

    Directory of Open Access Journals (Sweden)

    Yinchen Shen

    Full Text Available Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61, BRAF (exon 11 and exon 15, PIK3CA (exon 9 and exon 20 and NRAS (codons12, 13 and 61. Clinicopathological characteristics associations were analyzed together with overall survival (OS of metastatic colorectal cancer patients (mCRC. We found 35.9% (242/674 tumors harbored a KRAS mutation, 6.96% (47/675 harbored a BRAF mutation, 9.9% (62/625 harbored a PIK3CA mutation and 4.19% (26/621 harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027 while NRAS mutation almost existed in KRAS wild-types (P<0.001. Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively; BRAF (V600E mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively; proximal tumors appeared a higher PIK3CA mutation (P<0.001 and distant metastatic tumors shared a higher NRAS mutation (P = 0.010. However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.