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Sample records for brca1 tp53 nm-23

  1. Loss of heterozygosity at BRCA1/TP53 in serum DNA from ovarian cancer patients%卵巢癌患者血清DNA BRCA1/TP53基因杂合性丢失的研究

    Institute of Scientific and Technical Information of China (English)

    高海峰; 傅士龙; 屠红; 张国玲; 许凯黎

    2003-01-01

    目的通过对卵巢癌患者血清DNA及其相应肿瘤组织DNA的BRCA1/TP53等位基因杂合性丢失(Loss of Heterozy-gosity,LOH)的研究,探讨上述基因变异与卵巢癌发生发展之间的相关性.方法采用PCR并结合二核苷酸(CA)n重复序列多态性的方法,分别对76例卵巢癌(其中17例伴有匹配新鲜手术标本)及10例卵巢良性肿瘤患者的血清DNA中4个微卫星标志BRCA1(D17S579、D17S855)和TP53(TP53、D17S786)进行LOH检测.结果 17对卵巢癌血清DNA与相应肿瘤组织DNA中BRCA1/TP53 LOH发生频率之间存在明显的相关性(P<0.05).在76例血清DNA标本中59例(77.6%)至少存在一个位点LOH,以及43例(56.6%)可出现两个以上位点LOH,而10例良性肿瘤患者血清DNA均未发现LOH.卵巢癌患者血清DNA中上述基因杂合性丢失频率以及所累及的微卫星位点的数目与FIGO分期呈正相关.结论本文结果提示卵巢癌患者血清DNA与肿瘤组织DNA中BRCA1TP53基因LOH密切相关,从而证实了卵巢癌患者血清DNA主要来源于原发肿瘤组织.鉴于血清BRCA1/TP53 LOH与卵巢癌恶性程度相关,故检测卵巢癌患者血清DNA BRCA1/TP53等位基因LOH有望作为一种反映癌症患者分期及预后的分子标记.

  2. Differential Gene Expression of BRCA1,ERBB2 and TP53 biomarkers between Human Breast Tissue and Peripheral Blood Samples of Breast Cancer.

    Science.gov (United States)

    Zghair, Abdulrazzaq Neamah; Sinha, Deepak Kumar; Kassim, Arkan; Alfaham, Mohmmad; Sharma, Anil K

    2016-01-01

    Breast cancer is a most common malignancy especially in Iraqi women accounting for high morbidity and mortality. Mutations in BRCA1 gene is one of the important genetic predisposing factors inbreast cancer. Similarly ERBB2 and TP53 are also key prognostic markers in breast cancer treatment.We were interested to explore the gene expression profiles of BRCA1, ERBB2 and TP53 in breast cancer women patients from Iraq so as to assess the potential of such markers in breast cancer treatment. The mRNA levels were significantly over-expressed in tumor tissues in comparison to normal ones with p values (pTP53 and benign tissue samples as well. However in blood samples, no considerable expression of these markers was observed. Out of three selected genes, ERBB2 expression was significantly expressed in comparison to BRCA1 and TP53 in cancer tissue. Mutation analysis of BRCA1, ERBB2 and TP53 has been made to find out the region most susceptible to mutations in these genes The BRCA1 exon 11, ERBB2 16 and TP53 exon 5 displayed increased chances of having mutations. We can conclude from the study that differential gene expression of BRCA1, ERBB2 and TP53 at mRNA levels may act as a diagnostic marker of circulating tumor cells having important prognostic value in breast cancer patients.

  3. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Directory of Open Access Journals (Sweden)

    Dirce Maria Carraro

    Full Text Available Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22% [7 in BRCA1 (13%, 4 in BRCA2 (7% and one in TP53 (2% gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes. Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  4. The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil.

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    Schayek, Hagit; De Marco, Luiz; Starinsky-Elbaz, Sigal; Rossette, Mariana; Laitman, Yael; Bastos-Rodrigues, Luciana; da Silva Filho, Agnaldo Lopes; Friedman, Eitan

    2016-01-01

    In Brazil, several recurring mutations in BRCA1 and BRCA2 and a TP53 mutation (R337H) have been reported in high risk breast cancer cases. We hypothesized that these recurring mutations may also be detected in the general population and ovarian cancer cases in the state of Minas Gerais. To test this notion, participants were recruited from the outpatient and the Gynecological clinic in the UFMG Medical Center in Belo Horizonte, Minas Gerais, Brazil. BRCA1 (c.68_69delAG, c.5266dupC, c.181T>G, c.4034delA, c.5123C>A), BRCA2 (c.5946delT, c.8537_8538delAG, 4936_4939delGAAA), the c.156_157insAlu* BRCA2 and the c.1010G>A *TP53 mutation were genotyped using validated techniques. Overall, 513 cancer free participants (273 men) (mean age 47.7 ± 15.1 years) and 103 ovarian cancer cases (mean age at diagnosis 58.7 ± 9.6 years) were studied. None of the participants were found to carry any of the genotyped mutations. We conclude that the recurring mutations in BRCA1, BRCA2 and TP53 cannot be detected in the general population or consecutive ovarian cancer cases in this geographical region in Brazil.

  5. [TP53 mutations and molecular epidemiology].

    Science.gov (United States)

    Otsuka, Kazunori; Ishioka, Chikashi

    2007-05-01

    Tumor suppressor p53 protein is activated by a variety of cellular stresses through several pathways and transactivates its downstream genes, including regulators of cell cycle, apoptosis and DNA repair. The loss of p53 function by TP53 gene mutations therefore fails to activate these genes and is thought to be a critical cause of carcinogenesis and/or tumor progression. TP53 is one of the most frequently mutated genes in human cancer. TP53 mutations are found in about 50% of human cancers, although the frequency of TP53 mutations differs among tumor types. However, the degree of functional disorder of mutant p53 varies according to the type of TP53 mutation. And the effects of p53 on cancer formation and/or progression are influenced by the degree of p53 dysfunction. So it is important to analyze the effects of TP53 mutations carefully according to the oncogenicity of each mutation from the molecular epidemiological point of view. Here, together with some cautions needed for analyzing and interpreting the significance of TP53 gene mutations, we present some examples of the identified specific mutation spectrum and the correlation between the prognosis and TP53 mutation in some cancers.

  6. Expression signature based on TP53 target genes doesn't predict response to TP53-MDM2 inhibitor in wild type TP53 tumors.

    Science.gov (United States)

    Sonkin, Dmitriy

    2015-10-22

    A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.

  7. TP53 dysfunction in diffuse large B-cell lymphoma.

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    Lu, Ting-Xun; Young, Ken H; Xu, Wei; Li, Jian-Yong

    2016-01-01

    The aberrations of TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including malignant lymphomas, especially for diffuse large B cell lymphoma (DLBCL). By regulating many downstream target genes or molecules, TP53 governs major defenses against tumor growth and promotes cellular DNA repair, apoptosis, autophagy, cell cycle arrest, signaling, transcription, immune or inflammatory responses and metabolism. Dysfunction of TP53, including microRNA regulations, copy number alterations of TP53 pathway and TP53 itself, dysregulation of TP53 regulators, and somatic mutations by abnormal TP53 function modes, play an important role in lymphoma generation, progression and invasion. The role of TP53 in DLBCL has been widely explored recently. In this review, we summarized recent advances on different mechanisms of TP53 in DLBCL and new therapeutic approaches to overcome TP53 inactivation.

  8. Gene expression as a function of TP53 status; Genexpression in Abhaengigkeit vom TP53 Status

    Energy Technology Data Exchange (ETDEWEB)

    Wrona, A.; Zschenker, O.; Dikomey, E.; Borgmann, K. [Institut fuer Biophysik und Strahlenbiologie, Universitaetsklinikum Eppendorf Hamburg (Germany)

    2004-07-01

    The goal of the present study was to determine the influence of TP53 on gene expression following radiation exposure and whether this has an effect on the occurrence of chromosome aberrations. [German] Ziel dieser Untersuchung war es, festzustellen, welchen Einfluss TP53 auf die Expression von Genen nach Bestrahlung hat und ob sich dies auf die Bildung von Chromosomenaberrationen auswirkt. (orig.)

  9. Prevalence of TP53 germ line mutations in young Pakistani breast cancer patients.

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    Rashid, Muhammad U; Gull, Sidra; Asghar, Kashif; Muhammad, Noor; Amin, Asim; Hamann, Ute

    2012-06-01

    Women from Pakistan and India are more often diagnosed with early-onset breast cancer than Caucasian women. Given that only 12% of Pakistani women diagnosed with breast cancer at or before 30 years of age have previously been shown to harbor germ line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, the genetic causes of the majority of early-onset cases are unexplained. Since germ line mutations in the tumor suppressor gene TP53 predispose women to early-onset breast cancer, we assessed the prevalence of TP53 mutations in 105 early-onset breast cancer patients from Pakistan, who had previously been found to be negative for BRCA1 and BRCA2 germ line mutations. The patient group included 67 women diagnosed with early-onset breast cancer at or before age 30 with no family history of breast or ovarian cancer (EO30NFH group) and 38 women diagnosed with breast cancer at or before age 40 with one or more first- or second-degree relatives with breast or ovarian cancer (EO40FH group). Mutation analysis of the complete TP53 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. One deleterious mutation, c.499-500delCA in exon 5, was identified in the 105 breast cancer patients (1%). This mutation is novel in the germ line and has not been described in other populations. It was detected in a 28-year-old patient with no family history of breast or ovarian cancer. This mutation is rare as it was not detected in additional 157 recently recruited non-BRCA1 and non-BRCA2-associated early-onset breast cancer patients. Our findings show that TP53 mutations may account for a minimal portion of early-onset breast cancer in Pakistan.

  10. TP53 mutations, expression and interaction networks in human cancers.

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    Wang, Xiaosheng; Sun, Qingrong

    2017-01-03

    Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.

  11. Nutlin‐3a selects for cells harbouring TP 53 mutations

    OpenAIRE

    Kucab, Jill E.; Hollstein, Monica; Volker M. Arlt; Phillips, David H.

    2016-01-01

    TP53 mutations occur in half of all human tumours. Mutagen‐induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock‐in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen‐treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2–5 months) and much effort is expended maintaining TP53‐WT cultures. In order to improve the selectivity of th...

  12. Nutlin-3a selects for cells harbouring TP53 mutations.

    Science.gov (United States)

    Kucab, Jill E; Hollstein, Monica; Arlt, Volker M; Phillips, David H

    2017-02-15

    TP53 mutations occur in half of all human tumours. Mutagen-induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock-in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen-treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2-5 months) and much effort is expended maintaining TP53-WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin-3a, an MDM2 inhibitor that leads to stabilisation and activation of wild-type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin-3a to examine the effect on cell growth and p53 activation. Nutlin-3a induced the p53 pathway in TP53-WT HUFs and inhibited cell growth, whereas most TP53-mutated HUFs were resistant to Nutlin-3a. We then assessed whether Nutlin-3a treatment could discriminate between TP53-WT and TP53-mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin-3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin-3a-resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin-3a-sensitive clones were TP53-WT. These data suggest that including a Nutlin-3a counter-screen significantly improves the specificity and efficiency of the HIMA, whereby TP53-mutated clones are selected prior to sequencing and TP53-WT clones can be discarded.

  13. TP53 Promoter Methylation in Primary Glioblastoma: Relationship with TP53 mRNA and Protein Expression and Mutation Status

    OpenAIRE

    JESIONEK-KUPNICKA, DOROTA; Szybka, Malgorzata; Malachowska, Beata; Fendler, Wojciech; Potemski, Piotr; Piaskowski, Sylwester; Jaskolski, Dariusz; Papierz, Wielislaw; Skowronski, Wieslaw; Och, Waldemar; Kordek, Radzislaw; ZAWLIK, IZABELA

    2014-01-01

    Reduced expression of TP53 by promoter methylation has been reported in several neoplasms. It remains unclear whether TP53 promoter methylation is associated with reduced transcriptional and protein expression in glioblastoma (GB). The aim of our work was to study the impact of TP53 methylation and mutations on TP53 mRNA level and protein expression in 42 molecularly characterized primary GB tumors. We also evaluate the impact of all molecular alterations on the overall patient survival. The ...

  14. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.

    Science.gov (United States)

    Bouaoun, Liacine; Sonkin, Dmitriy; Ardin, Maude; Hollstein, Monica; Byrnes, Graham; Zavadil, Jiri; Olivier, Magali

    2016-09-01

    TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.

  15. TP53 dysfunction in CLL: Implications for prognosis and treatment.

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    Te Raa, Gera D; Kater, Arnon P

    2016-03-01

    Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays. TP53 defects highly affect outcome of immunochemotherapy but also alter response durations of tyrosine kinase inhibitors. Although BCR-targeting agents and Bcl-2-inhibitos have achieved durable responses in some patients with TP53 defects, long-term follow-up is currently lacking. In this review biological and clinical consequences of TP53 dysfunction as well as applicability of currently available methods to detect TP53 defects are described. In addition, proposed novel therapeutic strategies specifically for patients with TP53 dysfunction are discussed. In summary, the only curative treatment option for TP53-defective CLL is still allogeneic hematopoietic stem cell transplantation. Other treatment strategies such as rationale combinations of agents with different (TP53 independent) targets, including kinase inhibitors and inhibitors of anti-apoptotic molecules but also immunomodulatory agents need to be further explored.

  16. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer

    OpenAIRE

    Chien, Jeremy; Sicotte, Hugues; Fan, Jian-Bing; Humphray, Sean; Julie M Cunningham; Kalli, Kimberly R.; Oberg, Ann L.; Hart, Steven N.; Li, Ying; Davila, Jaime I; Baheti, Saurabh; Wang, Chen; Dietmann, Sabine; Atkinson, Elizabeth J.; Yan W Asmann

    2015-01-01

    To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis ...

  17. TP53 gene status affects survival in advanced mycosis fungoides

    Directory of Open Access Journals (Sweden)

    Gitte Wooler

    2016-11-01

    Full Text Available TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF, the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations and their prognostic significance in MF. In this study we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harboured mutations in TP53. Overall survival of the patients with mutated TP53 was significantly shorter than median survival in the age- and stage-matched patients treated in our Institution. Distribution of mutations was heterogenous in TP53 exons, however C>T transitions were common suggesting the causal role of ultraviolet radiation. We propose that TP53 mutation status would be useful for risk stratification of patients with advanced MF.

  18. Analysis list: TP53 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available encedbc.jp/kyushu-u/hg19/target/TP53.1.tsv http://dbarchive.biosciencedbc.jp/kyushu...-u/hg19/target/TP53.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP53.10.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/TP53.Blood.tsv,http://dbarchive.bioscienced...bc.jp/kyushu-u/hg19/colo/TP53.Bone.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TP53.Breast.tsv,http://dbarchive.bioscien...cedbc.jp/kyushu-u/hg19/colo/TP53.Digestive_tract.tsv,http://dbarchive.biosciencedbc

  19. 中国乳腺癌高风险人群中TP53基因胚系突变的研究%Germline mutations of TP53 gene among Chinese families with high risk for breast cancer

    Institute of Scientific and Technical Information of China (English)

    杨晓晨; 胡震; 吴炅; 柳光宇; 狄根红; 陈灿铭; 侯意枫; 黄晓燕; 刘哲斌

    2015-01-01

    Objective To evaluate the role of germline mutations of TP53 gene among a Chinese population with high risk for breast cancer.Methods A total of 81 BRCA-negative breast cancer probands from cancer families were analyzed using targeted capture and next-generation sequencing.Candidate mutations were verified with Sanger sequencing.Co-segregation analyses were carried out to explore the likely pathogenicity of the mutation.Results Of the 81 BRCA-negative patients, 3 exonic mutations in the TP53 gene were identified in 3 breast cancer patients.Of these, 2 mutations were previously reported and 1 was novel.One family with TP53 mutation has met the criteria for Li-Fraumeni syndrome (LFS) and accounted for 9.1% of all families who fulfilled the diagnostic criteria for LFS.Two of the carriers were diagnosed with breast cancer under the age of 30, and have accounted for 11.8% (2/17) of all very young (≤30 years) breast cancer patients in our study.Conclusion The TP53 germline mutation is more common in Chinese population with a high risk for breast cancer than previously thought.TP53 gene mutation screening should be considered particularly for patients with a family history of LFS and very young age of onset.%目的 研究中国乳腺癌高风险人群中TP53基因胚系突变的情况.方法 应用目标区域捕获和大规模平行测序的方法,对81个来自肿瘤高风险家系、BRCA1/2突变阴性的乳腺癌先证者基因组DNA进行TP53基因的突变检测.挑选候选突变进行Sanger测序验证及共分离研究.结果 在81例BRCA1/2突变阴性的乳腺癌先证者中,分别在3例乳腺癌先证者中发现3个位于TP53外显子区的突变.其中两个为已知突变,一个为新发现的突变.1例TP53突变携带者的家族史符合Li-Fraumeni综合征的标准,占所有符合Li-Fraumeni综合征标准家系的9.1%(1/11).2例TP53突变携带者诊断乳腺癌时的年龄小于30岁,占所有非常年轻乳腺癌患者(≤30岁)的11.8%(2

  20. TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers.

    Science.gov (United States)

    Schultheis, Anne M; Martelotto, Luciano G; De Filippo, Maria R; Piscuglio, Salvatore; Ng, Charlotte K Y; Hussein, Yaser R; Reis-Filho, Jorge S; Soslow, Robert A; Weigelt, Britta

    2016-07-01

    Endometrial carcinomas (ECs) are heterogeneous at the genetic level. Although TP53 mutations are highly recurrent in serous endometrial carcinomas (SECs), these are also present in a subset of endometrioid endometrial carcinomas (EECs). Here, we sought to define the frequency, pattern, distribution, and type of TP53 somatic mutations in ECs by performing a reanalysis of the publicly available data from The Cancer Genome Atlas (TCGA). A total of 228 EECs (n=186) and SECs (n=42) from the TCGA data set, for which an integrated genomic characterization was performed, were interrogated for the presence and type of TP53 mutations, and for mutations in genes frequently mutated in ECs. TP53 mutations were found in 15% of EECs and 88% of SECs, and in 91% of copy-number-high and 35% of polymerase (DNA directed), epsilon, catalytic subunit (POLE) integrative genomic subtypes. In addition to differences in prevalence, variations in the type and pattern of TP53 mutations were observed between histologic types and between integrative genomic subtypes. TP53 hotspot mutations were significantly more frequently found in SECs (46%) than in EECs (15%). TP53-mutant EECs significantly more frequently harbored a co-occurring PTEN mutation than TP53-mutant SECs. Finally, a subset of TP53-mutant ECs (22%) was found to harbor frameshift or nonsense mutations. Given that nonsense and frameshift TP53 mutations result in distinct p53 immunohistochemical results that require careful interpretation, and that EECs and SECs display different patterns, types, and distributions of TP53 mutations, the use of the TP53/p53 status alone for the differential diagnosis of EECs and SECs may not be sufficient.

  1. Telomere status in chronic lymphocytic leukemia with TP53 disruption.

    Science.gov (United States)

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-Bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-08-30

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.

  2. TP53 — EDRN Public Portal

    Science.gov (United States)

    TP53, also widely known as p53, acts as a tumor suppressor in many tumor types, responding to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. It is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. p53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell lines, where it's believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing transcription activation, DNA-binding, and oligomerization domains. It is postulated to bind to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion, and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Multiple p53 variants due to alternative promoters and multiple alternative splicing have been found. These variants encode distinct isoforms, which can regulate p53 transcriptional activity.

  3. TP53 Gene Status Affects Survival in Advanced Mycosis Fungoides

    DEFF Research Database (Denmark)

    Wooler, Gitte; Melchior, Linea; Ralfkiaer, Elisabeth

    2016-01-01

    TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF), the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations, and their prognostic s...... for risk stratification of patients with advanced MF....

  4. TP53 mutations in older adults with acute myeloid leukemia.

    Science.gov (United States)

    Yanada, Masamitsu; Yamamoto, Yukiya; Iba, Sachiko; Okamoto, Akinao; Inaguma, Yoko; Tokuda, Masutaka; Morishima, Satoko; Kanie, Tadaharu; Mizuta, Shuichi; Akatsuka, Yoshiki; Okamoto, Masataka; Emi, Nobuhiko

    2016-04-01

    The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

  5. TP53 Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Akira Mogi

    2011-01-01

    Full Text Available The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC and nonsmall cell lung cancer (NSCLC. The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

  6. Immunohistochemical correlates of TP53 somatic mutations in cancer.

    Science.gov (United States)

    Murnyák, Balázs; Hortobágyi, Tibor

    2016-10-04

    Despite controversy on the correlation between p53 accumulation and TP53 mutational status, immunohistochemical (IHC) detection of overexpressed protein has long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.

  7. CSNK1E/CTNNB1 Are Synthetic Lethal To TP53 in Colorectal Cancer and Are Markers for Prognosis

    Directory of Open Access Journals (Sweden)

    Khong-Loon Tiong

    2014-05-01

    Full Text Available Two genes are called synthetic lethal (SL if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC. Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed gene pairs. From the top-ranked pairs, ~20 genes were chosen for immunohistochemistry (IHC staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.

  8. Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

    OpenAIRE

    Loeb, Keith R.; Asgari, Maryam M; Hawes, Stephen E.; Qinghua Feng; Stern, Joshua E.; Mingjun Jiang; Argenyi, Zsolt B.; Ethel-Michele de Villiers; Kiviat, Nancy B.

    2012-01-01

    BACKGROUND: Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV ...

  9. A case of gastric cancer with heterogeneous components of EB virus (+)/TP53 (+) and EB virus (-)/TP53 (-).

    Science.gov (United States)

    Matsuda, Ikuo; Kan, Kazuomi; Doi, Sadayuki; Motoki, Yoshiyuki; Onodera, Masayuki; Hirota, Seiichi

    2015-01-01

    Epstein-Barr virus (EBV)-associated gastric adenocarcinoma is a histological subtype of gastric adenocarcinoma, in which all of the carcinoma cells are basically positive for EBV-encoded small RNA (EBER) by in situ hybridization. Although its typical histology has some overlap with gastric carcinoma with lymphoid stroma, absence of massive lymphoid infiltrate is sometimes observed either in whole or in part. EBV-associated adenocarcinoma is one of the four representative molecular pathological subtypes recently identified by comprehensive genomic analysis of gastric adenocarcinomas. According to the analysis, typical EBV-associated gastric adenocarcinoma constitutes an independent molecular pathological subgroup, which is mutually exclusive to TP53-mutated adenocarcinoma with chromosomal instability, another molecular pathological subtype in gastric adenocarcinomas. Here, we report a rare case of gastric cancer heterogeneously composed of EBER (+)/TP53 (+) and EBER (-)/TP53 (-) portions. The EBER (+)/TP53 (+) component with massive lymphoid infiltrate surrounded the EBER (-)/TP53 (-) component showing well to moderately differentiated tubular adenocarcinoma. Although collision of two independent gastric cancers could be the simplest and most possible explanation for this situation, we discussed another possibility. In the case of gastric collision tumors, concurrent development of EBER (+) gastric adenocarcinomas and EBER (-) gastric adenocarcinomas in a single stomach is a rare incident. Since presence of the EBER (+)/TP53 (+) tumor component is atypical in itself, we also discussed the mechanism of development of the clone.

  10. TP53 and Beta-catenin mutations in liver tumours

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73% and HCV RNA in 4 cases (15.4% cases, 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6% including 7 mutations at codon 249 (AGG to AGT, arginine to serine, considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection.

    CTNNB1 mutations were found in 6/26 cases (23%, 4 of whom also had TP53 mutation. There was no significant association between CTTNB1

  11. TP53 supports basal-like differentiation of mammary epithelial cells by preventing translocation of deltaNp63 into nucleoli

    Science.gov (United States)

    Munne, Pauliina M.; Gu, Yuexi; Tumiati, Manuela; Gao, Ping; Koopal, Sonja; Uusivirta, Sanna; Sawicki, Janet; Wei, Gong-Hong; Kuznetsov, Sergey G.

    2014-04-01

    Multiple observations suggest a cell type-specific role for TP53 in mammary epithelia. We developed an in vitro assay, in which primary mouse mammary epithelial cells (mMECs) progressed from lumenal to basal-like phenotypes based on expression of Krt18 or ΔNp63, respectively. Such transition was markedly delayed in Trp53-/- mMECs suggesting that Trp53 is required for specification of the basal, but not lumenal cells. Evidence from human basal-like cell lines suggests that TP53 may support the activity of ΔNp63 by preventing its translocation from nucleoplasm into nucleoli. In human lumenal cells, activation of TP53 by inhibiting MDM2 or BRCA1 restored the nucleoplasmic expression of ΔNp63. Trp53-/- mMECs eventually lost epithelial features resulting in upregulation of MDM2 and translocation of ΔNp63 into nucleoli. We propose that TP63 may contribute to TP53-mediated oncogenic transformation of epithelial cells and shed light on tissue- and cell type-specific biases observed for TP53-related cancers.

  12. LOS GENES BRCA1 y BRCA2. ESTUDIO MOLECULAR

    Directory of Open Access Journals (Sweden)

    N. Alonso

    2006-11-01

    Full Text Available RESUMENEn los últimos años, se realizaron numerosos estudios para establecer la predisposición hereditaria al cáncer y las alteraciones mutacionales a nivel de genes susceptibles de originar cáncer de mama y ovario. En 1994 se identificaron los genes BRCA1 (Breast Cancer Gene 1 y BRCA2 (Breast Cancer Gene 2 como susceptibles de cáncer de mama y ovario. En la actualidad se sabe que las mutaciones en BRCA1 y BRCA2 están lejos de explicar la totalidad de los casos de cáncer de mama y/o ovario, y a pesar de que se postulan alteraciones mutacionales en otros genes como CHEK2, TP53 y PTEN, el BRCA1 y BRCA2, siguen teniendo su importancia y utilidad en la valoración del riesgo de predisposición hereditaria. Aunque las cifras son variables según los distintos estudios y autores, se trata en cualquier caso de porcentajes importantes. Entre el 15 y el 85% de las mujeres portadoras de mutación BRCA 1 o BRCA 2 tienen riesgo de desarrollar un cáncer de mama y entre un 10 y 60% de desarrollar un cáncer de ovario. ABSTRACT:In the last years, numerous studies were made to establish the hereditary predisposition to the cancer and the mutationals alterations at level of genes susceptible to originate breast and ovarian cancers. In 1994 genes BRCA1 (Breast Cancer Gene 1 and BRCA2 were identified (Breast Cancer Gene 2 as susceptible of both of breast and ovarian cancers. At the present time, it is knows that the mutations in BRCA 1 and BRCA 2 are far from explaining the totality of the cases of breast cancer and/or ovary, and although mutationals alterations in other genes like CHEK2, TP53 and PTEN, the BRCA1 and BRCA2 are postulated, they continue having his importance and utility in the valuation of the risk of hereditary predisposition. Correlations between both BRCA1 and BRCA2 levels with tumour grade metastasis and prognostic accuracy. Between 15 and 85% of the carrying women of mutation BRCA 1 or BRCA 2 have risk of developing a cancer of breast

  13. Profile of TP53 gene mutations in sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula

    2010-01-01

    %) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation...... not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.......Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC...

  14. The fate of BRCA1-related germline mutations in triple-negative breast tumors

    Science.gov (United States)

    Kotoula, Vassiliki; Fostira, Florentia; Papadopoulou, Kyriaki; Apostolou, Paraskevi; Tsolaki, Eleftheria; Lazaridis, Georgios; Manoussou, Kyriaki; Zagouri, Flora; Pectasides, Dimitrios; Vlachos, Ioannis; Tikas, Ioannis; Lakis, Sotiris; Konstantopoulou, Irene; Pentheroudakis, George; Gogas, Helen; Papakostas, Pavlos; Christodoulou, Christos; Bafaloukos, Dimitrios; Razis, Evangelia; Karavasilis, Vasilios; Bamias, Christina; Yannoukakos, Drakoulis; Fountzilas, George

    2017-01-01

    The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001); PIK3CA mutations were exclusively present in non-carriers (P=0.007). Germline BRCA1/2 mutations were not detected in matched tumors and breast tissues from 14 out of 33 (42%) evaluable carriers. Microsatellite markers revealed tumor loss of the germline mutant allele in one case only. Tumors that had lost the germline mutation demonstrated a higher incidence of somatic TP53 mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumor TP53 mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumor TP53 mutations did not affect outcome; In carriers, those with mutated TP53 tumors experienced more relapses compared to those with wild-type TP53 tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germline BRCA1/2 mutations is not a rare event in TNBC. This finding, the observed differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and

  15. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

    Science.gov (United States)

    Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; DiNardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-03-22

    We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

  16. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.

    Science.gov (United States)

    Stengel, A; Kern, W; Haferlach, T; Meggendorfer, M; Fasan, A; Haferlach, C

    2017-03-01

    Alterations in TP53 have been described in many cancer types including hematological neoplasms. We aimed at comparing TP53 mutations (mut) and deletions (del) in a large cohort of patients with hematological malignancies (n=3307), including AML (n=858), MDS (n=943), ALL (n=358), CLL (n=1148). Overall, alterations in TP53 were detected in 332/3307 cases (10%). The highest frequency was observed in ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%), whereas TP53 alterations occurred less frequently in CLL (total: 8%) and MDS (total: 7%). TP53 mutations were significantly more frequent in patients ⩾60 vs TP53 deletion and mutation status.

  17. PIN1 in hepatocellular carcinoma is associated with TP53 gene status.

    Science.gov (United States)

    Bae, Jun Sang; Noh, Sang Jae; Kim, Kyoung Min; Jang, Kyu Yun; Park, Ho Sung; Chung, Myoung Ja; Park, Byung-Hyun; Moon, Woo Sung

    2016-10-01

    Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.

  18. File list: Oth.PSC.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.20.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.20.TP53.AllCell.bed ...

  19. File list: Oth.ALL.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.50.TP53.AllCell hg19 TFs and others TP53 All cell types SRX189250,SRX275504...672731,SRX396265,SRX396258,SRX396256,SRX275502,SRX278507,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.50.TP53.AllCell.bed ...

  20. File list: Oth.PSC.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.10.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.10.TP53.AllCell.bed ...

  1. File list: Oth.Bon.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.05.TP53.AllCell hg19 TFs and others TP53 Bone SRX020768,SRX275504,SRX016980...06,SRX275502,SRX020767,SRX020769,SRX020766 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.05.TP53.AllCell.bed ...

  2. File list: Oth.Lng.50.TP53.AllCell [Chip-atlas[Archive

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  3. File list: Oth.Lng.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.05.TP53.AllCell hg19 TFs and others TP53 Lung SRX208485,SRX208484,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.05.TP53.AllCell.bed ...

  4. File list: Oth.Lng.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.10.TP53.AllCell hg19 TFs and others TP53 Lung SRX208485,SRX208484,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.10.TP53.AllCell.bed ...

  5. File list: Oth.Dig.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.05.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX672732,SRX60337...2,SRX672731,SRX603373,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.05.TP53.AllCell.bed ...

  6. TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset

    NARCIS (Netherlands)

    Pinto, Carla; Veiga, Isabel; Pinheiro, Manuela; Peixoto, Ana; Pinto, Armando; Lopes, Jose M.; Reis, Rui M.; Oliveira, Carla; Baptista, Manuela; Roque, Lucia; Regateiro, Fernando; Cirnes, Luis; Hofstra, Robert M. W.; Seruca, Raquel; Castedo, Sergio; Teixeira, Manuel R.

    2009-01-01

    The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere

  7. File list: Oth.Brs.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.20.TP53.AllCell hg19 TFs and others TP53 Breast SRX647704,SRX647706,SRX6477...05,SRX285808,SRX647703,SRX647707 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.20.TP53.AllCell.bed ...

  8. File list: Oth.Dig.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.10.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX672732,SRX60337...3,SRX612780,SRX603372,SRX672731 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.10.TP53.AllCell.bed ...

  9. File list: Oth.PSC.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.50.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.50.TP53.AllCell.bed ...

  10. File list: Oth.ALL.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.10.TP53.AllCell hg19 TFs and others TP53 All cell types SRX020768,SRX189250...647704,SRX285808,SRX647705,SRX189249,SRX672731,SRX647703,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.10.TP53.AllCell.bed ...

  11. File list: Oth.Dig.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.50.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX603373,SRX67273...2,SRX603372,SRX672731,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.50.TP53.AllCell.bed ...

  12. File list: Oth.ALL.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.20.TP53.AllCell hg19 TFs and others TP53 All cell types SRX189250,SRX275504...285808,SRX361198,SRX189249,SRX647703,SRX647707,SRX612780,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.20.TP53.AllCell.bed ...

  13. File list: Oth.Lng.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.20.TP53.AllCell hg19 TFs and others TP53 Lung SRX208484,SRX208485,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.20.TP53.AllCell.bed ...

  14. File list: Oth.Bld.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.20.TP53.AllCell.bed ...

  15. File list: Oth.Bld.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.50.TP53.AllCell.bed ...

  16. File list: Oth.Bon.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.20.TP53.AllCell hg19 TFs and others TP53 Bone SRX275504,SRX016980,SRX020768...67,SRX020764,SRX020769,SRX020766,SRX361198 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.20.TP53.AllCell.bed ...

  17. File list: Oth.ALL.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.05.TP53.AllCell hg19 TFs and others TP53 All cell types SRX672732,SRX020768...647706,SRX647705,SRX285808,SRX612780,SRX189251,SRX647703,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.05.TP53.AllCell.bed ...

  18. File list: Oth.PSC.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.05.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.05.TP53.AllCell.bed ...

  19. File list: Oth.Brs.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.10.TP53.AllCell hg19 TFs and others TP53 Breast SRX647706,SRX647707,SRX6477...04,SRX285808,SRX647705,SRX647703 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.10.TP53.AllCell.bed ...

  20. File list: Oth.Bld.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.10.TP53.AllCell.bed ...

  1. File list: Oth.Bld.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.TP53.AllCell hg19 TFs and others TP53 Blood SRX278507,SRX278504,SRX27851...0,SRX278506 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.05.TP53.AllCell.bed ...

  2. File list: Oth.Brs.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.50.TP53.AllCell hg19 TFs and others TP53 Breast SRX647705,SRX647704,SRX2858...08,SRX647703,SRX647707,SRX647706 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.50.TP53.AllCell.bed ...

  3. File list: Oth.Bon.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.10.TP53.AllCell hg19 TFs and others TP53 Bone SRX020768,SRX275504,SRX016980...06,SRX020767,SRX275502,SRX020769,SRX020766 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.10.TP53.AllCell.bed ...

  4. File list: Oth.Bon.50.TP53.AllCell [Chip-atlas[Archive

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  5. The IARC TP53 mutation database: a resource for studying the significance of TP53 mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Magali Olivier

    2007-02-01

    Full Text Available

    The tumor suppressor gene TP53 is frequently inactivated by gene mutations in many types of human sporadic cancers, and inherited TP53 mutations predispose to a wide spectrum of early-onset tumors (Li-Fraumeni et Li-Fraumenilike Syndromes. All TP53 gene variations (somatic and germline mutations, as well as polymorphisms that are reported in the scientific literature or in SNP databases are compiled in the IARC TP53 Database. This database provides structured data and analysis tools to study mutation patterns in human cancers and cell-lines and to investigate the clinical impact of mutations. It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients. The IARC TP53 web site (http://www-p53.iarc.fr/ provides a search interface for the core database and includes a comprehensive user guide, a slideshow on TP53 mutations in human cancer, protocols and references for sequencing TP53 gene, and links to relevant publications and bioinformatics databases. The database interface allows download of entire data sets and propose various tools for the selection, analysis and downloads of specific sets of data according to user's query.

    Recently, new annotations on the functional properties of mutant p53 proteins have been integrated in this database. Indeed, the most frequent TP53 alterations observed in cancers (75% are missense mutations that result in the production of a mutant protein that differ from the wildtype by one single amino-acid. The characterization of the biological activities of these mutant proteins is thus very important. Over the last ten years, a great amount of systematic data has been generated from experimental assays performed in

  6. High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors

    NARCIS (Netherlands)

    Hayes, VM; Dirven, CMF; Verlind, E; Molenaar, WM; Mooij, JJA; Hofstra, RMW; Buys, CHCM; Dam, A.

    1999-01-01

    In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggesti

  7. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis.

    Science.gov (United States)

    Loghavi, Sanam; Al-Ibraheemi, Alyaa; Zuo, Zhuang; Garcia-Manero, Guillermo; Yabe, Mariko; Wang, Sa A; Kantarjian, Hagop M; Yin, Cameron C; Miranda, Roberto N; Luthra, Raja; Medeiros, L Jeffrey; Bueso-Ramos, Carlos E; Khoury, Joseph D

    2015-10-01

    Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high- and very-high risk IPSS-R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F.

  8. TP53 codon 72 polymorphism in pigmentary phenotypes

    Indian Academy of Sciences (India)

    Kárita Antunes Costa; Lidia Andreu Guillo

    2012-03-01

    The p53 protein exerts different cellular functions, and recent findings have demonstrated its influence on the cascade of skin pigmentation during UV exposure. Among TP53 gene polymorphisms, the most studied is the G to C transversion in exon 4 at codon 72, which results in three distinct genotypes, Arg/Arg, Pro/Pro and Arg/Pro, each one encoding different p53 isoforms. Therefore, this study aimed to determine the relationship between TP53 codon 72 polymorphism and skin protection against sunburn. Genomic DNA was extracted from peripheral blood samples and genotyping was performed by PCR and confirmed by restriction enzyme digestion. The genotype frequency was 50% for Arg/Arg and 14.6% for Pro/Pro genotype. The frequency of heterozygous subjects was 35.4%. In our population, p53 genotypes were in Hardy–Weinberg (HW) equilibrium ($\\chi^{2}_{\\text{HM}}$ < 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further analysis demonstrated a significant association between the genotype Pro/Pro and blue/green eyes among participants who presented redness (=0.016). Our findings indicate susceptibility to sun exposure when this phenotype (eye colour) occurs simultaneously with Pro/Pro genotype.

  9. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.

    Science.gov (United States)

    McCubrey, James A; Lertpiriyapong, Kvin; Fitzgerald, Timothy L; Martelli, Alberto M; Cocco, Lucio; Rakus, Dariusz; Gizak, Agnieszka; Libra, Massimo; Cervello, Melchiorre; Montalto, Guiseppe; Yang, Li V; Abrams, Stephen L; Steelman, Linda S

    2017-01-01

    TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21(Cip-1), PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.

  10. The TP53 Codon 72 Polymorphism and Risk of Sporadic Prostate Cancer among Iranian Patients.

    Directory of Open Access Journals (Sweden)

    Farhad Babaei

    2015-04-01

    Full Text Available The TP53 gene is one of the most frequently mutated genes amongst human malignancies, particularly TP53 codon 72 polymorphism. Furthermore, an association between the TP53 codon 72 variants and prostate cancer has been reported in several studies. Although some studies have indicated an association between the TP53 Arg/Arg variant and an increased risk for prostate cancer, other studies have shown a positive correlation between the TP53 Pro/Pro genotype instead. Therefore, to clarify if this polymorphism is associated with an increased risk of prostate cancer in Iranian men, we conducted a case-control study of 40 sporadic prostate cancer patients and 80 benign prostate hyperplasia cases.The TP53 codon 72 was genotyped using an allele specific PCR.A significant association between the TP53 codon 72 genotype and prostate cancer risk was found (OR = 6.8, 95% CI = [1.8-25.1], P = 0.005. However, the results of this study did not support an association between age, the Gleason score nor TP53 genotype at codon 72 in prostate cancer patients.TP53 codon 72 polymorphism may have a great impact in the development of prostate cancer.

  11. Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Simona Ognjanovic

    2012-01-01

    Full Text Available The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN. Available samples were frozen tumor tissues (N=48 and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3% carrying a TP53 mutation at codon 259 (p.D259Y and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522 and MDM2 SNP309 (rs no. 2279744, were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively. The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.

  12. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data

    Directory of Open Access Journals (Sweden)

    Zhe Chen

    2016-01-01

    Full Text Available Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR with a 95% confidence interval (95% CI was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P=0.01; I2=0%. There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients.

  13. TP53 mutation spectrum in smokers and never smoking lung cancer patients

    Directory of Open Access Journals (Sweden)

    Ann Rita Halvorsen

    2016-05-01

    Full Text Available AbstractBackground: TP53 mutations are among the most common mutations found in lung cancers, identified as an independent prognostic factor in many types of cancers. The purpose of this study was to investigate the frequency and prognostic impact of TP53 mutations in never-smokers and in different histological subtypes of lung cancer.Methods: We analysed tumour tissue from 394 non-small cell carcinomas including adenocarcinomas (n=229, squamous cell carcinomas (n=112, large cell carcinomas (n=30 and others (n=23 for mutations in TP53 by the use of Sanger sequencing (n=394 and next generation sequencing (n=100. Results: TP53 mutations were identified in 47.2% of the samples, with the highest frequency (65% of mutations among squamous cell carcinomas. Among never-smokers, 36% carried a TP53 mutation, identified as a significant independent negative prognostic factor in this subgroup. For large cell carcinomas, a significantly prolonged progression free survival was found for those carrying a TP53 mutation. In addition, the frequency of frameshift mutations was doubled in squamous cell carcinomas (20.3% compared to adenocarcinomas (9.1%.Conclusion: TP53 mutation patterns differ between the histological subgroups of lung cancers, as also influenced by smoking history. This indicates that the histological subtypes in lung cancer are genetically different, and that smoking-induced TP53 mutations may have a different biological impact than TP53 mutations occurring in never-smokers.

  14. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data.

    Science.gov (United States)

    Chen, Zhe; Guo, Jiayi; Zhang, Kun; Guo, Yanxing

    2016-01-01

    Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I (2) = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients.

  15. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts.

    Science.gov (United States)

    Kucab, Jill E; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; White, Paul A; Phillips, David H; Arlt, Volker M

    2015-03-01

    Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C>T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers' lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not enhance TP53

  16. Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    Gaballa, Sameh; Saliba, Rima M; Srour, Samer; Lu, Gary; Brammer, Jonathan E; Shah, Nina; Bashir, Qaiser; Patel, Krina; Bock, Fabian; Parmar, Simrit; Hosing, Chitra; Popat, Uday; Delgado, Ruby; Rondon, Gabriela; Shah, Jatin J; Manasanch, Elisabet E; Orlowski, Robert Z; Champlin, Richard; Qazilbash, Muzaffar H

    2016-10-01

    TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto-HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto-HCT at our institution during 2008-2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto-HCT was 59 years in the TP53-deletion group and 58 years in the control group (P = 0.4). Twenty-one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto-HCT (P = 0.97). Twenty-three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto-HCT (P = 0.01). Median progression-free survival was 8 months for patients with TP53 deletion and 28 months for controls (P TP53 deletion and 56 months for controls (P TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9-5.8, P TP53 deletion and relapsed disease at the time of auto-HCT are independent predictors of progression. Novel approaches should be evaluated in this high-risk population. Am. J. Hematol. 91:E442-E447, 2016. © 2016 Wiley Periodicals, Inc.

  17. BRCA1 and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Yong Weon Yi

    2014-04-01

    Full Text Available The breast cancer susceptibility gene 1 (BRCA1 has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.

  18. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

    NARCIS (Netherlands)

    Iacopetta, B.; Russo, A.; Bazan, V.; Dardanoni, G.; Gebbia, N.; Soussi, T.; Kerr, D.J.; Elsaleh, H.; Soong, R.; Kandioler, D.; Janschek, E.; Kappel, S.; Lung, M.; Leung, C.S.; Ko, J.M.; Yuen, S.; Ho, J.; Leung, S.Y.; Crapez, E.; Duffour, J.; Ychou, M.; Leahy, D.T.; O'Donoghue, D.P.; Agnese, V.; Cascio, S.; Fede, G. Di; Chieco-Bianchi, L.; Bertorelle, R.; Belluco, C.; Giaretti, W.; Castagnola, P.; Ricevuto, E.; Ficorella, C.; Bosari, S.; Arizzi, C.D.; Miyaki, M.; Onda, M.; Kampman, E.; Diergaarde, B.; Royds, J.; Lothe, R.A.; Diep, C.B.; Meling, G.I.; Ostrowski, J.; Trzeciak, L.; Guzinska-Ustymowicz, K.; Zalewski, B.; Capella, G.M.; Moreno, V.; Peinado, M.A.; Lonnroth, C.; Lundholm, K.; Sun, X.F.; Jansson, A.; Bouzourene, H.; Hsieh, L.L.; Tang, R.; Smith, D.R.; Allen-Mersh, T.G.; Khan, Z.A.; Shorthouse, A.J.; Silverman, M.L.; Kato, S.; Ishioka, C.

    2006-01-01

    BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. Th

  19. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

    NARCIS (Netherlands)

    Iacopetta, B.; Russo, A.; Bazan, V.; Kampman, E.; Diergaarde, B.

    2006-01-01

    Background: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. Th

  20. Bioinformatic dissecting of TP53 regulation pathway underlying butyrate-induced histone modification in epigenetic regulation

    Science.gov (United States)

    Butyrate affects cell proliferation, differentiation and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by IPA in our RNA sequencing data set. The TP53 signaling pathway pl...

  1. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

    DEFF Research Database (Denmark)

    Rausch, Tobias; Jones, David T W; Zapatka, Marc

    2012-01-01

    of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals...

  2. TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth.

    Science.gov (United States)

    Haricharan, Svasti; Brown, Powel

    2015-06-23

    Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.

  3. BRAF和TP53基因热点突变的构建%Construction of Hot-spot Mutations in Human BRAF and TP53 Genes

    Institute of Scientific and Technical Information of China (English)

    张环宇; 王改平; 李晓芳; 姚谨; 陈倩倩; 樊路娟

    2014-01-01

    目的:构建BRAF和TP53基因多个位点的点突变质粒,为进一步研究其在肿瘤形成中的作用奠定基础.方法:以HEK-293T基因组DNA为模板构建含BRAF600、TP53175和TP53248位点的野生型质粒,利用MutanBESTTM定点突变方法获得含BRAFV600E、TP53R175C和TP53R248W等突变位点的突变型质粒,并进行DNA测序鉴定.结果:DNA测序结果显示构建的三个点突变与实验设计完全一致.结论:成功构建了BRAFV600E、TP53R175C和TP53R248W三个具有不同突变位点的突变型质粒,MutanBESTTM定点突变技术是一种简单、快速、高效的基因定点突变方法.

  4. TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes.

    Science.gov (United States)

    Chang, Chun-Kang; Zhao, You-Shan; Xu, Feng; Guo, Juan; Zhang, Zheng; He, Qi; Wu, Dong; Wu, Ling-Yun; Su, Ji-Ying; Song, Lu-Xi; Xiao, Chao; Li, Xiao

    2017-02-01

    To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post-DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.

  5. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma.

    Science.gov (United States)

    Bousquet, Guilhem; El Bouchtaoui, Morad; Leboeuf, Christophe; Battistella, Maxime; Varna, Mariana; Ferreira, Irmine; Plassa, Louis-François; Hamdan, Diaddin; Bertheau, Philippe; Feugeas, Jean-Paul; Damotte, Diane; Janin, Anne

    2015-08-07

    Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC.

  6. LAMP3 and TP53 overexpression predicts poor outcome in laryngeal squamous cell carcinoma.

    Science.gov (United States)

    Qiu, Xiaoxia; You, Yiwen; Huang, Jianfei; Wang, Xudong; Zhu, Huijun; Wang, Zhiwei

    2015-01-01

    Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific and hypoxia-induced protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical, breast and gastrointestinal cancers. However, little is known of LAMP3 protein expression in laryngeal squamous cell carcinoma (LSCC) and its prognostic value. We determined protein expression of LAMP3 and TP53 in LSCC tissues (n=117) by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients' clinical parameters and overall survival. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to adjacent normal surgical margin tissues. Both high LAMP3 and high TP53 protein expression was significantly associated with tumor stage and size. Significant correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 or high TP53 expression had a poor overall survival. Our data suggest that both epithelial LAMP3 expression and TP53 expression are independent prognostic markers for LSCC.

  7. YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5.

    Science.gov (United States)

    Park, Soo-Yeon; Choi, Hyo-Kyoung; Jo, Seong-Ho; Seo, JaeSung; Han, Eun-Jeong; Choi, Kyung-Chul; Jeong, Jae-Wook; Choi, Youngsok; Yoon, Ho-Geun

    2015-05-01

    Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.

  8. Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors.

    Science.gov (United States)

    Ohnami, Shumpei; Ohshima, Keiichi; Nagashima, Takeshi; Urakami, Kenichi; Shimoda, Yuji; Saito, Junko; Naruoka, Akane; Hatakeyama, Keiichi; Mochizuki, Tohru; Serizawa, Masakuni; Ohnami, Sumiko; Kusuhara, Masatoshi; Yamaguchi, Ken

    2017-03-03

    The TP53 signal transduction pathway is an attractive target for cancer treatments. In this study, we conducted a comprehensive molecular evaluation of 907 patients with cancer in Japan to identify genomic alterations in the TP53 pathway. TP53 mutations were frequently detected in many cancers, except melanoma, thymic tumors, gastrointestinal stromal tumors, and renal cancers. The frequencies of non-synonymous single nucleotide variants (SNVs) in the TP53 family members TP63 and TP73 were relatively low, although genes with increased frequencies of SNVs were as follows: PTEN (11.7%) in breast cancer, CDKN2A (11.1 and 9.6%) in pancreas and head and neck cancers, and ATM (18.0 and 11.1%) in liver and esophageal cancers. MDM2 expression was decreased or increased in patients with mutant or wild-type TP53, respectively. CDKN1A expression was increased with mutant TP53 in head and neck cancers. Moreover, TP63 overexpression was characteristically observed in squamous cell carcinomas of the lung, esophagus, and head and neck region. Additionally, overexpression of TP63 and TP73 was frequently observed in thymomas. Our results reveal a spectrum of genomic alterations in the TP53 pathway that is characteristic of many tumor types, and these data may be useful in the trials of targeted therapies.

  9. Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients.

    Science.gov (United States)

    Yamaguchi, Ken; Urakami, Kenichi; Nagashima, Takeshi; Shimoda, Yuji; Ohnami, Shumpei; Ohnami, Sumiko; Ohshima, Keiichi; Mochizuki, Tohru; Hatakeyama, Keiichi; Serizawa, Masakuni; Akiyama, Yasuto; Maruyama, Kouji; Katagiri, Hirohisa; Ishida, Yuji; Takahashi, Kaoru; Nishimura, Seiichiro; Terashima, Masanori; Kawamura, Taiichi; Kinugasa, Yusuke; Yamakawa, Yushi; Onitsuka, Tetsuro; Ohde, Yasuhisa; Sugino, Takashi; Ito, Ichiro; Matsubayashi, Hiroyuki; Horiuchi, Yasue; Mizuguchi, Maki; Yamazaki, Mutsumi; Inoue, Kengo; Wakamatsu, Kimiko; Sugiyama, Misato; Uesaka, Katsuhiko; Kusuhara, Masatoshi

    2016-01-01

    Using whole exome sequencing data obtained from 1,685 Japanese cancer patients, we examined genetic variations of germline TP53 and found 10 types of non-synonymous single nucleotide variants. In the present study, we focused on 6 patients with germline D49H mutation located in the transactivation domain 2 of p53 protein, since the mutation seemed to be prevalent in cancer patients and to be pathogenic. According to the initial survey for family history of the proband with the germline TP53 D49H mutation, one osteosarcoma patient and his pedigree fulfill the criteria for Li-Fraumeni-like syndrome and the 2009 Chompret criteria for germline TP53 mutation screening. Since this patient possesses double germline mutations of TP53 D49H and A159D, further studies are required to evaluate contribution of the D49H mutation in this morbidity. The remaining 5 patients had family histories of cancer, but none fulfills the criteria either for the Li-Fraumeni/Li-Fraumeni-like syndromes or the 2009 Chompret criteria for germline TP53 mutation screening. It is possible to postulate that the germline TP53 D49H mutation is likely to be low-penetrant in some pedigrees. The present study also indicates that the survey for the germline TP53 mutation plays an important role in clinical practice as it will prevent mistaking cancer patients with unusual heredities for sporadic cases.

  10. Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation.

    Science.gov (United States)

    Yeo, Shi Yun; Itahana, Yoko; Guo, Alvin Kunyao; Han, Rachel; Iwamoto, Kozue; Nguyen, Hung Thanh; Bao, Yi; Kleiber, Kai; Wu, Ya Jun; Bay, Boon Huat; Voorhoeve, Mathijs; Itahana, Koji

    2016-03-09

    Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.

  11. TP53 drives invasion through expression of its Δ133p53β variant

    Science.gov (United States)

    Gadea, Gilles; Arsic, Nikola; Fernandes, Kenneth; Diot, Alexandra; Joruiz, Sébastien M; Abdallah, Samer; Meuray, Valerie; Vinot, Stéphanie; Anguille, Christelle; Remenyi, Judit; Khoury, Marie P; Quinlan, Philip R; Purdie, Colin A; Jordan, Lee B; Fuller-Pace, Frances V; de Toledo, Marion; Cren, Maïlys; Thompson, Alastair M

    2016-01-01

    TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression. DOI: http://dx.doi.org/10.7554/eLife.14734.001 PMID:27630122

  12. TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics.

    Science.gov (United States)

    Wheler, Jennifer J; Janku, Filip; Naing, Aung; Li, Yali; Stephen, Bettzy; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Karp, Daniel; Falchook, Gerald S; Tsimberidou, Apostolia M; Piha-Paul, Sarina; Anderson, Roosevelt; Ke, Danxia; Miller, Vincent; Yelensky, Roman; Lee, J Jack; Hong, David; Kurzrock, Razelle

    2016-10-01

    TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. ©2016 AACR.

  13. TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts.

    Science.gov (United States)

    Kucab, Jill E; Zwart, Edwin P; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; Phillips, David H; Arlt, Volker M

    2016-03-01

    3-Nitrobenzanthrone (3-NBA) is a highly mutagenic compound and possible human carcinogen found in diesel exhaust. 3-NBA forms bulky DNA adducts following metabolic activation and induces predominantly G:CT:A transversions in a variety of experimental systems. Here we investigated the influence of nucleotide excision repair (NER) on 3-NBA-induced mutagenesis of the human tumour suppressor gene TP53 and the reporter gene lacZ. To this end we utilised Xpa -knockout (Xpa-Null) human TP53 knock-in (Hupki) embryo fibroblasts (HUFs). As Xpa is essential for NER of bulky DNA adducts, we hypothesized that DNA adducts induced by 3-NBA would persist in the genomes of Xpa-Null cells and lead to an increased frequency of mutation. The HUF immortalisation assay was used to select for cells harbouring TP53 mutations following mutagen exposure. We found that Xpa-Null Hupki mice and HUFs were more sensitive to 3-NBA treatment than their wild-type (Xpa-WT) counterparts. However, following 3-NBA treatment and immortalisation, a similar frequency of TP53-mutant clones arose from Xpa-WT and Xpa-Null HUF cultures. In cells from both Xpa genotypes G:CT:A transversion was the predominant TP53 mutation type and mutations exhibited bias towards the non-transcribed strand. Thirty-two percent of 3-NBA-induced TP53 mutations occurred at CpG sites, all of which are hotspots for mutation in smokers' lung cancer (codons 157, 158, 175, 245, 248, 273, 282). We also examined 3-NBA-induced mutagenesis of an integrated lacZ reporter gene in HUFs, where we again observed a similar mutant frequency in Xpa-WT and Xpa-Null cells. Our findings suggest that 3-NBA-DNA adducts may evade removal by global genomic NER; the persistence of 3-NBA adducts in DNA may be an important factor in its mutagenicity.

  14. Detection of TP53 dysfunction in chronic lymphocytic leukemia by an in vitro functional assay based on TP53 activation by the non-genotoxic drug Nutlin-3: a proposal for clinical application

    OpenAIRE

    Pozzo, Federico; Dal Bo, Michele; Peragine, Nadia; Bomben, Riccardo; Zucchetto, Antonella; Rossi, Francesca Maria; Degan, Massimo; Rossi, Davide; Chiarenza, Annalisa; Grossi, Alberto; Di Raimondo, Francesco; Zaja, Francesco; Pozzato, Gabriele; Secchiero, Paola; Gaidano, Gianluca

    2013-01-01

    Background TP53 defects, i.e. 17p13 deletion and/or nucleotide mutations, associate with short survival and chemorefractoriness in chronic lymphocytic leukemia (CLL). In this context, since direct sequencing of the TP53 gene does not evaluate TP53 functionality, a functional assessment of TP53 pathway may be of interest to identify high risk CLL. By taking advantage of a training cohort of 100 CLL and a validation cohort of 40 CLL with different patterns of TP53 mutation/deletion by FISH and ...

  15. Neural network predicts sequence of TP53 gene based on DNA chip

    DEFF Research Database (Denmark)

    Spicker, J.S.; Wikman, F.; Lu, M.L.;

    2002-01-01

    We have trained an artificial neural network to predict the sequence of the human TP53 tumor suppressor gene based on a p53 GeneChip. The trained neural network uses as input the fluorescence intensities of DNA hybridized to oligonucleotides on the surface of the chip and makes between zero...... and four errors in the predicted 1300 bp sequence when tested on wild-type TP53 sequence....

  16. Three Common TP53 Polymorphisms and the Risk of Breast Cancer among Groups of Iranian Women

    Directory of Open Access Journals (Sweden)

    Mahin Ahangar Oskouee

    2015-11-01

    Full Text Available Background: The TP53 gene is the most important tumor suppressor gene in humans. The aim of our study was to determine the genotype frequency of three common TP53 polymorphisms (codon 72 BstUI and intron 6 MspI, as well as the intron 3 in a group of Iranian women with and without breast cancer. Methods: Paraffin-embedded specimens of 65 malignant breast cancer cases and 65 cases with benign breast lesions were investigated for the presence of three common TP53 polymorphisms by polymerase chain reaction. Samples were genotyped by polymerase chain reaction followed by variant specific restriction enzyme digestion. Results: In our study, age grouping as >50 and ≤50 showed that the highest number of cancerous and non-cancerous patients was in the age group under 50; according to statistical tests, the difference was significant and recessive alleles of all three hot spots of TP53 had the highest frequency in the cancerous group. The majority of the cases with recessive alleles of all three hot spots of TP53 were in the age group ≤ 50. The difference between cancerous and noncancerous groups was statistically significant. Conclusions: Our results indicate that recessive alleles in three hot spots of TP53 gene might play a role in the breast cancer development, especially in women younger than 50 years.

  17. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.

    Science.gov (United States)

    DE Oliveira, Daiane Teixeira; Savio, Andre Luiz Ventura; Marcondes, Joao Paulo DE Castro; Barros, Tatiane Martins; Barbosa, Ludmila Correia; Salvadori, Daisy Maria Favero; DA Silva, Glenda Nicioli

    2017-03-01

    Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

  18. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status

    Indian Academy of Sciences (India)

    DAIANE TEIXEIRA DE OLIVEIRA; ANDRÉ LUIZ VENTURA SÁVIO; JOÃO PAULO DE CASTRO MARCONDES; TATIANE MARTINS BARROS; LUDMILA CORREIA BARBOSA; DAISY MARIA FAVERO SALVADORI; GLENDA NICIOLI DA SILVA

    2017-03-01

    Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness forpreventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activityof silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used:RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates,genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 andmiR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutatedcells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survivalassay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 andmiR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion,despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR,AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role ofsilibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

  19. TP53 Mutation vis-a-vis Malignant Progression in Astrocytoma WHO Grade Ⅱ%TP53突变与胶质瘤恶性进展

    Institute of Scientific and Technical Information of China (English)

    岳伟英; 俞苏寰; 李志强; 赵世光; 陈忠平

    2008-01-01

    背景与目的:WHO Ⅱ级的星形细胞瘤手术后在部分患者可能复发,而且,复发时多出现恶性程度增加.本研究探讨TP53蛋白质分子的表达与胶质瘤恶性进展之问的关系.方法:收集第一次手术时为星形细胞瘤(WHO Ⅱ级)的石蜡包埋标本53例份,其中10例复发时第二次手术肿瘤仍然为Ⅱ级(复发无进展组);10例复发时肿瘤级别升高(Ⅲ级或Ⅳ级)(复发进展组);另外13例在5年内没有复发(无复发组).免疫组化检测TP53在肿瘤中的表达,并采用DNA测序法分析TP53蛋白阳性标本TP53外显子5、7、8的突变情况.结果:LTP53阳性率为45.5%(15/33).复发恶性进展组TP53高于无复发组和无进展组(P<0.05);TP53无进展组与无复发组之间差异无统计学意义.基因测序共在6例组织中发现7个(共4类)突变,其中1例同时存在2个突变.所有突变者都是恶性进展组病例.结论:TP53突变/蛋白质分子过表达可能是Ⅱ级星形胶质细胞瘤复发恶性进展的预示指标.

  20. microRNAs与TP53基因调控网络研究进展%Advances in microRNAs and TP53 Gene Regulatory Network

    Institute of Scientific and Technical Information of China (English)

    龚朝建; 黄宏斌; 徐柯; 梁芳; 李小玲; 熊炜; 曾朝阳; 李桂源

    2012-01-01

    TP53基因(编码p53蛋白)作为一个重要的抑瘤基因,通过调控一系列信号转导通路广泛参与了多种恶性肿瘤的发生发展,一直是肿瘤分子生物学研究领域的热点.最近的研究发现,microRNAs(miRNAs)参与了TP53的信号通路,它们之间存在着复杂的调控网络.一方面,p53通过调控一些miRNAs的转录及转录后成熟,促进细胞周期阻滞、诱导细胞凋亡和衰老,抑制肿瘤发生.另一方面,许多miRNAs,如miR-25、miR-30d、miR-125b和miR-504等可直接调控p53的表达与活性,参与TP53信号通路的调节,还有一些miRNAs则通过调节p53上下游基因,发挥重要的生物学功能.其中,最具有代表性的是miR-34家族,它们受p53直接调控并参与TP53信号通路,通过靶向抑制多个TP53信号通路关键分子的表达,发挥抑瘤作用.此外,它们还可以通过抑制沉默信息调节子,增强p53的活性,反馈调节TP53信号通路.miRNAs与TP53之间调控网络的研究,是对TP53抑瘤机制的重要补充.%The tumor suppressor TP53 gene, which encodes p53 protein, is a hotspot of all time in molecular oncology. p53 suppresses tumor initiation and progression through its regulation of many downstream genes. Recent studies have revealed that microRNAs (miRNAs) interact with the p53 pathway and form a complex regulatory network. On one hand, p53 promotes cell cycle arrest and induces cell apoptosis and senescence to suppress tumorigenesis by regulating the transcription and post-transcriptional maturation of multiple miRNAs. On the other hand, many miRNAs fine-tune the p53 pathway through regulation of TP53 and its upstream regulators or downstream effectors. The miR-34s family, directly transactivated by p53 represents a large number of p53-regulated miRNAs. They exert their tumor suppressing function via targeted inhibition of multiple key molecules in the p53 pathway. Furthermore, miR-34s enhance p53 activity through a feedback loop by inhibiting silent

  1. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.

    Science.gov (United States)

    Köbel, Martin; Piskorz, Anna M; Lee, Sandra; Lui, Shuhong; LePage, Cecile; Marass, Francesco; Rosenfeld, Nitzan; Mes Masson, Anne-Marie; Brenton, James D

    2016-10-01

    TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.

  2. Gaining insights into the codon usage patterns of TP53 gene across eight mammalian species.

    Directory of Open Access Journals (Sweden)

    Tarikul Huda Mazumder

    Full Text Available TP53 gene is known as the "guardian of the genome" as it plays a vital role in regulating cell cycle, cell proliferation, DNA damage repair, initiation of programmed cell death and suppressing tumor growth. Non uniform usage of synonymous codons for a specific amino acid during translation of protein known as codon usage bias (CUB is a unique property of the genome and shows species specific deviation. Analysis of codon usage bias with compositional dynamics of coding sequences has contributed to the better understanding of the molecular mechanism and the evolution of a particular gene. In this study, the complete nucleotide coding sequences of TP53 gene from eight different mammalian species were used for CUB analysis. Our results showed that the codon usage patterns in TP53 gene across different mammalian species has been influenced by GC bias particularly GC3 and a moderate bias exists in the codon usage of TP53 gene. Moreover, we observed that nature has highly favored the most over represented codon CTG for leucine amino acid but selected against the ATA codon for isoleucine in TP53 gene across all mammalian species during the course of evolution.

  3. The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells

    Science.gov (United States)

    Schwartz, Jeffrey L.; Jordan, Robert; Evans, Helen H.; Lenarczyk, Marek; Liber, Howard

    2003-01-01

    The dose and TP53 dependence for the induction of chromosome instability were examined in cells of three human lymphoblastoid cell lines derived from WIL2 cells: TK6, a TP53-normal cell line, NH32, a TP53-knockout created from TK6, and WTK1, a WIL2-derived cell line that spontaneously developed a TP53 mutation. Cells of each cell line were exposed to (137)Cs gamma rays, and then surviving clones were isolated and expanded in culture for approximately 35 generations before the frequency and characteristics of the instability were analyzed. The presence of dicentric chromosomes, formed by end-to-end fusions, served as a marker of chromosomal instability. Unexposed TK6 cells had low levels of chromosomal instability (0.002 +/- 0.001 dicentrics/cell). Exposure of TK6 cells to doses as low as 5 cGy gamma rays increased chromosome instability levels nearly 10-fold to 0.019 +/- 0.008 dicentrics/cell. There was no further increase in instability levels beyond 5 cGy. In contrast to TK6 cells, unexposed cultures of WTK1 and NH32 cells had much higher levels of chromosome instability of 0.034 +/- 0.007 and 0.041 +/- 0.009, respectively, but showed little if any effect of radiation on levels of chromosome instability. The results suggest that radiation exposure alters the normal TP53-dependent cell cycle checkpoint controls that recognize alterations in telomere structure and activate apoptosis.

  4. Genetic variants in TP53 and MDM2 associated with male infertility in Chinese population

    Institute of Scientific and Technical Information of China (English)

    Cong Huang; Wei Liu; Gui-Xiang Ji; Ai-Hua Gu; Jian-Hua Qu; Ling Song; Xin-Ru Wang

    2012-01-01

    The TP53,a transcriptional regulator and tumor suppressor,is functionally important in spermatogenesis.MDM2 is a key regulator of the p53 pathway and modulates p53 activity.Both proteins have been functionally linked to germ cell apoptosis,which may affect human infertility,but very little is known on how common polymorphisms in these genes may influence germ cell apoptosis and the risk of male infertility.Thus,this study was designed to test whether three previously described polymorphisms 72Arg>Pro (rs1042522) and the Ex2+ 19C>T (rs2287498) in TP53,and the 5' untranslated region (5' UTR) 309T>G (rs937283) in MDM2,are associated with idiopathic male infertility in a Chinese population.The three polymorphisms were genotyped using OpenArray assay in a hospital-based case-control study,including 580 infertile patients and 580 fertile controls.Our analyses revealed that TP53 Ex2+ 19C>T and MDM2309T>G polymorphisms are associated with mate infertility.Furthermore,we detected a nearly statistically significant additive interaction between TP53 rs2287498 and MDM2 rs937283 for the development of male.infertility (Pinteraction=0.055).In summary,this study found preliminary evidence,demonstrating that genetic variants in genes of the TP53 pathway are risk factors for male infertility.

  5. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

    Science.gov (United States)

    Ribi, Sebastian; Baumhoer, Daniel; Lee, Kristy; Edison; Teo, Audrey S M; Madan, Babita; Zhang, Kang; Kohlmann, Wendy K; Yao, Fei; Lee, Wah Heng; Hoi, Qiangze; Cai, Shaojiang; Woo, Xing Yi; Tan, Patrick; Jundt, Gernot; Smida, Jan; Nathrath, Michaela; Sung, Wing-Kin; Schiffman, Joshua D; Virshup, David M; Hillmer, Axel M

    2015-04-10

    Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

  6. TP53 mutations in clinically normal mucosa adjacent to oral carcinomas

    DEFF Research Database (Denmark)

    Thode, Christenze; Bilde, Anders; von Buchwald, Christian;

    2010-01-01

    products were separated by denatured gradient gel electrophoresis. Fragments with a deviant DGEE pattern were sequenced. RESULTS: TP53 mutations were found in six of 18 tumours. Fourteen specimens contained histologically normal mucosa adjacent to the tumour; 13 of these showed small clusters of p53...... positive cells. Seven specimens contained both histological normal and dysplastic epithelial tissues adjacent to the tumour. A TP53 mutation was found in only one specimen; this mutation appeared in the normal mucosa, the adjacent tumour, and the epithelial dysplasia. CONCLUSION: We found that upregulation...... of p53 was a frequent event in histological normal mucosa adjacent to OSCC; however, it was rarely associated with a mutation in the TP53 gene....

  7. Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

    Science.gov (United States)

    Liu, Tuoen; Krysiak, Kilannin; Shirai, Cara Lunn; Kim, Sanghyun; Shao, Jin; Ndonwi, Matthew; Walter, Matthew J

    2017-01-01

    Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

  8. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.

    Science.gov (United States)

    Gao, Weimin; Jin, Jide; Yin, Jinling; Land, Stephanie; Gaither-Davis, Autumn; Christie, Neil; Luketich, James D; Siegfried, Jill M; Keohavong, Phouthone

    2017-02-01

    Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc.

  9. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

    Directory of Open Access Journals (Sweden)

    Srivastava Kumar

    2008-12-01

    Full Text Available Abstract Background The germline TP53-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context. Methods We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing TP53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H. Results The R337H mutation was found in three patients but in none of the controls (p = 0.0442. Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant TP53 allele rather than the wild-type allele. Polymorphisms were identified within the TP53 (R72P and Ins16 and MDM2 (SNP309 genes that may further diminish TP53 tumor suppressor activity. Conclusion These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant TP53 alleles can differentially influence tumor susceptibility.

  10. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

    Science.gov (United States)

    Kandioler, Daniela; Mittlböck, Martina; Kappel, Sonja; Puhalla, Harald; Herbst, Friedrich; Langner, Cord; Wolf, Brigitte; Tschmelitsch, Jörg; Schippinger, Walter; Steger, Günther; Hofbauer, Friedrich; Samonigg, Hellmut; Gnant, Michael; Teleky, Bela; Kührer, Irene

    2015-08-01

    We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

  11. Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand

    Directory of Open Access Journals (Sweden)

    Olivier Galy

    2011-01-01

    Full Text Available Hepatocellular carcinoma (HCC may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C was detected in 19 (73% of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.

  12. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes.

    Science.gov (United States)

    Andrade, Raissa Coelho; Dos Santos, Anna Claudia Evangelista; de Aguirre Neto, Joaquim Caetano; Nevado, Julián; Lapunzina, Pablo; Vargas, Fernando Regla

    2017-04-01

    Li-Fraumeni and Li-Fraumeni like syndromes (LFS/LFL) represent rare cancer-prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li-Fraumeni syndrome, and in 20-60 % of families with Li-Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.

  13. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    Science.gov (United States)

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases.

  14. 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

  15. 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

    to wood dust, using capillary electrophoresis single-strand conformation polymorphism analysis and direct sequencing. A significant association between wood-dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0-31.6]. TP53 mutations...

  16. TP53 and outcome in DLBCL: not only the coding region.

    Science.gov (United States)

    Jardin, Fabrice; Coiffier, Bertrand

    2013-05-30

    In this issue of Blood, Li et al report mutations in the 3′ untranslated region (3′UTR) of TP53 that modify the expression of p53 and thus its effect on response to therapy in diffuse large B-cell lymphoma (DLBCL) patients.

  17. Wood dust-related mutational profile of TP53 in intestinal-type sinonasal adenocarcinoma.

    Science.gov (United States)

    Pérez-Escuredo, Jhudit; Martínez, Jorge García; Vivanco, Blanca; Marcos, César Álvarez; Suárez, Carlos; Llorente, José Luis; Hermsen, Mario A

    2012-11-01

    Intestinal-type sinonasal adenocarcinoma represents 8% to 25% of all malignant sinonasal cancer and is etiologically related to occupational exposure to wood dust. Despite its clear etiology, the mechanisms behind the carcinogenic effects of wood dust are unclear. Because it is known that carcinogens can leave specific mutational fingerprints, we aimed to analyze the spectrum of TP53 mutations and to relate the findings to the wood dust etiology of the patients. Forty-four primary tumors were examined for TP53 mutations by direct sequencing. In addition, p53 protein expression was analyzed by immunohistochemistry using a tissue microarray consisting of 92 tumors. We report a frequency of 41% (18/44) TP53 mutations and 72% (66/92) p53 immunopositivity in intestinal-type sinonasal adenocarcinoma, significantly related to wood dust, but not to tobacco etiology. G→A transition (50%, 9/18 cases) was the most common alteration detected, almost exclusively found in nonsmokers, whereas G→T (27%, 5/18 cases) was detected in smokers only. These data point to wood dust exposure as the causal factor in the mutagenesis of TP53, possibly caused by reactive nitrogen species generated through a chronic inflammatory process.

  18. TP53 Arg72Pro polymorphism is associated with esophageal cancer risk: A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    De-Ke Jiang; Lei Yao; Wen-Zhang Wang; Bo Peng; Wei-Hua Ren; Xian-Mei Yang; Long Yu

    2011-01-01

    AIM: To investigate the association between TP53 Ar-g72Pro polymorphism and esophageal cancer (EC) risk using meta-analysis.METHODS: All eligible studies published before March 1, 2010 were selected by searching PubMed using key-words “p53” or “TP53”, “polymorphism” or “variation”, “esophageal” and “cancer” or “carcinoma”. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for EC risk associated with TP53 Arg72Pro polymorphism using fixed- and random-effects models.RESULTS: Nine case-control studies involving 5545 subjects were included in this meta-analysis. Signifi-cantly reduced risk of EC was associated with TP53 genotypes for Arg/Arg + Arg/Pro vs Pro/Pro (OR = 0.73, 95% CI: 0.57-0.94, P = 0.014). Subgroup analy-ses according to the source of controls and the speci-mens used for determining TP53 Arg72Pro genotypes or sample size showed that significantly reduced risk was observed only in studies which have population-based controls (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.66, P < 0.001), and use white blood cells or normal tissue to assess TP53 genotypes of cases (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001) or include at least 200 subjects (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001). Analysis restricted to well-designed studies also sup-ported the significantly decreased risk of EC (Arg/Arg vs Pro/Pro: OR = 0.54, 95% CI: 0.46-0.64, P < 0.001). CONCLUSION: TP53 Arg72 carriers are significantly as-sociated with decreased EC risk. Nevertheless, more well-designed studies are needed to confirm our findings.

  19. Extremely high Tp53 mutation load in esophageal squamous cell carcinoma in Golestan Province, Iran.

    Directory of Open Access Journals (Sweden)

    Behnoush Abedi-Ardekani

    Full Text Available BACKGROUND: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. METHODOLOGY/PRINCIPAL FINDINGS: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%, including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs. Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. CONCLUSION/SIGNIFICANCE: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.

  20. TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

    Directory of Open Access Journals (Sweden)

    M.A.C. Smith

    2007-11-01

    Full Text Available TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. TP53 codon 72 (TP53:72 polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study. We investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type II diabetes, obesity, neoplasia, low cognitive level (dementia, and depression. We also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. DNA was isolated from blood cells, amplified by PCR using sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' primers and digested with the BstUI enzyme. This polymorphism is within exon 4 at nucleotide residue 347. Descriptive statistics, logistic regression analysis and Student t-test using the multiple comparison test were used. Allele frequencies, R (Arg = 0.69 and P (Pro = 0.31, were similar to other populations. Genotype distributions were within Hardy-Weinberg equilibrium. This polymorphism did not show significant association with any age-related disease or serum variables. However, R allele carriers showed lower HDL levels and a higher frequency of cardiovascular disease than P allele subjects. These findings may help to elucidate the physiopathological role of TP53:72 polymorphism in Brazilian elderly people.

  1. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Young, Ken H; Leroy, Karen; Møller, Michael Boe;

    2008-01-01

    The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients and the overall survival (OS) of pati...

  2. Human papillomavirus type 16 and TP53 mutation in oral cancer: matched analysis of the IARC multicenter study.

    NARCIS (Netherlands)

    Dai, M; Clifford, GM; Calvez, F le; Castellsague, X; Snijders, P.J.F.; Pawlita, M; Herrero, R; Hainaut, P; Franceschi, S

    2004-01-01

    TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption. Wild-type TP53 was found more frequently in cancer specimens tha

  3. [Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma].

    Science.gov (United States)

    Voropaeva, E N; Pospelova, T I; Voevoda, M I; Maksimov, V N

    2017-01-01

    A comparative analysis of oncogene mutations shows that variations in their frequency, spectrum, and hot-spot locations depends on the type of tumor and the ethnic origin of the population studied. The current version of the IARC TP53 Mutation Database lacks information about the frequency and spectrum of TP53 mutations in patients with DLBCL in Russia. The aim of this study was to assess the frequency and functional significance of TP53 mutations in patients with DLBCL in Novosibirsk. The TP53 coding sequence and the adjacent intron regions were analyzed by direct sequencing in the tumor material from 74 patients with DLBCL. Mutations of the TP53 coding sequence were found in 18 (24.3%) patients. These data are consistent with the frequency of TP53  mutations observed in other studies. The spectrum of nucleotide substitutions found in DLBCL specimens corresponded to that described in the IARC TP53 Mutation Database. According to bioinformatic data and to reported experiments in vitro, most of the mutations detected result in the production of functionally inactive p53. Our results show that DLBCL progression is accompanied by the functional selection for mutations in TP53 exons 5-8.

  4. MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

    NARCIS (Netherlands)

    F.H. Groenendijk (Floris); W. Taal (Walter); H.J. Dubbink (Erik Jan); C.R. Haarloo (Cathleen); M.C.M. Kouwenhoven (Mathilde); M.J. van den Bent (Martin); J.M. Kros (Johan); W.N.M. Dinjens (Winand)

    2011-01-01

    textabstractHypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII

  5. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations

    DEFF Research Database (Denmark)

    Farooqui, Mohammed Z H; Valdez, Janet; Martyr, Sabrina

    2015-01-01

    BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53...

  6. Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

    Science.gov (United States)

    Xie, Xiaolei; Le, Li; Fan, Yanxin; Lv, Lin; Zhang, Junjie

    2012-07-01

    Mitoribosome in mammalian cells is responsible for synthesis of 13 mtDNA-encoded proteins, which are integral parts of four mitochondrial respiratory chain complexes (I, III, IV and V). ERAL1 is a nuclear-encoded GTPase important for the formation of the 28S small mitoribosomal subunit. Here, we demonstrate that knockdown of ERAL1 by RNA interference inhibits mitochondrial protein synthesis and promotes reactive oxygen species (ROS) generation, leading to autophagic vacuolization in HeLa cells. Cells that lack ERAL1 expression showed a significant conversion of LC3-I to LC3-II and an enhanced accumulation of autophagic vacuoles carrying the LC3 marker, all of which were blocked by the autophagy inhibitor 3-MA as well as by the ROS scavenger NAC. Inhibition of mitochondrial protein synthesis either by ERAL1 siRNA or chloramphenicol (CAP), a specific inhibitor of mitoribosomes, induced autophagy in HTC-116 TP53 (+/+) cells, but not in HTC-116 TP53 (-/-) cells, indicating that tumor protein 53 (TP53) is essential for the autophagy induction. The ROS elevation resulting from mitochondrial protein synthesis inhibition induced TP53 expression at transcriptional levels by enhancing TP53 promoter activity, and increased TP53 protein stability by suppressing TP53 ubiquitination through MAPK14/p38 MAPK-mediated TP53 phosphorylation. Upregulation of TP53 and its downstream target gene DRAM1, but not CDKN1A/p21, was required for the autophagy induction in ERAL1 siRNA or CAP-treated cells. Altogether, these data indicate that autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

  7. 头颈部鳞癌中TP53基因的调控网络分析%TP53-related gene regulatory network analysis on head and neck squamous carcinoma

    Institute of Scientific and Technical Information of China (English)

    徐明义; 郑艳秋; 孙娟; 胡文良; 王亚平; 崔晓波; 李玲香

    2016-01-01

    Objective To find out the TP53-related mechanism underlying head and neck squamous cell carcinoma.Methods We used cbioportal to analyse the expression of TP53 and identify the co-expressed genes of TP53 in 279 samples from head and neck squamous cell carcinoma in TCGA database.We used String and DAVID database to establish the co-expression network of TP53 and analyze its func-tion.We used lncRNA2target and StarBase database to screen the microRNA,lncRNA and ceRNA that regulate TP53.Finally,Cytoscape soft-ware was used to establish TP53-related ceRNA network.Results In the 279 samples,77%samples were abnormal expression,and the sur-vival rate of patients with abnormal expression of TP53 was significantly lower than that of normal expression of TP53.Besides,we found 288 TP53-related co-expressed gene.(Spearman score and Pearson score>0.3)The functions of these genes were mainly transcription regulation, cell apoptosis,propagation and immune response.Gene regulatory network revealed that 43 microRNAs (i.g.,has-miR-186-5p and has-miR-202-3p),6 lncRNAs (e.g.,MEG1,TUG1 and MALAT1)and 56 ceRNAs (e.g.,PHC2,FZD4 and TUB)could regulate TP53.Conclusion We established TP53-related gene regulatory network and identified microRNA,lncRNA and ceRNA that regulate TP53.The data generated from this study could provide a new pointcut in research and treatment of head and neck squamous cell carcinoma.%目的:挖掘隐藏在头颈部鳞癌中抑癌基因TP53表达异常的机制。方法从TCGA数据库中选取279例头颈部鳞癌样本的测序数据,利用cbioportal获得TP53基因在头颈部鳞癌中的表达情况及其对患者生存的影响,并筛选样本中与TP53存在共表达关系的基因。利用String和DAVID数据库,建立TP53的共表达网络并分析网络功能,通过lncRNA2target和StarBase数据库,筛选出能够调控TP53的短链非编码RNA(microRNA),长链非编码RNA(lncRNA)和竞争性内源性RNA(ceRNA),利用Cyto-scape软件建立TP

  8. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia.

    Science.gov (United States)

    Navas, Maria-Cristina; Suarez, Iris; Carreño, Andrea; Uribe, Diego; Rios, Wilson Alfredo; Cortes-Mancera, Fabian; Martel, Ghyslaine; Vieco, Beatriz; Lozano, Diana; Jimenez, Carlos; Gouas, Doriane; Osorio, German; Hoyos, Sergio; Restrepo, Juan Carlos; Correa, Gonzalo; Jaramillo, Sergio; Lopez, Rocio; Bravo, Luis Eduardo; Arbelaez, Maria Patricia; Scoazec, Jean-Yves; Abedi-Ardekani, Behnoush; Santella, Regina M; Chemin, Isabelle; Hainaut, Pierre

    2011-01-01

    Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.

  9. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation.

    LENUS (Irish Health Repository)

    Curry, Sarah

    2012-02-01

    The 2004 World Health Organization classification includes the new entity "neuroblastoma-associated renal cell carcinoma." The pathogenetic link between these entities is unknown as yet. The patient reported herein developed renal cell carcinoma after anaplastic embryonal rhabdomyosarcoma, a previously unknown association. The 2nd malignancy developed very soon after the 1st one, prompting concern for inherent cancer predisposition rather than a therapy-induced 2nd malignancy. A variety of features raised suspicion for Tp53 mutation, and indeed a pathogenic germline Tp53 mutation was identified in this child, despite a negative family history for Li-Fraumeni syndrome. Consideration of underlying predisposition is advocated in the context of rapid evolution of 2nd childhood malignancy.

  10. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Schildkraut, Joellen M; Goode, Ellen L; Clyde, Merlise A;

    2009-01-01

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2......,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP......) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations...

  11. Deep sequencing of the TP53 gene reveals a potential risk allele for non-small cell lung cancer and supports the negative prognostic value of TP53 variants.

    Science.gov (United States)

    Deben, Christophe; Van den Bossche, Jolien; Van Der Steen, Nele; Lardon, Filip; Wouters, An; de Beeck, Ken Op; Hermans, Christophe; Jacobs, Julie; Peeters, Marc; Van Camp, Guy; Rolfo, Christian; Deschoolmeester, Vanessa; Pauwels, Patrick

    2017-02-01

    The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

  12. Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.

    Science.gov (United States)

    Santos, Gilson C; da Silva, Ana P A; Feldman, Lucas; Ventura, Grasiella M; Vassetzky, Yegor; de Moura Gallo, Claudia V

    2015-04-01

    In the present paper we aimed to characterize epigenetic aspects and analyze TP53 transcription in the 21 T series, composed of breast cell lines: non-cancerous H16N2; Atypical Ductal Hyperplasia 21PT; Ductal Carcinoma in situ 21NT and Invasive Metastatic Carcinoma 21MT1. We detected a global genomic hypomethylation in 21NT and 21MT1. The histone modification markers analysis showed an important global decrease of the active chromatin mark H4Ac in 21MT1 relative to the other cell lines while the repressive mark H3K9Me3 were not significantly altered. The mRNA levels of DNA methylation and histone modification key enzymes are consistent with the observed genomic hypomethylation and histone hypoacetylation. The expression of DNMT3A/B increased at the initial stages of oncogenesis and the expression of DNMT1 and HAT1 decreased at the advanced stages of breast cancer. Using a confocal immunofluorescent assay, we observed that H4Ac was mostly located at the periphery and the repressive mark H3K9Me3, at the center of 21NT and 21MT1 cells nuclei. TP53 P1 promoter was found to be in an open chromatin state, with a relatively high enrichment of H4Ac and similar TP53 transcription levels in all 21 T cell lines. In conclusion, we observed epigenetic alterations (global genome hypomethylation, global hypoacetylation and accumulation of pericentric heterochromatin) in metastatic breast cancer cells of the 21 T series. These alterations may act at later stages of breast cancer progression and may not affect TP53 transcription at the P1 promoter.

  13. 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.

  14. KRAS, BRAF, and TP53 deep sequencing for colorectal carcinoma patient diagnostics.

    Science.gov (United States)

    Rechsteiner, Markus; von Teichman, Adriana; Rüschoff, Jan H; Fankhauser, Niklaus; Pestalozzi, Bernhard; Schraml, Peter; Weber, Achim; Wild, Peter; Zimmermann, Dieter; Moch, Holger

    2013-05-01

    In colorectal carcinoma, KRAS (alias Ki-ras) and BRAF mutations have emerged as predictors of resistance to anti-epidermal growth factor receptor antibody treatment and worse patient outcome, respectively. In this study, we aimed to establish a high-throughput deep sequencing workflow according to 454 pyrosequencing technology to cope with the increasing demand for sequence information at medical institutions. A cohort of 81 patients with known KRAS mutation status detected by Sanger sequencing was chosen for deep sequencing. The workflow allowed us to analyze seven amplicons (one BRAF, two KRAS, and four TP53 exons) of nine patients in parallel in one deep sequencing run. Target amplification and variant calling showed reproducible results with input DNA derived from FFPE tissue that ranged from 0.4 to 50 ng with the use of different targets and multiplex identifiers. Equimolar pooling of each amplicon in a deep sequencing run was necessary to counterbalance differences in patient tissue quality. Five BRAF and 49 TP53 mutations with functional consequences were detected. The lowest mutation frequency detected in a patient tumor population was 5% in TP53 exon 5. This low-frequency mutation was successfully verified in a second PCR and deep sequencing run. In summary, our workflow allows us to process 315 targets a week and provides the quality, flexibility, and speed needed to be integrated as standard procedure for mutational analysis in diagnostics.

  15. TP53 polymorphisms are involved in inverse colorectal cancer comorbidity in Chinese schizophrenia patients

    Institute of Scientific and Technical Information of China (English)

    Sun Liming; Huang Guoxin; Zhao Leyong; Chen Xiaofen; Chen Wenjiao

    2015-01-01

    The inverse cancer comorbidity in schizophrenia patients may be related to the genetic factors ,involving the regu‐lation of apoptosis .The tumour suppressor gene TP53 ,involved in neural apoptosis ,is one of the potential candidate genes associat‐ed with schizophrenia which might reduce colorectal cancer risk .We recruited 270 schizophrenia patients and 312 colorectal cancer patients without schizophrenia .To examine the genetic association between schizophrenia and colorectal cancer ,we analysed eight SNPs (rs12951053 ,rs1625895 ,rs2909430 ,rs9895829 ,rs1042522 ,rs8079544 ,rs8064946 ,rs17806770) covering 14 .35 kb in the re‐gion of TP53 .We observed that one of the eight genetic polymorphisms showed statistically significant differences between the colo‐rectal cancer subjects and the schizophrenia subjects (rs12951053 ,P=0 .000 1 ,OR 1 .70 ,95% CI 1 .30-2 .23) .In addition ,the hap‐lotype of A‐G (rs12951053‐rs8064946) ,giving a global P=0 .001 8 ,was the most significant .Our data indicate that the polymor‐phisms of rs12951053 in TP53 confer reduced susceptibility to colorectal cancer and suggest a potential protective mechanism a‐gainst colorectal cancer in the schizophrenia patients of Han Chinese origin .

  16. Molecular Characterization of TP53 Gene in Human Populations Exposed to Low-Dose Ionizing Radiation

    Directory of Open Access Journals (Sweden)

    Igor Brasil-Costa

    2013-01-01

    Full Text Available Ionizing radiation, such as that emitted by uranium, may cause mutations and consequently lead to neoplasia in human cells. The TP53 gene acts to maintain genomic integrity and constitutes an important biomarker of susceptibility. The present study investigated the main alterations observed in exons 4, 5, 6, 7, and 8 of the TP53 gene and adjacent introns in Amazonian populations exposed to radioactivity. Samples were collected from 163 individuals. Occurrence of the following alterations was observed: (i a missense exchange in exon 4 (Arg72Pro; (ii 2 synonymous exchanges, 1 in exon 5 (His179His, and another in exon 6 (Arg213Arg; (iii 4 intronic exchanges, 3 in intron 7 (C → T at position 13.436; C → T at position 13.491; T → G at position 13.511 and 1 in intron 8 (T → G at position 13.958. Alteration of codon 72 was found to be an important risk factor for cancer development (P=0.024; OR=6.48; CI: 1.29–32.64 when adjusted for age and smoking. Thus, TP53 gene may be an important biomarker for carcinogenesis susceptibility in human populations exposed to ionizing radiation.

  17. Human tumor cells segregate into radiosensitivity groups that associate with ATM and TP53 status

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Jerry R.; Yonggang Zhang; Russell, James [Radiobiology Laboratory, Johns Hopkins Oncology Center. Baltimore, MD (United States); Koch, Cameron [Dept. of Radiation Oncology, Univ. of Pennsylvania, Philadelphia, PA (United States); Little, John B. [John B. Little Center, Harvard School of Public Health. Boston, MA (United States)

    2007-07-15

    We seek to determine whether cellular radiosensitivity in nineteen human colorectal tumor cell lines and three human glioblastoma tumor cell lines segregate into statistically distinct groups and whether such groups correlate with gene expression. We measure clonogenic survival in 22 cell lines that vary in radiosensitivity and in expression of selected genes: ATM, TP53, CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. We describe and compare radiosensitivity in these cell lines by one-parameter or two parameter analysis. Radiosensitivity varies among and between colorectal tumor cell lines and glioblastoma cell lines. When compared directly using survival, or using two-parameter analysis of radiosensitivity, cell lines distribute into four statistically-significant radiosensitivity groups. These groups associate strongly with the status of two genes, ATM and TP53, but do not associate with CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. Intrinsic cellular radiosensitivity of 22 colorectal and glioblastoma cell lines fall into four radiosensitivity groups that associate with expression of ATM and TP53. These analyses suggest multiple mechanisms underlay intrinsic cellular radiosensitivity.

  18. Evaluation of sgRNA target sites for CRISPR-mediated repression of TP53.

    Directory of Open Access Journals (Sweden)

    Ingrid E B Lawhorn

    Full Text Available The CRISPR (clustered regularly interspaced short palindromic repeats platform has been developed as a general method to direct proteins of interest to gene targets. While the native CRISPR system delivers a nuclease that cleaves and potentially mutates target genes, researchers have recently employed catalytically inactive CRISPR-associated 9 nuclease (dCas9 in order to target and repress genes without DNA cleavage or mutagenesis. With the intent of improving repression efficiency in mammalian cells, researchers have also fused dCas9 with a KRAB repressor domain. Here, we evaluated different genomic sgRNA targeting sites for repression of TP53. The sites spanned a 200-kb distance, which included the promoter, transcript sequence, and regions flanking the endogenous human TP53 gene. We showed that repression up to 86% can be achieved with dCas9 alone (i.e., without use of the KRAB domain by targeting the complex to sites near the TP53 transcriptional start site. This work demonstrates that efficient transcriptional repression of endogenous human genes can be achieved by the targeted delivery of dCas9. Yet, the efficiency of repression strongly depends on the choice of the sgRNA target site.

  19. Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.

    Science.gov (United States)

    Mäkinen, Netta; Aavikko, Mervi; Heikkinen, Tuomas; Taipale, Minna; Taipale, Jussi; Koivisto-Korander, Riitta; Bützow, Ralf; Vahteristo, Pia

    2016-02-01

    Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  20. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    Science.gov (United States)

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  1. TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

    Science.gov (United States)

    La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

    2016-03-01

    The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

  2. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine.

    Science.gov (United States)

    Bally, Cecile; Adès, Lionel; Renneville, Aline; Sebert, Marie; Eclache, Virginie; Preudhomme, Claude; Mozziconacci, Marie-Joelle; de The, Hugues; Lehmann-Che, Jacqueline; Fenaux, Pierre

    2014-07-01

    TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, pmutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.

  3. Clinical Impact of TP53 Gene Mutations in Diffuse Large B-Cell Lymphoma (DLBCL)

    DEFF Research Database (Denmark)

    Young, Ken H; Patten, Nancy; Truong, Sim

    2009-01-01

    survival=50 months) and 41% in patients with the DNA-binding domain mutations (median survival=49 months) compared to 52% for those with wt-TP53 (median survival=69 months). The complete remission rate was 51% in patients with any TP53 mutation and 44% in patients with the DNA-binding domain mutations...... decreased median OS (17 months) when compared to patients with Loop L2 (16% of all mutations) or loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) with median OS of 49 and 50 months, respectively. In contrast to our previous CHOP series study, median survival was significantly improved...... of TP53 mutations, while TP53 deletion did not correlate with mutation or OS. In comparison to our previous series of patients treated only with CHOP, Rituxan-CHOP regimen improved OS in both wt-TP53 and TP53 mutated groups. The 5-year survival rate was 42% in patients with any TP53 mutation (median...

  4. Transactivation of repair genes by BRCA1.

    Science.gov (United States)

    El-Deiry, Wafik S

    2002-01-01

    Recent studies have identified a link between the BRCA1 tumor suppressor and transcriptional regulation of a group of genes involved in nucleotide excision repair. There is some controversy regarding the precise mechanism of upregulation of XPE DDB2 or XPC by BRCA1, with some evidence suggesting that p53 is involved in their regulation. Some evidence suggests BRCA1 may stabilize p53 and direct regulation of DNA repair genes, although how BRCA1 stabilizes p53 remains unclear and whether BRCA1 can upregulate DNA repair genes in a p53-independent manner remains a possibility. A transcriptional component to the action of BRCA1 and involvement of XP genes brings up new and interesting questions about breast cancer development and therapy.

  5. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana

    2016-02-04

    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.

  6. Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis.

    Science.gov (United States)

    Hansen, Sarah A; Hart, Marcia L; Busi, Susheel; Parker, Taybor; Goerndt, Angela; Jones, Kevin; Amos-Landgraf, James M; Bryda, Elizabeth C

    2016-10-01

    Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53(tm1(EGFP-Pac)Qly)/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

  7. Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer.

    Science.gov (United States)

    Almeida, B C; Kleine, J P F O; Camargo-Kosugi, C M; Lisboa, M R; França, C N; França, J P; Silva, I D C G

    2016-02-22

    The association between TP53 gene polymorphisms and breast cancer (BC) in Brazilian women is a controversial topic. In this cross-sectional study, we evaluated the association between clinical pathological variables and three polymorphisms (TP53*11, TP53*72, and TP53*248) in BC patients and controls. Genomic DNA was extracted from the blood cells of 393 participants; the cancer-free control subjects were 26-72 years old (41 ± 11.03) and the BC patients were 28-80 years old (51 ± 10.70). We used standard polymerase chain reaction-restriction fragment length polymorphism and confirmed the results by genetic sequencing. In TP53*11, there was 100% homozygous Glu distribution in both groups. TP53*72 showed genotypic distribution: in the control group, there was 16.10% homozygous Pro, and 42.44% heterozygous and 41.46% homozygous Arg; in the BC group, there was 15.43% homozygous Pro, and 42.55% heterozygous and 42.02% homozygous Arg. The relative frequency of each allele was 0.37% for Pro and 0.63% for Arg in the control group, and 0.37% for Pro and 0.63% for Arg in the BC group. The nuclear grade (P = 0.0084) and adapted histological grade (P = 0.0265) were associated with TP53*72. The distribution of the codon 72 genotypes did not deviate from Hardy-Weinberg equilibrium in either group. In TP53*248, there was 100% homozygous Arg distribution in both groups. In codon 72, the Arg allele is the most prevalent in Brazilian women. TP53*72 may be associated with susceptibility to BC, although more studies are required to evaluate the profile of Brazilian women with BC.

  8. TP53结构功能及活性调节的最新研究进展

    Institute of Scientific and Technical Information of China (English)

    李虹; 姚开泰

    2001-01-01

    TP53是一种广谱肿瘤抑制基因,其产物为多功能的转录调节因子,可以发挥调节细胞生长、细胞凋亡和DNA修复的作用.对TP53的结构与功能的研究一直是TP53研究的热点和重点内容.本文阐述了有关该蛋白结构功能及活性调节的最新研究进展.

  9. Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.

    Science.gov (United States)

    Samassekou, Oumar; Bastien, Nathalie; Lichtensztejn, Daniel; Yan, Ju; Mai, Sabine; Drouin, Régen

    2014-11-01

    TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.

  10. TP 53基因在特定血液病和淋巴瘤中的研究进展%Dysfunction of the TP53 in some lymphoid malignancies and blood cancer

    Institute of Scientific and Technical Information of China (English)

    濮晓红; 叶庆

    2014-01-01

    TP53 is a tumor suppressor gene for gene network, tumor suppressor p53 protein ( cellular tumor antigen p53) , is“the guardian of the genome,” preserves genome stability under cellular stress, and is involved in various processes of development, differentiation, aging and disease. Dysfunction of TP53 with wild-type coding sequence can result deregulated gene expression, stability and activity of p53. Mutation and dysfunction of TP53 gene is important in the pathogensis of many human cancers. Besides, the status of TP53 is an independent prognostic factor in most blood cancer and lymphoma types. We review the significance of TP53 dysfunction and discuss the role of TP53 associated with lymphomagenesis and blood cancer.%TP53基因是重要的抑癌基因之一,其编码的蛋白---肿瘤抑制蛋白p53能够使许多基因保持其稳定性,并调节细胞的生长、分化、衰老,避免疾病产生,被称为“基因守护者”。当TP53基因缺失、突变和调节紊乱时,将直接影响p53蛋白的功能和活性,从而导致很多肿瘤的发生;除此之外TP53的基因状态也成为判断淋巴瘤和血液病预后的重要指标。本文通过综述TP53基因缺失和突变在不同血液病和淋巴瘤中的意义,使人们对TP53基因与血液肿瘤和淋巴瘤的关系有更清晰的认识。

  11. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

    Science.gov (United States)

    Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K; García-Closas, Montserrat; Heikkilä, Päivi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomäki, Kristiina; Liu, Jianjun; Ali, H Raza; Andrulis, Irene L; Beckmann, Matthias W; Behrens, Sabine; Blows, Fiona M; Brenner, Hermann; Chang-Claude, Jenny; Couch, Fergus J; Czene, Kamila; Fasching, Peter A; Figueroa, Jonine; Floris, Giuseppe; Glendon, Gord; Guo, Qi; Hall, Per; Hallberg, Emily; Hamann, Ute; Holleczek, Bernd; Hooning, Maartje J; Hopper, John L; Jager, Agnes; Kabisch, Maria; Keeman, Renske; Kosma, Veli-Matti; Lambrechts, Diether; Lindblom, Annika; Mannermaa, Arto; Margolin, Sara; Provenzano, Elena; Shah, Mitul; Southey, Melissa C; Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli

    2017-02-05

    TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

  12. TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma.

    Science.gov (United States)

    Gros, Audrey; Laharanne, Elodie; Vergier, Marie; Prochazkova-Carlotti, Martina; Pham-Ledard, Anne; Bandres, Thomas; Poglio, Sandrine; Berhouet, Sabine; Vergier, Béatrice; Vial, Jean-Philippe; Chevret, Edith; Beylot-Barry, Marie; Merlio, Jean-Philippe

    2017-01-01

    Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, TP53 mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a TP53 deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited TP53 mutation and/or deletion (83%). No difference in prognosis was observed according to TP53 status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with TP53 alterations displayed a younger age and the presence of TP53 alteration at initial diagnosis stage supports a pivotal oncogenic role for TP53 mutation in SS as well as in erythrodermic MF making TP53 assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display TP53 alteration.

  13. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

    NARCIS (Netherlands)

    Holstege, H.; Horlings, H.M.; Velds, A.; Langerod, A.; Borresen-Dale, A.L.; van de Vijver, M.J.; Nederlof, P.M.; Jonkers, J.

    2010-01-01

    ABSTRACT: BACKGROUND: Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble

  14. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions

    Energy Technology Data Exchange (ETDEWEB)

    De Marini, D.M.; Landi, S.; Tian, D.F.; Hanley, N.M.; Li, X.M.; Hu, F.D.; Roop, B.C.; Mass, M.J.; Keohavong, P.; Gao, W.M.; Olivier, M.; Hainaut, P.; Mumford, J.L. [US EPA, Research Triangle Park, NC (United States). Environmental Carcinogenesis Division

    2001-09-15

    The TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal were determined. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G to T transversions at either KRAS (86%) or TP53 (76%), (b) clustered at the G-rich codons 153-158 of TP53 (33%), and (c) had 100% of the guanines of the G to T transversions on the nontranscribed strand. This mutation spectrum is consistent with an exposure to polycyclic aromatic hydrocarbons, which are the primary component of the smoky coal emissions. These results show that mutations in the TP53 and KRAS genes can reflect a specific environmental exposure.

  15. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.

    Science.gov (United States)

    Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Chiadini, Elisa; Dazzi, Claudio; Papi, Maximilian; Capelli, Laura; Casanova, Claudia; De Luigi, Nicoletta; Mariotti, Marita; Gamboni, Alessandro; Chiari, Rita; Bennati, Chiara; Calistri, Daniele; Ludovini, Vienna; Crinò, Lucio; Amadori, Dino; Ulivi, Paola

    2016-10-25

    Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 1-8. ©2016 AACR.

  16. FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma.

    Science.gov (United States)

    Tanuma, Jun-Ichi; Izumo, Toshiyuki; Hirano, Masato; Oyazato, Yoshitaka; Hori, Fumiya; Umemura, Eri; Shisa, Hayase; Hiai, Hiroshi; Kitano, Motoo

    2010-03-01

    The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

  17. TP53通路分子遗传学改变与肝细胞癌

    Institute of Scientific and Technical Information of China (English)

    王岩(综述); 黄坚(审校)

    2013-01-01

    肝细胞癌是一种常见的恶性肿瘤,TP53突变在其发病机制中有重要作用。在我国大陆地区,约有50% HCC患者携带TP53突变,最常见的是黄曲霉毒素导致的R249S突变。MDM2和p14ARF是TP53通路的两个重要调节因子,近来研究显示MDM2扩增和p14ARF纯合性缺失/启动子甲基化也参与了HCC的发生发展过程。目前,有越来越多关于TP53通路改变在HCC早期诊断、预后和治疗中应用的研究,但还需要更多的研究证实。本文重点介绍了TP53通路分子遗传学改变(包括TP53突变、MDM2扩增和p14ARF纯合性缺失/启动子甲基化)与肝细胞癌发生的关系。

  18. KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis.

    Science.gov (United States)

    Du, Lijun; Kim, John J; Shen, Jinhua; Chen, Binrui; Dai, Ning

    2017-01-07

    Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; PTP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC.

  19. TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

    Science.gov (United States)

    Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

    2001-01-01

    Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

  20. Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.

    Directory of Open Access Journals (Sweden)

    Netta Mäkinen

    2016-02-01

    Full Text Available Uterine leiomyosarcomas (ULMSs are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%, alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%, and mediator complex subunit 12 (MED12; 4/19; 21%. Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52% showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT, and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX, another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  1. TP53 Polymorphisms allow for genetic sub-grouping of the canine transmissible venereal tumor

    Science.gov (United States)

    Sánchez-Servín, Abel; Córdova-Alarcon, Emilio; Fajardo, Raúl

    2009-01-01

    The canine transmissible venereal tumor (CTVT) is found mainly in dogs' sexual organs. Currently, it is widely accepted that all samples of CTVT show similar histopathological characteristics and share common genetic alterations. Despite the common genetic origin of CTVT, mutations in the P53 gene have been reported. In this study, we proposed that tumor samples can be genetically grouped using this gene. The presence of different subgroups of CTVT was determined in Mexican dogs using the TP53 gene sequence in CTVT samples. Four new polymorphisms were found and therefore, the CTVT samples were classified in five subgroups. PMID:19934603

  2. Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis.

    Science.gov (United States)

    N'guessan, Prudence; Pouyet, Laurent; Gosset, Gaëlle; Hamlaoui, Sonia; Seillier, Marion; Cano, Carla E; Seux, Mylène; Stocker, Pierre; Culcasi, Marcel; Iovanna, Juan L; Dusetti, Nelson J; Pietri, Sylvia; Carrier, Alice

    2011-09-15

    The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.

  3. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia

    Directory of Open Access Journals (Sweden)

    Maria-Cristina Navas

    2011-01-01

    Full Text Available Hepatocellular Carcinoma (HCC is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV and/or Hepatitis C Virus (HCV, chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.

  4. Occurrence of Neuroblastoma among TP53 p.R337H Carriers.

    Science.gov (United States)

    Seidinger, Ana Luiza; Fortes, Fernanda Paschoal; Mastellaro, Maria José; Cardinalli, Izilda Aparecida; Zambaldi, Lilian Girotto; Aguiar, Simone Santos; Yunes, José Andrés

    2015-01-01

    The high incidence of adrenocortical tumors and choroid plexus carcinoma in children from South and Southeastern regions of Brazil is associated with the germline p.R337H mutation of TP53 gene. The concomitant occurrence of neuroblastoma and adrenocortical tumors in pediatric patients harboring the p.R337H mutation at our institution prompted us to investigate the putative association between p.R337H and pediatric neuroblastoma. Genomic DNA samples from 83 neuroblastoma patients referred to a single institution during the period of 2000-2014 were screened for the p.R337H mutation. Available samples from carriers were investigated for both nuclear p53 accumulation and loss of heterozigosity in tumor. Clinical data were obtained from medical records in order to assess the impact of 337H allele on manifestation of the disease. Seven out 83 neuroblastoma patients (8.4%) were carriers of the TP53 p.R337H mutation in our cohort. Immunohistochemical analysis of p.R337H-positive tumors revealed nuclear p53 accumulation. Loss of heterozigosity was not found among available samples. The presence of 337H allele was associated with increased proportion of stage I tumors. Our data indicate that in addition to adrenocortical tumors, choroid plexus carcinoma, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential neoplasia affecting p.R337H carriers.

  5. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.

    Science.gov (United States)

    Stacey, Simon N; Sulem, Patrick; Jonasdottir, Aslaug; Masson, Gisli; Gudmundsson, Julius; Gudbjartsson, Daniel F; Magnusson, Olafur T; Gudjonsson, Sigurjon A; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Ragnarsson, Rafn; Benediktsdottir, Kristrun R; Nexø, Bjørn A; Tjønneland, Anne; Overvad, Kim; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Hemminki, Kari; Corredera, Cristina; Fuentelsaz, Victoria; Grasa, Pilar; Navarrete, Sebastian; Fuertes, Fernando; García-Prats, Maria D; Sanambrosio, Enrique; Panadero, Angeles; De Juan, Ana; Garcia, Almudena; Rivera, Fernando; Planelles, Dolores; Soriano, Virtudes; Requena, Celia; Aben, Katja K; van Rossum, Michelle M; Cremers, Ruben G H M; van Oort, Inge M; van Spronsen, Dick-Johan; Schalken, Jack A; Peters, Wilbert H M; Helfand, Brian T; Donovan, Jenny L; Hamdy, Freddie C; Badescu, Daniel; Codreanu, Ovidiu; Jinga, Mariana; Csiki, Irma E; Constantinescu, Vali; Badea, Paula; Mates, Ioan N; Dinu, Daniela E; Constantin, Adrian; Mates, Dana; Kristjansdottir, Sjofn; Agnarsson, Bjarni A; Jonsson, Eirikur; Barkardottir, Rosa B; Einarsson, Gudmundur V; Sigurdsson, Fridbjorn; Moller, Pall H; Stefansson, Tryggvi; Valdimarsson, Trausti; Johannsson, Oskar T; Sigurdsson, Helgi; Jonsson, Thorvaldur; Jonasson, Jon G; Tryggvadottir, Laufey; Rice, Terri; Hansen, Helen M; Xiao, Yuanyuan; Lachance, Daniel H; O Neill, Brian Patrick; Kosel, Matthew L; Decker, Paul A; Thorleifsson, Gudmar; Johannsdottir, Hrefna; Helgadottir, Hafdis T; Sigurdsson, Asgeir; Steinthorsdottir, Valgerdur; Lindblom, Annika; Sandler, Robert S; Keku, Temitope O; Banasik, Karina; Jørgensen, Torben; Witte, Daniel R; Hansen, Torben; Pedersen, Oluf; Jinga, Viorel; Neal, David E; Catalona, William J; Wrensch, Margaret; Wiencke, John; Jenkins, Robert B; Nagore, Eduardo; Vogel, Ulla; Kiemeney, Lambertus A; Kumar, Rajiv; Mayordomo, José I; Olafsson, Jon H; Kong, Augustine; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari

    2011-09-25

    To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

  6. Overexpression of RBBP6, alone or combined with mutant TP53, is predictive of poor prognosis in colon cancer.

    Directory of Open Access Journals (Sweden)

    Jian Chen

    Full Text Available Retinoblastoma binding protein 6 (RBBP6 plays an important role in chaperone-mediated ubiquitination and interacts with TP53 in carcinogenesis. However, the clinicopathologic significance of RBBP6 expression in colon cancer is unknown; in particular, the prognostic value of RBBP6 combined with TP53 expression has not been explored. Therefore, quantitative real-time PCR and western blot analyses were performed to detect RBBP6 expression in colon cancer tissues. RBBP6 and TP53 expression were assessed by immunohistochemistry in a tissue microarray format, in which the primary colon cancer tissue was paired with noncancerous tissue. Tissue specimens were obtained from 203 patients. We found that RBBP6 was overexpressed in colon tumorous tissues and was significantly associated with clinical stage, depth of tumor invasion, lymph node metastasis (LNM, distant metastasis, and histologic grade. Further studies revealed that a corresponding correlation between RBBP6 overexpression and mutant TP53 was evident in colon cancer (r = 0.450; P<0.001. RBBP6 expression was an independent prognostic factor for overall survival (OS and disease free survival (DFS. Interestingly, patients with tumors that had both RBBP6 overexpression and mutant TP53 protein accumulation relapsed and died within a significantly short period after surgery (P<0.001. Multivariate analysis showed that patients with LNM and patients with both RBBP6- and TP53-positive tumors had extremely poor OS (HR 6.75; 95% CI 2.63-17.35; P<0.001 and DFS (HR 8.08; 95% CI 2.80-23.30; P<0.001. These clinical findings indicate that the assessment of both RBBP6 and mutant TP53 expression will be helpful in predicting colon cancer prognosis.

  7. Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues.

    Science.gov (United States)

    Krimmel, Jeffrey D; Schmitt, Michael W; Harrell, Maria I; Agnew, Kathy J; Kennedy, Scott R; Emond, Mary J; Loeb, Lawrence A; Swisher, Elizabeth M; Risques, Rosa Ana

    2016-05-24

    Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with high-grade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.

  8. Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1.

    Science.gov (United States)

    Seillier, Marion; Pouyet, Laurent; N'Guessan, Prudence; Nollet, Marie; Capo, Florence; Guillaumond, Fabienne; Peyta, Laure; Dumas, Jean-François; Varrault, Annie; Bertrand, Gyslaine; Bonnafous, Stéphanie; Tran, Albert; Meur, Gargi; Marchetti, Piero; Ravier, Magalie A; Dalle, Stéphane; Gual, Philippe; Muller, Dany; Rutter, Guy A; Servais, Stéphane; Iovanna, Juan L; Carrier, Alice

    2015-03-30

    The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.

  9. BRCA1 and BRCA2 gene testing

    Science.gov (United States)

    ... of br east ca ncer. What is the BRCA Gene Mutation? BRCA1 and BRCA2 are genes that ... even negative results, with your genetic counselor. References BRCA and BRCA2: Cancer Risk and Genetic Testing. National ...

  10. Evaluation of TP53 Pro72Arg and MDM2 SNP285-SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations.

    Science.gov (United States)

    Ponti, Francesca; Corsini, Serena; Gnoli, Maria; Pedrini, Elena; Mordenti, Marina; Sangiorgi, Luca

    2016-10-01

    Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.

  11. Research on the correlationship with the expression of MYC, PTEN, TP53 and esophageal carcinoma in Kazakh%MYC、PTEN和TP53表达与哈萨克族食管癌相关性研究

    Institute of Scientific and Technical Information of China (English)

    郭琼; 沙亚哈提·别尔克哈之; 李惠武

    2014-01-01

    [目的]检测MYC、PTEN、TP53在哈萨克族食管癌组织和远端无癌组织的表达,分析与临床病理因素的关系,探讨它们在哈萨克族食管癌发生发展中可能存在的关系.[方法] Trizol一步法获取组织标本总RNA,逆转录为cDNA,运用半定量RT-PCR技术检测食管癌组织、远端无癌组织中三个基因mRNA表达量及阳性表达率.[结果]①MYC mRNA表达量在食管癌组织中高于远端无癌组织(P <0.01);PTEN、TP53 mRNA表达量在远端无癌组织中高于癌组织(P <0.01,P<0.05);②MYC阳性表达率在食管癌组织中高于远端无癌组织(P<0.01);PTEN、TP53阳性表达率在远端无癌组织中高于癌组织(P <0.01,P<0.05));③MYC表达与分化程度(P<0.05)、TNM分期(P<0.05)、淋巴结转移(P<0.01)和侵犯深度(P<0.05)有关;PTEN表达与分化程度有关(P <0.05);TP53的表达与上述指标无关;④MYC和PTEN、TP53表达呈负相关(r=-0.494;r=-0.428);PTEN、TP53表达呈正相关(r=0.531).[结论]哈萨克族食管癌组织中MYC表达上调,PTEN、TP53低表达或不表达.上述结果说明MYC参与哈萨克族食管癌的发生和发展,PTEN、TP53则是阻止食管组织发生癌变的保护性基因.

  12. Identification of a novel TP53 germline mutation in one child with adrenocortical carcinoma%肾上腺皮质癌患儿TP53基因的一个新生殖系突变

    Institute of Scientific and Technical Information of China (English)

    司锘; 孙淼; 卢超霞; 刘彦山; 齐展; 杨威; 赵秀丽; 张学

    2009-01-01

    Objective To detect the germline TP53 gene mutation in a child with pediatric adrenocortical carcinoma (ADCC) in order to provide genetic diagnosis and counseling. Methods Genomic DNA was extracted from peripheral blood from a girl with ADCC and her parents. All TP53 exons and their flanking intronic sequences were PCR-amplified and subjected to automatic DNA sequencing. Results Direct sequencing of PCR products revealed a heterozygous G insertion between nucleotide 522 and 523 (c.522-523insG) in TP53 exon 5. This novel mutation is predicted to result in a frame shift at codon 175, producing a new reading frame ending in a stop at position 6 (p.R175AfsX6). The same heterozygous mutation was also found in her father, but not in her mother. Conclusion A novel germline mutation in the TP53 gene has been identified in one case with pediatric ADCC.%目的 研究1例肾上腺皮质癌患儿TP53基因突变情况,为该病的基因诊断与遗传咨询提供依据.方法 提取1例肾上腺皮质癌患儿及父母外周血基因组DNA,针对TP53基因设计特异性引物,采用聚合酶链式反应(PCR)扩增基因的全部编码及侧翼序列,对扩增产物进行直接测序.结果 PCR结合DNA测序发现患者TP53基因第5外显子存在异常:第522与523位核苷酸间插入一个鸟嘌呤(c.522-523insG),导致P53蛋白DNA结合域第175位密码子由精氨酸(R)变为丙氨酸(A),并从突变位置起发生移码,产生移码突变(p.R175AfsX6).患者父亲带有相同的突变,而母亲未发现此突变.结论 TP53基因p.R175AfsX6生殖系突变是导致该例患者肾上腺皮质癌的特异突变.

  13. Genetic evolution of nevus of Ota reveals clonal heterogeneity acquiring BAP1 and TP53 mutations.

    Science.gov (United States)

    Vivancos, Ana; Caratú, Ginevra; Matito, Judit; Muñoz, Eva; Ferrer, Berta; Hernández-Losa, Javier; Bodet, Domingo; Pérez-Alea, Mileidys; Cortés, Javier; Garcia-Patos, Vicente; Recio, Juan A

    2016-03-01

    Melanoma presents molecular alterations based on its anatomical location and exposure to environmental factors. Due to its intrinsic genetic heterogeneity, a simple snapshot of a tumor's genetic alterations does not reflect the tumor clonal complexity or specific gene-gene cooperation. Here, we studied the genetic alterations and clonal evolution of a unique patient with a Nevus of Ota that developed into a recurring uveal-like dermal melanoma. The Nevus of Ota and ulterior lesions contained GNAQ mutations were c-KIT positive, and tumors showed an increased RAS pathway activity during progression. Whole-exome sequencing of these lesions revealed the acquisition of BAP1 and TP53 mutations during tumor evolution, thereby unmasking clonal heterogeneity and allowing the identification of cooperating genes within the same tumor. Our results highlight the importance of studying tumor genetic evolution to identify cooperating mechanisms and delineate effective therapies.

  14. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.

    Science.gov (United States)

    Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos; Areškevičiūtė, Aušrinė; Brown, Peter; Girkov, Mia Seremet; Pedersen, Anja; Sjö, Lene D; Heegaard, Steffen; Broholm, Helle; Kristensen, Lasse S; Ralfkiaer, Elisabeth; Grønbæk, Kirsten

    2016-04-22

    Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This

  15. Association between TP53 gene Arg72Pro polymorphism and Wilms' tumor risk in a Chinese population.

    Science.gov (United States)

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms' tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms' tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms' tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms' tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003-4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms' tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

  16. Association between TP53 gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

    Science.gov (United States)

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms’ tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms’ tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms’ tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003–4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms’ tumor risk in Chinese children. These findings need further validations in other populations with larger sample size. PMID:28260929

  17. Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer.

    Science.gov (United States)

    Zhang, Le-Le; Kan, Mengyuan; Zhang, Man-Man; Yu, Sha-Sha; Xie, Hui-Jun; Gu, Zhao-Hui; Wang, Hai-Ning; Zhao, Shuang-Xia; Zhou, Guang-Biao; Song, Huai-Dong; Zheng, Cui-Xia

    2017-01-01

    Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.

  18. Germline TP53 mutations and single nucleotide polymorphisms in children Mutaciones y polimorfismos de un único nucleótido del gen TP53 en línea germinal en niños

    Directory of Open Access Journals (Sweden)

    Pamela Valva

    2009-02-01

    Full Text Available Mutations in the gene TP53, which codifies the tumor suppressor protein p53, are found in about 50% of tumors. These mutations can occur not only at somatic level, but also in germline. Pediatric cancer patients, mostly with additional family history of malignancy, should be considered as potential TP53 germline mutation carriers. Germline TP53 mutations and polymorphisms have been widely studied to determine their relation with different tumors' pathogenesis. Our aim was to analyze the occurrence frequency of germline TP53 mutations and polymorphisms and to relate these to tumor development in a pediatric series. Peripheral blood mononuclear cell samples from 26 children with solid tumors [PST] and 21 pediatric healthy donors [HD] were analyzed for germline mutations and polymorphisms in TP53 gene spanning from exon 5 to 8 including introns 5 and 7. These PCR amplified fragments were sequenced to determine variations. A heterozygous mutation at codon 245 was found in 1/26 PST and 0/21 HD. Comparative polymorphisms distribution, at position 14181 and 14201(intron 7, between HD and PST revealed a trend of association (p= 0.07 with cancer risk. HD group disclosed a similar polymorphism distribution as published data for Caucasian and Central/South American populations. This is the first study about TP53 variant frequency and distribution in healthy individuals and cancer patients in Argentina.El gen que codifica para la proteína supresora de tumor p53 (TP53 se encuentra mutado en aproximadamente el 50% de los tumores. Estas mutaciones pueden presentarse como somáticas o en línea germinal. Los niños con tumores, sobre todo aquellos con historia familiar de enfermedad oncológica, deben considerarse potenciales portadores de mutaciones en línea germinal. Las mutaciones de TP53 y los polimorfismos son estudiados para determinar su relación con la patogénesis de diferentes tumores. El objetivo del trabajo fue analizar la frecuencia de

  19. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

    Science.gov (United States)

    Rücker, Frank G; Schlenk, Richard F; Bullinger, Lars; Kayser, Sabine; Teleanu, Veronica; Kett, Helena; Habdank, Marianne; Kugler, Carla-Maria; Holzmann, Karlheinz; Gaidzik, Verena I; Paschka, Peter; Held, Gerhard; von Lilienfeld-Toal, Marie; Lübbert, Michael; Fröhling, Stefan; Zenz, Thorsten; Krauter, Jürgen; Schlegelberger, Brigitte; Ganser, Arnold; Lichter, Peter; Döhner, Konstanze; Döhner, Hartmut

    2012-03-01

    To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

  20. Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma.

    Science.gov (United States)

    Lapke, Nina; Lu, Yen-Jung; Liao, Chun-Ta; Lee, Li-Yu; Lin, Chien-Yu; Wang, Hung-Ming; Ng, Shu-Hang; Chen, Shu-Jen; Yen, Tzu-Chen

    2016-07-12

    TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients.

  1. Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter.

    Science.gov (United States)

    Blackburn, James; Roden, Daniel L; Ng, Robert; Wu, Jianmin; Bosman, Alexis; Epstein, Richard J

    2016-12-01

    Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide. Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53-wildtype) and cancerous (TP53-mutant) human cells and tissues revealed focal cancer-associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. © 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

  2. Pediatric inherited cancer predisposition syndromes and TP53 germ-line mutation%儿童遗传性肿瘤易感综合征和TP53基因种系突变

    Institute of Scientific and Technical Information of China (English)

    唐月佳; 高怡瑾

    2016-01-01

    Pediatric inherited cancer predisposition syndromes are a group of diseases caused by germ-line mutation of cancer related genes. The patients are susceptible to cancers. TP53 germ-line mutation is the most commonly seen mutant gene in cancers that accounts for 20%-30%of all germ-line mutations of inherited cancers. TP53 gene mutation screening could help clinicians to better manage the patients and their family members.%儿童遗传性肿瘤易感综合征是由于肿瘤相关基因的种系突变所导致的一类遗传性疾病,患者具有明显的肿瘤易感倾向。TP53基因的种系突变占到所有遗传性肿瘤的20%~30%,是最常见的肿瘤突变基因。通过对TP53基因的检测,可以帮助临床医师更好的对遗传性肿瘤患者及家庭成员进行管理。

  3. Imunorreatividade da p53 associada à ausência de mutações no gene TP53 em linfomas caninos Immunostaing of p53 associated with absence of mutations in TP53 gene in dogs with lymphoma

    Directory of Open Access Journals (Sweden)

    Sabryna Gouveia Calazans

    2010-06-01

    Full Text Available Sabendo-se da influência das mutações no gene TP53 no desenvolvimento das neoplasias e da discrepância entre os resultados obtidos pelas técnicas de sequenciamento e imunoistoquímica, esta pesquisa teve como objetivo relacionar a sequência do TP53 com a imunorreatividade da p53. Foram obtidas amostras de linfoma de 12 cães. O diagnóstico histopatológico foi determinado pela classificação de Kiel. O imunofenótipo e a imunomarcação da p53 foram determinados por imunoistoquímica. Para reação com a p53, utilizou-se anticorpo policlonal anti-p53 (CM1 na diluição de 1:500. A região do gene TP53 compreendida entre os exons quatro e nove foi amplificada por PCR e submetida ao sequenciamento. Apesar dos resultados obtidos pela imunoistoquímica, nenhuma mutação foi encontrada nas sequências analisadas. Conclui-se que a imunorreatividade da p53 pela imunoistoquímica não pode ser atribuída à presença de mutações no domínio central do gene TP53.TP53 mutations are usually involved in cancer, but sequencing and immunohistochemistry results are often controversial. Thus, the aim of this study was to associate TP53 sequence with p53 immunostaining in dogs with lymphoma. Tumor samples were collected from 12 dogs with lymphoma and were included in this study. Histopathological diagnosis was performed according to Kiel classification. Immunohistochemistry was performed to identify immunophenotype as well as p53 expression. Polyclonal antibody anti-p53 (CM1 was used at a 1:500 dilution. The region that encompasses exons 4-9 was amplified by f PCR reactions and sequencing was then performed. Nevertheless, gene mutations were not observed in any sequence. In conclusion, immunoreactivity of p53 by means of immunohistochemistry should not be indicator of presence of mutations in the core domain of TP53 gene.

  4. Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue

    NARCIS (Netherlands)

    Hayes, V M; Bleeker, W; Verlind, E; Timmer, T; Karrenbeld, A; Plukker, J T; Marx, M P; Hofstra, R M; Buys, C H

    1999-01-01

    A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue

  5. A novel splice mutation in the TP53 gene associated with Leydig cell tumor and primitive neuroectodermal tumor

    DEFF Research Database (Denmark)

    Stecher, C.W.; Hasle, H.; Grønbæk, Kirsten

    2008-01-01

    A 20-month-old boy presented with precocious puberty due to a Leydig cell tumor, and at the age of 6 years with a primitive neuroectodermal brain-tumor (PNET). A novel splice site mutation of the TP53-gene, likely to be associated with a nonfunctional protein, was found in the proband, his father...

  6. DNA methylation patterns of candidate genes regulated by thymine DNA glycosylase in patients with TP53 germline mutations

    Energy Technology Data Exchange (ETDEWEB)

    Fortes, F.P. [CIPE, Laboratrio de Oncogentica Molecular, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Kuasne, H. [CIPE, Laboratrio NeoGene, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Departamento de Urologia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP (Brazil); Marchi, F.A. [CIPE, Laboratrio NeoGene, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Programa Inter-Institucional em Bioinformtica, Instituto de Matemtica e Estatstica, Universidade So Paulo, So Paulo, SP (Brazil); Miranda, P.M. [CIPE, Laboratrio NeoGene, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Rogatto, S.R. [CIPE, Laboratrio NeoGene, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Departamento de Urologia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP (Brazil); Achatz, M.I. [CIPE, Laboratrio de Oncogentica Molecular, A.C. Camargo Cancer Center, São Paulo, SP (Brazil); Departamento de Oncogentica, A.C. Camargo Cancer Center, So Paulo, SP (Brazil)

    2015-04-28

    Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary cancer predisposition disorder. In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome. The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability. However, the extent of involvement of such events has not been clarified. It is well established that p53 regulates several pathways, including the thymine DNA glycosylase (TDG) pathway, which regulates the DNA methylation of several genes. This study aimed to identify the DNA methylation pattern of genes potentially related to the TDG pathway (CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17) in 30 patients with germline TP53mutations, 10 patients with wild-type TP53, and 10 healthy individuals. We also evaluated TDG expression in patients with adrenocortical tumors (ADR) with and without the p.R337H TP53 mutation. Gene methylation patterns of peripheral blood DNA samples assessed by pyrosequencing revealed no significant differences between the three groups. However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR. Considering the rarity of this phenotype and the relevance of these findings, further studies using a larger sample set are necessary to confirm our results.

  7. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NON-SMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    Science.gov (United States)

    Abstract We determined the TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G -+ T transver...

  8. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NONSMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    Science.gov (United States)

    Lung Tumor KRAS and TP53 Mutations in Nonsmokers Reflect Exposure to PAH-Rich Coal Combustion Emissions Use of smoky coal in unvented homes in Xuan Wei County, Yunnan Province, China, is associated with lung cancer among nonsmoking females. Such women have the highest...

  9. POSSIBLE REASONS FOR TP53 ACCUMULATION IN NASO- PHARYNGEAL CARCINOMA USING ATLAS HUMAN CANCER cDNA EXPRESSION ARRAY

    Institute of Scientific and Technical Information of China (English)

    李虹; 韩为农; 张玲; 冯湘玲; 姚开泰

    2002-01-01

    Objective: To compare gene expression profiles of nasopharyngeal carcinoma (NPC) tissue with that of control tissue by cDNA Array and to discuss possible reasons of TP53 accumulation in NPC tissue. Methods: (1) hybridization of Atlas Human Cancer cDNA Expression Array 7742-1; (2) analysis of Atlas Arrays using Atlasimage 1.01a; (3) verification of results of array by RT-PCR; (4) verification of protein expression alterations by immuno- histochemistry. Results: (1) Of 588 tumor-related genes, 134 genes were upregulated, 88 downregulated; (2) Of 32 TP53-regulated genes, 13 genes were shown differential expression, 11 upregulated, 2 downregulated; (3) ATM and JNK2 were upregulated; (4) mRNA expression of ubiquitin-conjugating enzyme E2 (M74524) and ubiquitin- conjugating enzyme E2 (L22005) has no evident changes; Conclusion: (1) TP53 dysfunction exists in NPC tissues; (2) ATM and JNK might be the important causes of TP53 accumulation.

  10. A substantial proportion of microsatellite-unstable colon tumors carry TP53 mutations while not showing chromosomal instability

    NARCIS (Netherlands)

    Westra, JL; Boven, LG; van der Wes, P; Faber, H; Sikkema, B; Schaapveld, M; Dijkhuizen, T; Hollema, H; Buys, CHCM; Plukker, JTM; Kok, K; Hofstra, RMW

    2005-01-01

    Chromosomal instability in colon tumors implies the presence of numerical and structural chromosome aberrations and is further characterized by the absence of microsatellite instability and the occurrence of KRAS and/or TP53 mutations. In a previous screening of 194 colon tumors for both microsatell

  11. TP53基因在非增生不良性Barrett食管中少有突变

    Institute of Scientific and Technical Information of China (English)

    Novotna; K.; Trkova; M.; Pazdro; A.; 陈云茹(译); 史敏(校)

    2006-01-01

    在对可能的预后指标研究中,作者分析了一大系列Barrett食管组织及来源于Barrett食管段的腺癌标本,通过直接测序法得到该段TP53基因存在外显子5~9的突变。虽然21例腺癌标本中有9例存在TP53基因突变体,但24例Barrett食管标本未检测到基因突变。该结果提示TP53基因突变可能在无异常增生性Barrett食管发展至食管腺癌的过程中发生相对较晚。因此,单独的TP53基因突变并不是评估病变发展至恶性肿瘤风险性的一个广泛有效的预后指标,至少在无异常增生的Barrett食管中如此。

  12. DNA methylation patterns of candidate genes regulated by thymine DNA glycosylase in patients with TP53 germline mutations

    Directory of Open Access Journals (Sweden)

    F.P. Fortes

    2015-07-01

    Full Text Available Li-Fraumeni syndrome (LFS is a rare, autosomal dominant, hereditary cancer predisposition disorder. In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome. The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability. However, the extent of involvement of such events has not been clarified. It is well established that p53 regulates several pathways, including the thymine DNA glycosylase (TDG pathway, which regulates the DNA methylation of several genes. This study aimed to identify the DNA methylation pattern of genes potentially related to the TDG pathway (CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17 in 30 patients with germline TP53 mutations, 10 patients with wild-type TP53, and 10 healthy individuals. We also evaluated TDG expression in patients with adrenocortical tumors (ADR with and without the p.R337H TP53 mutation. Gene methylation patterns of peripheral blood DNA samples assessed by pyrosequencing revealed no significant differences between the three groups. However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR. Considering the rarity of this phenotype and the relevance of these findings, further studies using a larger sample set are necessary to confirm our results.

  13. Association between TP53 gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

    Directory of Open Access Journals (Sweden)

    Fu W

    2017-02-01

    Full Text Available Wen Fu,1,2,* Zhen-Jian Zhuo,3,* Wei Jia,1,2 Jinhong Zhu,4 Shi-Bo Zhu,1,2 Ze-Feng Lin,1,2 Feng-Hua Wang,1,2 Huimin Xia,1,2 Jing He,1,2 Guo-Chang Liu1,2 1Department of Pediatric Urology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 2Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 3Faculty of Medicine, School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, 4Molecular Epidemiology Laboratory, Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Abstract: Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G, has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms’ tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms’ tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms’ tumor risk in children not older

  14. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism.

    Science.gov (United States)

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34(+) cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1α - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  15. Sp1 regulates Raf/MEK/ERK-induced p21(CIP1) transcription in TP53-mutated cancer cells.

    Science.gov (United States)

    Karkhanis, Mansi; Park, Jong-In

    2015-03-01

    We previously reported that the upregulation of mortalin, an Hsp70 family chaperone, is important for B-Raf(V600E) tumor cells to bypass p21(CIP1) expression, which is activated as a tumor-suppressive mechanism in response to aberrant MEK/ERK activation (Wu et al., 2013). Interestingly, mortalin depletion induced p21(CIP1) transcription not only in wild-type TP53 but also in TP53-mutated B-Raf(V600E) cancer cells, suggesting the presence of an additional mechanism for p21(CIP1) regulation. In the present study, using luciferase reporter truncation analysis in a TP53-mutated B-Raf(V600E) cancer cell line, SK-MEL28, we identified a proximal p21(CIP1) promoter region responsive to mortalin depletion. Interestingly, when Sp1-like cis-elements in this promoter region were mutagenized, the p21(CIP1) promoter luciferase reporter was no longer responsive to mortalin depletion. Consistent with this, our ChIP analysis revealed that mortalin knockdown could induce Sp1 binding to p21(CIP1) promoter in a MEK/ERK-dependent manner. Moreover, RNA interference of Sp1 substantially attenuated p21(CIP1) expression induced by mortalin depletion in SK-MEL28 cells. Consistent with this observation in SK-MEL28 cells, Sp1 was necessary for the tamoxifen-regulated ∆Raf-1:ER to induce p21(CIP1) transcription in U251 cells, in which TP53 is mutated. However, in contrast, Sp1 was not necessary for ∆Raf-1:ER to induce p21(CIP1) transcription in LNCaP cells, in which TP53 is wild type. These data suggest that Sp1 may address TP53-independent p21(CIP1) transcription in Raf/MEK/ERK-activated cancer cells and that its requirement in Raf/MEK/ERK-induced p21(CIP1) transcription is subject to TP53 status.

  16. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann;

    2011-01-01

    Objective. It is believed that 24 - 40% of ovarian cancers have dysfunction in the BRCA1 or BRCA2 (BRCAness) genes, either due to inherited or somatic mutations or due to epigenetic inactivation. Demonstration of ovarian cancers with BRCAness is becoming important both due to the possibility...... of offering genetic counseling and due to beneficial effects of PARP inhibitor treatment in this group. Since DNA sequencing is expensive and time-consuming efforts have been devoted to develop more indirect methods for BRCA screening that can improve the selection of patients for sequence-based BRCA testing....... Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history...

  17. Tissue array for Tp53, C-myc, CCND1 gene over-expression in different tumors

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To rapidly detect molecular alterations in different malignancies and investigate the possible role of Tp53, C-myc, and CCND1 genes in development of tumors in human organs and their adjacent normal tissues, as well as the possible relation between well- and poorly-differentiated tumors. METHODS: A tissue array consisting of seven different tumors was generated. The tissue array included 120 points of esophagus, 120 points of stomach, 80 points of rectum, 60 points of thyroid gland, 100 points of mammary gland, 80 points ofliver, and 80 points of colon. Expressions of Tp53, C-myc, and CCND1 were determined by RNA in situ hybridization. 3' terminal digoxin-labeled anti-sense single stranded oligonucleotide and locked nucleic acid modifying probe were used.RESULTS: The expression level of Tp53 gene was higher in six different carcinoma tissue samples than in paracancerous tissue samples with the exception in colon carcinoma tissue samples (P < 0.05). The expression level of CCND1 gene was significantly different in different carcinoma tissue samples with the exception in esophagus and colon carcinoma tissue samples. The expression level of C-myc gene was different in esophagus carcinoma tissue samples (x2 = 18.495, P = 0.000), stomach carcinoma tissue samples (x2 = 23.750, P = 0.000), and thyroid gland tissue samples (x2 = 10.999, P = 0.004). The intensity of signals was also different in different carcinoma tissue samples and paracancerous tissue samples.CONCLUSION: Over-expression of the Tp53, CCND1, and C-myc genes appears to play a role in development of human cancer by regulating the expression of mRNA. Tp53, CCND1 and C-myc genes are significantly correlated with the development of different carcinomas.

  18. TP53 codon 72 polymorphism may predict early tumour progression in paediatric pilocytic astrocytoma

    Science.gov (United States)

    Mascelli, Samantha; Nozza, Paolo; Jones, David T.W.; Colin, Carole; Pistorio, Angela; Milanaccio, Claudia; Ravegnani, Marcello; Consales, Alessandro; Witt, Olaf; Morana, Giovanni; Cama, Armando; Capra, Valeria; Biassoni, Roberto; Pfister, Stefan M.; Figarella-Branger, Dominique; Garrè, Maria Luisa; Raso, Alessandro

    2016-01-01

    Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed. The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses. In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism. The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan. PMID:27374106

  19. Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.

    Science.gov (United States)

    Yang, Annan; Kimmelman, Alec C

    2014-09-01

    Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status.

  20. TP53 codon 72 polymorphism may predict early tumour progression in paediatric pilocytic astrocytoma.

    Science.gov (United States)

    Mascelli, Samantha; Nozza, Paolo; Jones, David T W; Colin, Carole; Pistorio, Angela; Milanaccio, Claudia; Ravegnani, Marcello; Consales, Alessandro; Witt, Olaf; Morana, Giovanni; Cama, Armando; Capra, Valeria; Biassoni, Roberto; Pfister, Stefan M; Figarella-Branger, Dominique; Garrè, Maria Luisa; Raso, Alessandro

    2016-07-26

    Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed.The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses.In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism.The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.

  1. TP53 Mutation, Epithelial-Mesenchymal Transition, and Stemlike Features in Breast Cancer Subtypes

    Directory of Open Access Journals (Sweden)

    Danila Coradini

    2012-01-01

    Full Text Available Altered p53 protein is prevalently associated with the pathologic class of triple-negative breast cancers and loss of p53 function has recently been linked to the induction of an epithelial-mesenchymal transition (EMT and acquisition of stemness properties. We explored the association between TP53 mutational status and expression of some genes involved in the canonical TGF-β signaling pathway (the most potent EMT inducer and in two early EMT associated events: loss of cell polarity and acquisition of stemness-associated features. We used a publicly accessible microarray dataset consisting of 251 p53-sequenced primary breast cancers. Statistical analysis indicated that mutant p53 tumors (especially those harboring a severe mutation were consistent with the aggressive class of triple-negative cancers and that, differently from cell cultures, surgical tumors underexpressed some TGF-β related transcription factors known as involved in EMT (ID1, ID4, SMAD3, SMAD4, SMAD5, ZEB1. These unexpected findings suggest an interesting relationship between p53 mutation, mammary cell dedifferentiation, and the concomitant acquisition of stemlike properties (as indicated by the overexpression of PROM1 and NOTCH1 genes, which improve tumor cells aggressiveness as indicated by the overexpression of genes associated with cell proliferation (CDK4, CDK6, MKI67 and migration (CXCR4, MMP1.

  2. Analysis of TP53 gene mutation and its intratumoral heterogeneity in esophageal squamous cell carcinoma%食管鳞癌TP53基因突变及其瘤内异质性分析

    Institute of Scientific and Technical Information of China (English)

    江烨; 常晨; 马赛; 潘蓓青; 张钰; 徐昕; 蔡岩; 王明荣; 郝佳洁

    2016-01-01

    目的 探讨食管鳞癌瘤内多个取材位点中TP53基因突变异质性状态及其与临床病理特征的相关性.方法 对食管鳞癌原发肿瘤及其配对的手术切端组织,采用聚合酶链式反应(PCR)法和直接测序法检测TP53基因第2~11号外显子突变状态,评估各病例瘤灶内4个不同位点TP53基因突变与临床病理参数的相关性及其在瘤内的异质性.结果 在30例被测食管鳞癌肿瘤中,发现18例患者存在TP53基因突变,占60% (18/30).16例为点突变,其中3例为无义突变,13例为错义突变;另2例为导致移码的缺失突变.大部分突变集中于TP53基因5~8号外显子,其中5号外显子的突变率最高,为23.3%(7/18).在2例肿瘤中检测到第282位密码子突变(R282W),3例检测到第175位密码子突变(R175H).观察每例肿瘤各位点突变等位基因峰高与正常等位基因峰高之比(relative intensity,RI值),发现在有点突变的16例中,12例的4个肿瘤位点的RI之间存在很大差异,其余4例瘤内各位点RI值也不一致.结论 食管鳞癌存在较高频率的TP53基因突变,而且每例肿瘤均存在不同程度的瘤内异质性.

  3. Single nucleotide variation in the TP53 3' untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP

    DEFF Research Database (Denmark)

    Li, Yong; Gordon, Michael W; Xu-Monette, Zijun Y;

    2013-01-01

    We identified multiple single nucleotide variants (SNVs) in the TP53 3' untranslated region (3'UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 3'UTR SNVs had a better 5-year survival rate ...

  4. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

    Science.gov (United States)

    Hou, H-A; Chou, W-C; Kuo, Y-Y; Liu, C-Y; Lin, L-I; Tseng, M-H; Chiang, Y-C; Liu, M-C; Liu, C-W; Tang, J-L; Yao, M; Li, C-C; Huang, S-Y; Ko, B-S; Hsu, S-C; Chen, C-Y; Lin, C-T; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

    2015-07-31

    The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

  5. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

    NARCIS (Netherlands)

    Ruijs, M.W.G.; Verhoef, S.; Rookus, M.A.; Pruntel, R.; van der Hout, A.H.; Hogervorst, F.B.L.; Kluijt, I.; Sijmons, R.H.; Aalfs, C.M.; Wagner, A.; Ausems, M.G.E.M.; Hoogerbrugge, N.; van Asperen, C.J.; Gómez García, E.B.; Meijers-Heijboer, H.; ten Kate, L.P.; Menko, F.H.; van 't Veer, L.J.

    2010-01-01

    Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria a

  6. Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Dufour, Annika; Palermo, Giuseppe; Zellmeier, Evelyn;

    2013-01-01

    in a large cohort of previously treated and relapsed CLL patients. Here, we present the results of TP53 gene sequencing and fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). Of the 457 patients, 52 had TP53...

  7. Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study.

    Science.gov (United States)

    Pilat, N; Grünberger, T; Längle, F; Mittlböck, M; Perisanidis, B; Kappel, S; Wolf, B; Starlinger, P; Kührer, I; Mühlbacher, F; Kandioler, D

    2015-05-01

    The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.

  8. Deletion/duplication mutation screening of TP53 gene in patients with transitional cell carcinoma of urinary bladder using multiplex ligation-dependent probe amplification.

    Science.gov (United States)

    Bazrafshani, Mohammad Reza R; Nowshadi, Pouriaali A; Shirian, Sadegh; Daneshbod, Yahya; Nabipour, Fatemeh; Mokhtari, Maral; Hosseini, Fatemehsadat; Dehghan, Somayeh; Saeedzadeh, Abolfazl; Mosayebi, Ziba

    2016-02-01

    Bladder cancer is a molecular disease driven by the accumulation of genetic, epigenetic, and environmental factors. The aim of this study was to detect the deletions/duplication mutations in TP53 gene exons using multiplex ligation-dependent probe amplification (MLPA) method in the patients with transitional cell carcinoma (TCC). The achieved formalin-fixed paraffin-embedded tissues from 60 patients with TCC of bladder were screened for exonal deletions or duplications of every 12 TP53 gene exons using MLPA. The pathological sections were examined by three pathologists and categorized according to the WHO scoring guideline as 18 (30%) grade I, 22 (37%) grade II, 13 (22%) grade III, and 7 (11%) grade IV cases of TCC. None mutation changes of TP53 gene were detected in 24 (40%) of the patients. Furthermore, mutation changes including, 15 (25%) deletion, 17 (28%) duplication, and 4 (7%) both deletion and duplication cases were observed among 60 samples. From 12 exons of TP53 gene, exon 1 was more subjected to exonal deletion. Deletion of exon 1 of TP53 gene has occurred in 11 (35.4%) patients with TCC. In general, most mutations of TP53, either deletion or duplication, were found in exon 1, which was statistically significant. In addition, no relation between the TCC tumor grade and any type of mutation were observed in this research. MLPA is a simple and efficient method to analyze genomic deletions and duplications of all 12 exons of TP53 gene. The finding of this report that most of the mutations of TP53 occur in exon 1 is in contrast to that of the other reports suggesting that exons 5-8 are the most (frequently) mutated exons of TP53 gene. The mutations of exon 1 of TP53 gene may play an important role in the tumorogenesis of TCC.

  9. Species Identification of Biological Samples by Amplifying Intron 8 of the TP53 Gene%扩增TP53内含子8用于生物检材的种属鉴定

    Institute of Scientific and Technical Information of China (English)

    王闯; 张林; 周斌; 梁伟波

    2005-01-01

    目的扩增常见动物TP53内含子8片段,确定其在法医学生物检材种属鉴定中的应用价值.方法收集标本为包括人在内的15种常见动物的血痕或肌肉组织,提取DNA后定量,应用PCR扩增TP53内含子8,PAGE电泳,银染后观察结果.结果人和猕猴都扩增出一条长度为460bp的片段,鳝鱼、鲢鱼、青蛙、鸭、兔、猫、小白鼠、豚鼠、猪、牛、羊虽有扩增产物,但不在分型区内,鸡、狗未见扩增产物.结论扩增TP53内含子8进行种属鉴定,方法简单,灵敏度较高.

  10. TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

    Directory of Open Access Journals (Sweden)

    Markowska Janina

    2008-01-01

    Full Text Available Abstract Background Taxane-platinum therapy (TP has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC. Methods We compared the effectiveness of PC/PAC (n = 253 and TP (n = 199 with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+] and without TP53 accumulation [TP53(-]. Results The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+, and not in the TP53(- group. In the TP53(+ group taxane-platinum therapy enhanced the probability of complete remission (p = .018, platinum sensitivity (p = .014, platinum highly sensitive response (p = .038 and longer survival (OS, p = .008. Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+ group. In the TP53(- group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010. However, in the TP53(- group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077. Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation. Conclusion Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+ tumors or older

  11. Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

    Science.gov (United States)

    Jacovas, Vanessa Cristina; Rovaris, Diego Luiz; Peréz, Orlando; de Azevedo, Soledad; Macedo, Gabriel Souza; Sandoval, José Raul; Salazar-Granara, Alberto; Villena, Mercedes; Dugoujon, Jean-Michel; Bisso-Machado, Rafael; Petzl-Erler, Maria Luiza; Salzano, Francisco Mauro; Ashton-Prolla, Patricia; Ramallo, Virginia; Bortolini, Maria Cátira

    2015-01-01

    The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

  12. Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

    Directory of Open Access Journals (Sweden)

    Vanessa Cristina Jacovas

    Full Text Available The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271 were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90% of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco were analyzed. The populations were classified as living in high altitude (≥ 2,500 m or in lowlands (< 2,500 m. Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

  13. Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes

    Science.gov (United States)

    Peréz, Orlando; de Azevedo, Soledad; Macedo, Gabriel Souza; Sandoval, José Raul; Salazar-Granara, Alberto; Villena, Mercedes; Dugoujon, Jean-Michel; Bisso-Machado, Rafael; Petzl-Erler, Maria Luiza; Salzano, Francisco Mauro; Ashton-Prolla, Patricia; Ramallo, Virginia; Bortolini, Maria Cátira

    2015-01-01

    The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes. PMID:26382048

  14. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.

    Science.gov (United States)

    Paillas, Salome; Causse, Annick; Marzi, Laetitia; de Medina, Philippe; Poirot, Marc; Denis, Vincent; Vezzio-Vie, Nadia; Espert, Lucile; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Céline

    2012-07-01

    Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38α is involved in resistance of colon cancer cells to camptothecin-related drugs. Here we further investigated the cellular mechanisms involved in such drug resistance and showed that, in HCT116 human colorectal adenocarcinoma cells in which TP53 was genetically ablated (HCT116-TP53KO), overexpression of constitutively active MAPK14/p38α decreases cell sensitivity to SN-38 (the active metabolite of irinotecan), inhibits cell proliferation and induces survival-autophagy. Since autophagy is known to facilitate cancer cell resistance to chemotherapy and radiation treatment, we then investigated the relationship between MAPK14/p38α, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38α activation. Finally, we showed that inhibition of MAPK14/p38α or autophagy both sensitizes HCT116-TP53KO cells to drug therapy. Our data proved that the two effects are interrelated, since the role of autophagy in drug resistance required the MAPK14/p38α. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38α is activated and triggers survival-promoting autophagy to protect tumor cells against the cytotoxic effects of the drug. Colon cancer cells could thus be sensitized to drug therapy by inhibiting either MAPK14/p38 or autophagy.

  15. Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer.

    Science.gov (United States)

    Mitra, Sanga; Mukherjee, Nupur; Das, Smarajit; Das, Pijush; Panda, Chinmay Kumar; Chakrabarti, Jayprokas

    2014-01-01

    The prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b, but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-à-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC.

  16. Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma.

    Science.gov (United States)

    Yang, Ching-Yao; Liau, Jau-Yu; Huang, Wei-Ju; Chang, Yu-Ting; Chang, Ming-Chu; Lee, Jen-Chieh; Tsai, Jia-Huei; Su, Yi-Ning; Hung, Chia-Cheng; Jeng, Yung-Ming

    2015-01-01

    Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. The genetic changes of leiomyosarcoma remain to be discovered. In this study, we analyzed the genetic changes of 44 cancer-related genes by using next-generation sequencing in 54 leiomyosarcomas. We identified TP53 mutations in 19 of the 54 tumors (35%) and ATRX mutations in 9 of the 54 tumors (17%). The TP53-mutated leiomyosarcomas were limited to female patients (P = 0.006). All but 2 of the TP53-mutated leiomyosarcomas were located in the uterus (n = 11) or retroperitoneum (n = 6). The ATRX mutations were associated with poorly differentiated leiomyosarcomas (P = 0.028) and the presence of tumor necrosis (P = 0.015). Kaplan-Meier survival analysis showed that patients with ATRX-mutated leiomyosarcomas had worse overall survival than did patients with ATRX-wild-type leiomyosarcomas. All of the ATRX-mutated leiomyosarcomas showed the alternative lengthening of telomere phenotype. The ATRX mutations did not correlate with ATRX protein expression, as detected using immunohistochemistry. In conclusion, we identified loss of function of the p53 and ATRX pathways being the main mechanisms for leiomyosarcomas. The molecular mechanisms may provide new opportunities to treat these aggressive neoplasms.

  17. A positive feedback loop of p53/miR-19/TP53INP1 modulates pancreatic cancer cell proliferation and apoptosis.

    Science.gov (United States)

    Wang, Xiaofang; Wang, Lei; Mo, Qingjiang; Jia, Ankui; Dong, Yuqian; Wang, Guoqiang

    2016-01-01

    Pancreatic cancer is a common malignancy whose prognosis and treatment of pancreatic cancer is extremely poor, with only 20% of patients reaching two years of survival. Previous findings have shown that the tumor suppressor p53 is involved in the development of various types of cancer, including pancreatic cancer. Additionally, p53 is able to activate TP53INP1 transcription by regulating several phenotypes of cancer cells. Using gain and loss-of-function assays, the aim of the present study was to examine the relationships between miR-19a/b and cancer development as well as potential underlying mechanisms. The results showed that miR-19a/b identified a positive feedback regulation of p53/TP53INP1 axis. Additionally, p53 upregulated the TP53INP1 level in pancreatic cancer cells. However, overexpressed miR-19a/b partially restored the TP53 function in the pancreatic cancer cells while miR-19a/b downregulated TP53INP1 protein by directly targeting 3'UTR of its mRNA at the post-transcriptional level. In addition, the patient tissues identified that the miR-19a/b level in pancreatic cancer tissues was conversely correlated with TP53 and TP53INP1 expression. The results provide evidence for revealing the molecular mechanism involved in the development of pancreatic cancer and may be useful in the identification of new therapeutic targets for pancreatic cancer.

  18. Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel.

    Directory of Open Access Journals (Sweden)

    Ranjan Chrisanthar

    Full Text Available BACKGROUND: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. EXPERIMENTAL DESIGN: Each patient was randomly assigned to treatment with epirubicin 90 mg/m(2 (n = 109 or paclitaxel 200 mg/m(2 (n = 114 every 3rd week as monotherapy for 4-6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. PRINCIPAL FINDINGS: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007 but also MDM2 309TG/GG genotype status (p = 0.012 were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039 but not among individuals with TP53 mutated tumors (p>0.5. CONCLUSION: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy.

  19. Combined Immunohistochemistry of PLK1, p21, and p53 for Predicting TP53 Status: An Independent Prognostic Factor of Breast Cancer.

    Science.gov (United States)

    Watanabe, Gou; Ishida, Takanori; Furuta, Akihiko; Takahashi, Shin; Watanabe, Mika; Nakata, Hideaki; Kato, Shunsuke; Ishioka, Chikashi; Ohuchi, Noriaki

    2015-08-01

    It is difficult to predict the TP53 status by p53 immunohistochemistry (IHC). We aimed to improve the accuracy of p53 IHC with p53-regulated proteins for predicting the TP53 mutation status. TP53 mutations were detected in 19 of 38 breast cancer patients (50%). Five of 7 cases of protein-truncating mutation of TP53 were completely negative for p53 IHC, whereas 11 of 12 cases of TP53 point mutation were strongly positive for p53 IHC. Therefore, to avoid false negatives, we extracted p53-dependent universally downregulated genes using microarray analysis from 38 breast cancer patients and 2 p53-inducible cell lines. From 9 commonly repressed genes, we evaluated 3 genes, baculoviral IAP repeat-containing 5 (BIRC5), polo-like kinase 1 (PLK1), and BUB1 mitotic checkpoint serine/threonine kinase (BUB1), which were previously identified as p53-dependent repressed genes. PLK1≥Allred total score (TS) 5 showed the highest correlation with TP53 mutation. To decrease false positivity, we evaluated p21 IHC. Although strong staining of p21 was observed in 4 cases (10.5%), all 4 were wild-type TP53. Thus, p53 mutation-like (p53mt-like) IHC was identified by p53 TS7,8 with PLK1≥TS 5 and p21 TS≤6. p53 mt-like IHC correlated with TP53 mutation (predictive value=0.94). In other 157 breast cancer cases, p53 mt-like was an independent prognostic marker in multivariate analysis and a strong prognostic factor. Stratification with p53 mt-like IHC identified patients with a poorer prognosis. In conclusion, we identified reliable IHC conditions to predict the TP53 status of breast cancer patients.

  20. TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer.

    Science.gov (United States)

    Wang, Yuxia; Xu, Ye; Chen, Jiuan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-01-15

    The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

  1. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

    Science.gov (United States)

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George

    2016-07-01

    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  2. Analysis list: BRCA1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available BRCA1 Blood,Breast,Digestive tract,Liver,Pluripotent stem cell,Uterus + hg19 http:/.../dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BRCA1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BRCA...1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BRCA1.10.tsv http://dbarchive.bio...sciencedbc.jp/kyushu-u/hg19/colo/BRCA1.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BRCA...1.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BRCA1.Digestive_t

  3. The mechanism of BRCA1 participate sporadic breast carcinomas genesis

    Institute of Scientific and Technical Information of China (English)

    WEI Min-jie; REN Jie

    2008-01-01

    Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters. Methods BRCA1 statues were respectively analyzed in frozen samples or paraffine fixed sporadic breast carcinoma and benign breast tissues by three methods: protein expression by immunohistochemistry (IHC), the methylation of BRCA 1 promoter by methylation specific PCR (MSP), gene copy number by interphase fluorescence in situ hybridization (FISH). Results 14.2 % (29/204) cases were detected hypermethylation of BRCA1 promoter in sporadic breast cancer. BRCA1 mean copy number in sporadic breast cancer (1.70±0.14) less than those in benign tissues (2.03±0.08, P<0.05), and in sporadic breast cancer with hypermethylation of BRCA1 (1.62±0.09) significantly less than in those without hypermethylation (1.84±0.26, P<0.05). The loss copy related to the methylation of BRCA1 promoter. There were significant of 41.1% (88/214) cases no BRCA1 nuclei expression in sporadic breast cancers. Loss expression of BRCA1 had significant correlation with higher histological stages, axillary' s lymph nodal metastasis (P<0.01), lower expression of ERα, and overexpression of HER-2 protein( P<0.01). Conclusions There are BRCA 1 methylations, loss BRCA 1 gene copy and loss protein expression in the sporadic breast cancer, the three statues of BRCA1 is correlated to each other;and the loss expression of BRCA1 protein related to part of pathology and clinic parameters.

  4. Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

    Institute of Scientific and Technical Information of China (English)

    Joonyoung Her; Nam Soo Lee; Yonghwan Kim; Hongtae Kim

    2016-01-01

    Sustaining genomic integrity is essential for preventing onset of cancers.Therefore,human cells evolve to have refined biological pathways to defend genetic materials from various genomic insults.DNA damage response and DNA repair pathways essential for genome maintenance are accomplished by cooperative executions of multiple factors including breast cancer type 1 susceptibility protein (BRCA1).BRCAI is initially identified as an altered gene in the hereditary breast cancer patients.Since then,tremendous efforts to understand the functions of BRAC1 reveal that BRCA1 is found in distinct complexes,including BRCA1-A,BRCA1-B,BRCA1-C,and the BRCA1a PALB2aBRCA2 complex,and plays diverse roles in a context-dependent manner.Among the complexes,BRCA1-A is critical for BRCA1 recruitment to the sites of DNA damage.Factors comprising the BRCA1-A include RAP80,CCDC98aAbraxas,BRCC36,BRCC45,BARD1,BRCA1,and MERIT40,a RAP80-associated factor.In this review,we summarize recent findings of the factors that form the BRCA1-A complex.

  5. Polimorfismo do gene tp53 no códon 72 em pacientes com suspeita de LMC Codon 72 polymorphism of the TP53 gene in patients suspected to have CML

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    Camila S. Hamú

    2007-12-01

    Full Text Available A leucemia mielóide crônica (LMC é uma doença proliferativa do sistema hematopoiético, caracterizada pela expansão clonal de uma célula-tronco primitiva e pluripotente denominada stem cell. Este tipo de leucemia está associado, em 90% dos casos, à translocação t(9;22(q34;q11. Essa alteração cromossômica estrutural codifica para uma proteína quimérica BCR-ABL, que confere às células leucêmicas uma alta resistência à morte, independente do agente indutor desse processo. A proteína p53 é uma reguladora transcricional induzida por danos no DNA, fato que resulta na parada do ciclo celular com conseqüente ativação de mecanismos de reparo ou mesmo na indução à apoptose. As mutações no gene TP53 são as alterações genéticas mais comuns em tumores malignos humanos. O presente estudo teve como objetivo genotipar e determinar a freqüência alélica do polimorfismo do TP53 no códon 72 (arginina - Arg e prolina - Pro, em pacientes com suspeita de LMC, pela Reação em Cadeia da Polimerase. Desta forma, os resultados indicaram que 73,4% (23/30 dos pacientes apresentaram homozigose para arginina (Arg/Arg e 26,6% (7/30 heterozigose (Arg/Pro. Não foi encontrado nenhum paciente homozigoto para prolina (Pro/Pro. Os resultados obtidos sugerem que o polimorfismo do gene TP53 no códon 72 não é um fator de risco importante para a iniciação, promoção e progressão da LMC.Chronic myeloid leukemia (CML is a proliferative disorder of the hematopoietic system characterized by clonal expansion of a primitive and pluripotent stem cell. In this type of leukemia, up to 90% of all cases is associated to a specific chromosomal translocation, t(9;22(q34;q11. The genomic alteration results in a chimeric protein, BCR-ABL, that confers a high resistance leukemia cells to death, independent of the induction mechanism of this process. Protein p53 is a transcriptional factor expressed after DNA damage which ceases cell cycle progression and

  6. BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.

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    Yoshiko Shimizu

    Full Text Available INTRODUCTION: Women with HER2(+ or triple negative/basal-like (TN/BL breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+ and/or TN/BL tumors. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU, followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+ or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. CONCLUSION/SIGNIFICANCE: BRCA1-IRIS overexpression triggers aggressive

  7. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

    DEFF Research Database (Denmark)

    Xu-Monette, Zijun Y; Wu, Lin; Visco, Carlo;

    2012-01-01

    TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. ...

  8. L-Leucine improves the anaemia in models of Diamond Blackfan anaemia and the 5q- syndrome in a TP53-independent way.

    Science.gov (United States)

    Narla, Anupama; Payne, Elspeth M; Abayasekara, Nirmalee; Hurst, Slater N; Raiser, David M; Look, A Thomas; Berliner, Nancy; Ebert, Benjamin L; Khanna-Gupta, Arati

    2014-11-01

    Haploinsufficiency of ribosomal proteins (RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner.

  9. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf(-/-) mouse model.

    Science.gov (United States)

    Chapeau, Emilie A; Gembarska, Agnieszka; Durand, Eric Y; Mandon, Emeline; Estadieu, Claire; Romanet, Vincent; Wiesmann, Marion; Tiedt, Ralph; Lehar, Joseph; de Weck, Antoine; Rad, Roland; Barys, Louise; Jeay, Sebastien; Ferretti, Stephane; Kauffmann, Audrey; Sutter, Esther; Grevot, Armelle; Moulin, Pierre; Murakami, Masato; Sellers, William R; Hofmann, Francesco; Jensen, Michael Rugaard

    2017-03-21

    Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf(-/-) mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposon-mediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.

  10. Benzo[a]pyrene, aflatoxine B₁ and acetaldehyde mutational patterns in TP53 gene using a functional assay: relevance to human cancer aetiology.

    Directory of Open Access Journals (Sweden)

    Vincent Paget

    Full Text Available Mutations in the TP53 gene are the most common alterations in human tumours. TP53 mutational patterns have sometimes been linked to carcinogen exposure. In hepatocellular carcinoma, a specific G>T transversion on codon 249 is classically described as a fingerprint of aflatoxin B(1 exposure. Likewise G>T transversions in codons 157 and 158 have been related to tobacco exposure in human lung cancers. However, controversies remain about the interpretation of TP53 mutational pattern in tumours as the fingerprint of genotoxin exposure. By using a functional assay, the Functional Analysis of Separated Alleles in Yeast (FASAY, the present study depicts the mutational pattern of TP53 in normal human fibroblasts after in vitro exposure to well-known carcinogens: benzo[a]pyrene, aflatoxin B(1 and acetaldehyde. These in vitro patterns of mutations were then compared to those found in human tumours by using the IARC database of TP53 mutations. The results show that the TP53 mutational patterns found in human tumours can be only partly ascribed to genotoxin exposure. A complex interplay between the functional impact of the mutations on p53 phenotype and the cancer natural history may affect these patterns. However, our results strongly support that genotoxins exposure plays a major role in the aetiology of the considered cancers.

  11. Molecular spectrum of TP53 mutations in plasma cell dyscrasias by next generation sequencing: an Italian cohort study and overview of the literature.

    Science.gov (United States)

    Lionetti, Marta; Barbieri, Marzia; Manzoni, Martina; Fabris, Sonia; Bandini, Cecilia; Todoerti, Katia; Nozza, Filomena; Rossi, Davide; Musto, Pellegrino; Baldini, Luca; Neri, Antonino

    2016-04-19

    The prevalence of TP53 mutations greatly varies between tumor types; in multiple myeloma (MM) they were rarely detected at presentation, while increased frequency was reported with disease progression. Using next-generation sequencing, we analyzed TP53 exons 4-9 in a large representative cohort comprising patients with MM at diagnosis and more aggressive forms of plasma cell (PC) dyscrasia, identifying mutations in 4/129 (3%) MM, 6/24 (25%) primary PC leukemia, and 2/10 (20%) secondary PC leukemia cases. A similar increase in prevalence associated with disease aggressiveness (5%, 29.2% and 44%, respectively) was observed for TP53 deletion. Interestingly, in five patients mutations were not concomitant with TP53 deletion. Furthermore, longitudinal analysis revealed the acquisition of TP53 mutations in three of nineteen cases analyzed at relapse. Identified variants were mostly missense mutations concentrated in the DNA binding domain, only partly reflecting the pattern globally observed in human cancers. Our data confirm that TP53 mutations are rare in MM at presentation and rather represent a marker of progression, similarly to del(17p); however, their occurrence even in absence of deletions supports the importance of their assessment in patients with PC dyscrasia, in terms of both risk stratification and therapeutic implications.

  12. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

    Science.gov (United States)

    van Ginkel, Joost H; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M

    2016-09-20

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients.

  13. Study of polymorphisms in the TP53 and RB1 genes in children with retinoblastoma in northern Mexico

    Science.gov (United States)

    Nares-Cisneros, Jesús; Cárdenas-Hernández, Rubén I.; Jaramillo-Rodríguez, Yolanda; Zambrano-Galván, Graciela

    2017-01-01

    Purpose To determine the frequency and association of polymorphisms in the TP53 and RB1 genes with clinical characteristics in a group of children with retinoblastoma (RB) in northern Mexico. Methods A prospective, longitudinal, and analytical study of 11 patients diagnosed with RB was conducted. Endpoint PCR and high-resolution real-time PCR were performed. Chi-square and Student t tests were used to evaluate associations between variables. Allelic frequencies, as well as genotypic and Hardy–Weinberg equilibriums, were evaluated using Guo and Thompson’s method. Results We found a statistically significant difference between the polymorphism RB1-GG/rs9568036 and tumor chemoresistance (p<0.05). The allelic variants RB1-AA and AG/rs9568036 were determined to be associated with tumor chemosensitivity (p<0.05). A statistically significant relation between the polymorphism RB1-GG/rs9568036 and males (p = 0.0386), rate ratio (RR) = 2.0 (95% confidence interval [CI] = 0.76–5.32), as well as between the allelic variants RB1-AA and AG/rs9568036 and females (p = 0.0027), RR = 8.0 (95% CI = 1.28–50.04), was observed. We also observed a statistically significant association between the rs1042522 polymorphism in the TP53 gene and unilateral presentation of the disease. Conclusions The rs9568036 polymorphism in the RB1 gene and the allelic variants can be associated with type of response to medical therapy and associated with male sex, while the allelic variant rs1042522 polymorphism in the TP53 gene is associated with the unilateral presentation of the disease in a group of Mexican children with RB. PMID:28210099

  14. Gene co-expression analyses differentiate networks associated with diverse cancers harbouring TP53 missense or null mutations

    Directory of Open Access Journals (Sweden)

    Kathleen Oros Klein

    2016-08-01

    Full Text Available In a variety of solid cancers, missense mutations in the well-established TP53 tumour suppressor gene may lead to presence of a partially-functioning protein molecule, whereas mutations affecting the protein encoding reading frame, often referred to as null mutations, result in the absence of p53 protein. Both types of mutations have been observed in the same cancer type. As the resulting tumour biology may be quite different between these two groups, we used RNA-sequencing data from The Cancer Genome Atlas (TCGA from four different cancers with poor prognosis, namely ovarian, breast, lung and skin cancers, to compare the patterns of co-expression of genes in tumours grouped according to their TP53 missense or null mutation status. We used Weighted Gene Coexpression Network analysis (WGCNA and a new test statistic built on differences between groups in the measures of gene connectivity. For each cancer, our analysis identified a set of genes showing differential coexpression patterns between the TP53 missense- and null mutation-carrying groups that was robust to the choice of the tuning parameter in WGCNA. After comparing these sets of genes across the four cancers, one gene (KIR3DL2 consistently showed differential coexpression patterns between the null and missense groups. KIR3DL2 is known to play an important role in regulating the immune response, which is consistent with our observation that this gene’s strongly-correlated partners implicated many immune-related pathways. Examining mutation-type-related changes in correlations between sets of genes may provide new insight into tumour biology.

  15. CYP1A1, GSTM1, GSTT1 and TP53 Polymorphisms and Risk of Gallbladder Cancer in Bolivians.

    Science.gov (United States)

    Sakai, Kazuaki; Loza, Ernesto; Roig, Guido Villa-Gomez; Nozaki, Ryoko; Asai, Takao; Ikoma, Toshikazu; Tsuchiya, Yasuo; Kiyohara, Chikako; Yamamoto, Masaharu; Nakamura, Kazutoshi

    2016-01-01

    The Plurinational State of Bolivia (Bolivia) has a high incidence rate of gallbladder cancer (GBC). However, the genetic and environmental risk factors for GBC development are not well understood. We aimed to assess whether or not cytochrome P450 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), theta 1 (GSTT1) and tumor suppressor protein p53 (TP53) genetic polymorphisms modulate GBC susceptibility in Bolivians. This case-control study covered 32 patients with GBC and 86 healthy subjects. GBC was diagnosed on the basis of histological analysis of tissues at the Instituto de Gastroenterologia Boliviano-Japones (IGBJ); the healthy subjects were members of the staff at the IGBJ. Distributions of the CYP1A1 rs1048943 and TP53 rs1042522 polymorphisms were assayed using PCR-restriction fragment length polymorphism assay. GSTM1 and GSTT1 deletion polymorphisms were detected by a multiplex PCR assay. The frequency of the GSTM1 null genotype was significantly higher in GBC patients than in the healthy subjects (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.03-5.37; age-adjusted OR, 3.53; 95% CI, 1.29-9.66; age- and sex-adjusted OR, 3.40; 95% CI, 1.24-9.34). No significant differences were observed in the frequencies of CYP1A1, GSTT1, or TP53 polymorphisms between the two groups. The GSTM1 null genotype was associated with increased GBC risk in Bolivians. Additional studies with larger control and case populations are warranted to confirm the association between the GSTM1 deletion polymorphism and GBC risk suggested in the present study.

  16. Frequently increased epidermal growth factor receptor (EGFR copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers

    Directory of Open Access Journals (Sweden)

    Sugiura Hiroshi

    2008-10-01

    Full Text Available Abstract Background Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative (TNBC is a high risk breast cancer that lacks specific therapy targeting these proteins. Methods We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years. Results A total of 110 (11.3% patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers. Conclusion TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.

  17. A novel splice mutation in the TP53 gene associated with Leydig cell tumor and primitive neuroectodermal tumor

    DEFF Research Database (Denmark)

    Stecher, Chalotte Willemann; Grønbaek, Kirsten; Hasle, Henrik

    2008-01-01

    A 20-month-old boy presented with precocious puberty due to a Leydig cell tumor, and at the age of 6 years with a primitive neuroectodermal brain-tumor (PNET). A novel splice site mutation of the TP53-gene, likely to be associated with a nonfunctional protein, was found in the proband, his father...... and younger sister, but only the proband has so far developed malignancy. The clinical phenotype in the boy is suggestive of Li-Fraumeni syndrome, but the family does not strictly conform to the canonical definition. Udgivelsesdato: 2008-Mar...

  18. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy

    DEFF Research Database (Denmark)

    Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos;

    2016-01-01

    that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL...

  19. Unambiguous detection of multiple TP53 gene mutations in AAN-associated urothelial cancer in Belgium using laser capture microdissection.

    Directory of Open Access Journals (Sweden)

    Selda Aydin

    Full Text Available In the Balkan and Taiwan, the relationship between exposure to aristolochic acid and risk of urothelial neoplasms was inferred from the A>T genetic hallmark in TP53 gene from malignant cells. This study aimed to characterize the TP53 mutational spectrum in urothelial cancers consecutive to Aristolochic Acid Nephropathy in Belgium. Serial frozen tumor sections from female patients (n=5 exposed to aristolochic acid during weight-loss regimen were alternatively used either for p53 immunostaining or laser microdissection. Tissue areas with at least 60% p53-positive nuclei were selected for microdissecting sections according to p53-positive matching areas. All areas appeared to be carcinoma in situ. After DNA extraction, mutations in the TP53 hot spot region (exons 5-8 were identified using nested-PCR and sequencing. False-negative controls consisted in microdissecting fresh-frozen tumor tissues both from a patient with a Li-Fraumeni syndrome who carried a p53 constitutional mutation, and from KRas mutated adenocarcinomas. To rule out false-positive results potentially generated by microdissection and nested-PCR, a phenacetin-associated urothelial carcinoma and normal fresh ureteral tissues (n=4 were processed with high laser power. No unexpected results being identified, molecular analysis was pursued on malignant tissues, showing at least one mutation in all (six different mutations in two patients, with 13/16 exonic (nonsense, 2; missense, 11 and 3/16 intronic (one splice site mutations. They were distributed as transitions (n=7 or transversions (n=9, with an equal prevalence of A>T and G>T (3/16 each. While current results are in line with A>T prevalence previously reported in Balkan and Taiwan studies, they also demonstrate that multiple mutations in the TP53 hot spot region and a high frequency of G>T transversion appear as a complementary signature reflecting the toxicity of a cumulative dose of aristolochic acid ingested over a short period

  20. Breast cancer risk and the BRCA1 interacting protein CTIP.

    Science.gov (United States)

    Gorringe, Kylie L; Choong, David Y H; Lindeman, Geoffrey J; Visvader, Jane E; Campbell, Ian G

    2008-11-01

    Mutations in BRCA1 predispose to breast cancer. CTIP interacts with BRCA1 and so could also be associated with increased risk. We screened CTIP for germline mutations in 210 probands of breast cancer families including 129 families with no mutations in BRCA1 or BRCA2. No coding variants were detected in CTIP, therefore, it is unlikely to be involved in breast cancer risk.

  1. TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death.

    Science.gov (United States)

    Seillier, M; Peuget, S; Gayet, O; Gauthier, C; N'Guessan, P; Monte, M; Carrier, A; Iovanna, J L; Dusetti, N J

    2012-09-01

    TP53INP1 (tumor protein 53-induced nuclear protein 1) is a tumor suppressor, whose expression is downregulated in cancers from different organs. It was described as a p53 target gene involved in cell death, cell-cycle arrest and cellular migration. In this work, we show that TP53INP1 is also able to interact with ATG8-family proteins and to induce autophagy-dependent cell death. In agreement with this finding, we observe that TP53INP1, which is mainly nuclear, relocalizes in autophagosomes during autophagy where it is eventually degraded. TP53INP1-LC3 interaction occurs via a functional LC3-interacting region (LIR). Inactivating mutations of this sequence abolish TP53INP1-LC3 interaction, relocalize TP53INP1 in autophagosomes and decrease TP53INP1 ability to trigger cell death. Interestingly, TP53INP1 binds to ATG8-family proteins with higher affinity than p62, suggesting that it could partially displace p62 from autophagosomes, modifying thereby their composition. Moreover, silencing the expression of autophagy related genes (ATG5 or Beclin-1) or inhibiting caspase activity significantly decreases cell death induced by TP53INP1. These data indicate that cell death observed after TP53INP1-LC3 interaction depends on both autophagy and caspase activity. We conclude that TP53INP1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy.

  2. BRCA1-mediated repression of select X chromosome genes

    Directory of Open Access Journals (Sweden)

    Ropers H Hilger

    2004-09-01

    Full Text Available Abstract Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling. Significance was determined using parametric statistics with P

  3. Immunohistochemical expression of BRCA1 and lethal prostate cancer

    Science.gov (United States)

    Fiorentino, Michelangelo; Judson, Gregory; Penney, Kathryn; Flavin, Richard; Stark, Jennifer; Fiore, Christopher; Fall, Katja; Martin, Neil; Ma, Jing; Sinnott, Jennifer; Giovannucci, Edward; Stampfer, Meir; Sesso, Howard D.; Kantoff, Philip W.; Finn, Stephen; Loda, Massimo; Mucci, Lorelei

    2011-01-01

    BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell-cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell-cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumors samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1 positive tumors had substantially increased tumor proliferation index compared to negative tumors (47.0 Ki67 positive nuclei vs. 10.3, p=0.0016), and were more likely to develop lethal cancer compared to BRCA1 negative tumors (Hazard ratio=4.6; 95% Confidence interval: 2.4, 8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell-cycle control and demonstrate that BRCA1 is a marker of clinical prostate cancer prognosis. PMID:20388772

  4. Analysis list: Brca1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Brca1 Blood + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.1.tsv... http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Br...ca1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Brca1.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml ...

  5. Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay.

    Science.gov (United States)

    Legal, Edith Falcon-de; Ascurra, Marta; Custódio, Gislaine; Ayala, Horacio Legal; Monteiro, Magna; Vega, Celeste; Fernández-Nestosa, María José; Vega, Sonia; Sade, Elis R; Coelho, Izabel M M; Ribeiro, Enilze M S F; Cavalli, Iglenir J; Figueiredo, Bonald C

    2015-04-01

    The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer, and the germline TP53 R337H mutation is the most common mutation reported to date. However, this mutation is associated with a lower cumulative lifetime cancer risk than other mutations in the p53 DNA-binding domain. A detailed statistical analysis of 171,500 DNA tests in Brazilian neonates found that 0.27% of the general population is positive for this mutation, and some of the estimated 200,000 Brazilian R337H carriers in southern and southeastern Brazil have already developed cancer. The present study was designed to estimate R337H prevalence in neighboring Paraguay. To address this question, 10,000 dried blood samples stored in Guthrie cards since 2008 were randomly selected from the Paraguayan municipalities located at the border with Brazil. These samples were tested for R337H mutation using the PCR-restriction fragment length polymorphism assay. This germline mutation was detected in five samples (5/10,000), indicating that the total number of R337H carriers in Paraguay may be as high as 3500. Previous studies have shown that other countries (i.e., Portugal, Spain, and Germany) presented one family with this mutation, leading us to conclude that, besides Brazil and Paraguay, other countries may have multiple families carrying this mutation, which is an inherited syndrome that is difficult to control.

  6. Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.

    Directory of Open Access Journals (Sweden)

    Yeliz Boglev

    Full Text Available Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (tti(s450, which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In tti(s450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in tti(s450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in tti(s450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.

  7. Association of TP53 gene polymorphisms with genetic susceptibility to liver metastases of colorectal cancer%TP53基因多态与结直肠癌肝转移遗传易感性的相关性

    Institute of Scientific and Technical Information of China (English)

    王爱忠; 朱忠政; 丛文铭; 贾杭若; 金夏祥; 何向蕾; 朱冠山

    2008-01-01

    Objective To investigate the possible association between the single nucleotide polymorphisms (SNPs)(C-8343G,C-1863T and R72P)in TP53 gene and susceptibility to liver metastases of coloreetal cancer(CRC)in a Chinese popuation.Methods The genotypes of each SNP in TP53 gene were determined by either TaqMan assays or PCR-based restriction fragment length polymorphism(RFLP)method in 121 colorectal cancer patients with liver metastases and sex-,age-matched 280 cases with nonmetastatic CRC as a control.Immunohistochemical stainirig for P=53 was performed on paraffin-embedded sections.Odds ratios(ORs)for colorectal liver metastases and 95%coatidence intervals(CIs)from unconditional logistic regression models were used to evaluate relative risks.Results No significant association of C-8343G or C-1863T with colorectal liver metastases risk was observed.However,the R allele of the TP53 R72P polymorphism was more frequenfly found in metastatic cases than in nonmetastatic cases(P=0.037).When compared with PP homozygotes,the ORs of metastases for RP heterozygotes was 2.21(95%CI:1.13-4.33),for RR homozygotes was 2.26(95%CI:1.03-4.94),and for carriers of the 72R allele(RP or RR genotype)was 2.22(95%CI:1.16-4.26).Stratified analysis indicated that carrying the 72R allele had a more pronounced inerease in colorectal liver metastases risk among patients with positive P53 expression tumors(OR=3.28,95%CI:1.21-8.88),whereas no significantly increased metastases risk was found in patienm with negative P53 expression tumors(OR=1.37,95%CI:0.52-3.62).Conclusion The R allele of the TP53 R72P polymorphism may contribute to the etiology of liver metastases in CRC patients,particularly among those with positive P53 expression tumors.BothTP53 C-8343G and C-1863T may be not associated with colorectal liver metastases risk.%目的 探讨TP53基因C-8343G、C-1863T及第72密码子(R72P)单核苷酸多态性与结直肠癌(colorectal cancer,CRC)肝转移风险的关系.方法 采用TaqMan和聚

  8. Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.

    Science.gov (United States)

    Osman, Abdullah A; Monroe, Marcus M; Ortega Alves, Marcus V; Patel, Ameeta A; Katsonis, Panagiotis; Fitzgerald, Alison L; Neskey, David M; Frederick, Mitchell J; Woo, Sang Hyeok; Caulin, Carlos; Hsu, Teng-Kuei; McDonald, Thomas O; Kimmel, Marek; Meyn, Raymond E; Lichtarge, Olivier; Myers, Jeffrey N

    2015-02-01

    Although cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC.

  9. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

    Science.gov (United States)

    Saya, Sibel; Killick, Emma; Thomas, Sarah; Taylor, Natalie; Bancroft, Elizabeth K; Rothwell, Jeanette; Benafif, Sarah; Dias, Alexander; Mikropoulos, Christos; Pope, Jenny; Chamberlain, Anthony; Gunapala, Ranga; Izatt, Louise; Side, Lucy; Walker, Lisa; Tomkins, Susan; Cook, Jackie; Barwell, Julian; Wiles, Vicki; Limb, Lauren; Eccles, Diana; Leach, Martin O; Shanley, Susan; Gilbert, Fiona J; Hanson, Helen; Gallagher, David; Rajashanker, Bala; Whitehouse, Richard W; Koh, Dow-Mu; Sohaib, S Aslam; Evans, D Gareth; Eeles, Rosalind A

    2017-01-16

    In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.

  10. MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation.

    Science.gov (United States)

    Lu, Yuntao; Xiao, Limin; Liu, Yawei; Wang, Hai; Li, Hong; Zhou, Qiang; Pan, Jun; Lei, Bingxi; Huang, Annie; Qi, Songtao

    2015-01-01

    The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53(+/+) and TP53(-/-) HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

  11. Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.

    Science.gov (United States)

    Janavičius, Ramūnas; Rudaitis, Vilius; Mickys, Ugnius; Elsakov, Pavel; Griškevičius, Laimonas

    2014-05-01

    There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

  12. BRCA1 in the DNA damage response and at telomeres

    Directory of Open Access Journals (Sweden)

    Eliot Michael Rosen

    2013-06-01

    Full Text Available Abstract. Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1 account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s is (are most important for tumor suppression, nor is it clear why BRCA1 mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR, which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.

  13. The Role of BRCA1 in Lethal Prostate Cancer

    Science.gov (United States)

    2013-08-01

    Burga LN, Tung NM, Troyan SL, et al. Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation...apoptosis. Cancer Res. 2003;63:6221-8. 26. Wang L, Wei J, Qian X, Yin H, Zhao Y, Yu L, et al. ERCC1 and BRCA1 mRNA expression levels in metastatic

  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. An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases.

    Science.gov (United States)

    Worrillow, L; Baskaran, P; Care, M A; Varghese, A; Munir, T; Evans, P A; O'Connor, S J; Rawstron, A; Hazelwood, L; Tooze, R M; Hillmen, P; Newton, D J

    2016-10-06

    Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

  16. MYC, TP53, and Chromosome 17 Copy-Number Alterations in Multiple Gastric Cancer Cell Lines and in Their Parental Primary Tumors

    Directory of Open Access Journals (Sweden)

    Mariana Ferreira Leal

    2011-01-01

    Full Text Available We evaluated whether MYC, TP53, and chromosome 17 copy-number alterations occur in ACP02, ACP03, and AGP01 gastric cancer cell lines and in their tumor counterpart. Fluorescence in situ hybridization for MYC and TP53 genes and for chromosome 17 was applied in the 6th, 12th, 60th, and 85th passages of the cell lines and in their parental primary tumors. We observed that three and four MYC signals were the most common alterations in gastric cell lines and tumors. ACP02 presented cells with two copies of chr17 and loss of one copy of TP53 more frequently than ACP03 and AGP01. Only ACP03 and AGP01 presented clonal chr17 trisomy with three or two TP53 copies. The frequency of MYC gain, TP53 loss, and chromosome 17 trisomy seems to increase in gastric cell lines compared to their parental tumors. Our findings reveal that these cell lines retain, in vitro, the genetic alterations presented in their parental primary tumors.

  17. 朗格汉斯细胞组织细胞增生症中TP53蛋白表达及基因突变检测%Detection TP53 Protein Expression and Gene Mutation in Langerhans' Cell Histiocytosis

    Institute of Scientific and Technical Information of China (English)

    孙忠辉; 石梅; 李明; 余红

    2013-01-01

    Objective To determine whether TP53 gene plays a role in the pathogenesis of Langerhans' Cell Histiocytosis (LCH) ,we studied the expression of TP53 protein and mutation of TP53 gene in LCH biopsies. Methods The expression of TP53 protein was detected by immunohistochemical SP method in 38 cases of Langerhans cell histiocytosis. The mutation in TP53 gene exon 2 to 11 was identified by polymerase chain reaction and subsequently conformed by DNA sequencing in the 16 TP53 protein positive biopsies. Results TP53 protein expression was detected in 16/38(42. 11% ) LCH biopsies. In those biopsies, there were no significant difference between the average optical density of multisystem (MS,0. 120 6 ±0.008 8) and single-system (SS,0. 122 1 ±0.0030) respectively(P>0.05). No mutations in the TP53 gene exon 2 to 11 were detected in those positive biopsies. For genetic genotype of the polymorphism of TP53 gene codon 72, there were PRO in 3 cases,ARG in 5 cases, PRO/ARG in 8 cases in LCH group (TP53 protein positive). Compared with 40 normal controls,Chi-square analysis showed there was no significant difference for distribution of the three genotypes( P > 0. 05 ). Then, for the clinical classification, the cases of PRO, ARG and PRO/ ARG were 2,3 ,5 in MS and 1 ,2,3 in SS,respectively. Chi-square analysis also showed no significant differences (P>0. 05). Conclusion The TP53 protein is abnormally expressed in LCH,although there was no significant difference with the clinical classification. There is no TP53 gene mutation in LCH. The TP53 codon 72 genotype distribution was consistent with the normal population and not related with clinical classification. We speculate that the abnormality of TP53 gene expression in LCH may not result from gene mutation but an unknown mechanism.%目的 检测朗格汉斯细胞组织细胞增生症(LCH)中TP53蛋白表达和TP53基因全外显子突变,以探讨TP53在LCH发生发展中的作用机制.方法 应用免疫纽化SP法检测38例LCH中TP

  18. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, T.v.O.; Ejlertsen, B.; Albrechtsen, Anders;

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight...... of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit...

  19. Breast cancer risk in relation to TP53 codon 72 and CDH1 gene polymorphisms in the Bangladeshi women.

    Science.gov (United States)

    Shabnaz, Samia; Ahmed, Maizbha Uddin; Islam, Md Siddiqul; Islam, Md Reazul; Al-Mamun, Mir Md Abdullah; Islam, Mohammad Safiqul; Hasnat, Abul

    2016-06-01

    Pharmacogenomic studies play a significant role in understanding the risk of breast cancer where genetic abnormalities are implicated as the etiology of cancer. Various polymorphisms of tumor suppressor gene TP53 and E-cadherin (CDH1) have been found to be associated with increased breast cancer risk worldwide. This study aimed to analyze the contribution of TP53 and CDH1 gene anomalies in breast cancer risk in the Bangladeshi breast cancer patients. For risk determination, 310 patients with breast cancer and 250 controls from Bangladeshi women were recruited who are matched up with age and use of contraceptives with patients. Genetic polymorphisms were detected by using polymerase chain reaction restriction fragment length polymorphism. A significant association was found between TP53Arg72Pro (rs1042522) and CDH1 -160 C/A (rs16260) polymorphisms and breast cancer risk. In case of P53rs1042522 polymorphism, Arg/Pro (P = 0.0053, odds ratio (OR) = 1.69) and Pro/Pro (P = 0.018, OR = 1.83) genotypes were associated with increased risk of breast cancer in comparison to the Arg/Arg genotype. Arg/Pro + Pro/Pro genotype and Pro allele also increased the risk of breast cancer (P = 0.002, OR = 1.73; P = 0.004, OR = 1.43, respectively). In case of CDH1rs16260 polymorphism, C/A heterozygote and combined C/A + A/A genotypes were found to be strongly associated (P = 0.005, OR = 1.67; P = 0.0037, OR = 1.68) with increased risk of breast cancer. The variant A allele also increased the breast cancer risk (P = 0.0058, OR = 1.52). The present study demonstrates that P53Arg72Pro and CDH1rs16260 polymorphisms are associated with elevated breast cancer risk in the Bangladeshi population.

  20. Absence of loss of heterozygosity of BRCA1 in a renal tumor from a BRCA1 germline mutation carrier

    OpenAIRE

    Alanee, Shaheen; Shah, Sohela; Murali, Rajmohan; Rau-Murthy, Rohini; Kasmintan A Schrader; Offit, Kenneth

    2013-01-01

    BRCA1 functions as a tumor suppressor gene and germline and somatic mutations in this gene have been shown to be associated with many types of cancer. We report the first tumor study of renal cell carcinoma in a carrier of the deleterious BRCA1 mutation-c.68_69delAG.

  1. SV40 large T-p53 complex: evidence for the presence of two immunologically distinct forms of p53

    Energy Technology Data Exchange (ETDEWEB)

    Milner, J.; Gamble, J.

    1985-11-01

    The transforming protein of SV40 is the large T antigen. Large T binds a cellular protein, p53, which is potentially oncogenic by virtue of its functional involvement in the control of cell proliferation. This raises the possibility that p53 may mediate, in part, the transforming function of SV40 large T. Two immunologically distinct forms of p53 have been identified in normal cells: the forms are cell-cycle dependent, one being restricted to nondividing cells (p53-Go) and the second to dividing cells (p53-G divided by). The authors have now dissociated and probed the multimeric complex of SV40 large T-p53 for the presence of immunologically distinct forms of p53. Here they present evidence for the presence of p53-Go and p53-G divided by complexed with SV40 large T.

  2. Transitions at CpG dinucleotides, geographic clustering of TP53 mutations and food availability patterns in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Fabio Verginelli

    Full Text Available BACKGROUND: Colorectal cancer is mainly attributed to diet, but the role exerted by foods remains unclear because involved factors are extremely complex. Geography substantially impacts on foods. Correlations between international variation in colorectal cancer-associated mutation patterns and food availabilities could highlight the influence of foods on colorectal mutagenesis. METHODOLOGY: To test such hypothesis, we applied techniques based on hierarchical clustering, feature extraction and selection, and statistical pattern recognition to the analysis of 2,572 colorectal cancer-associated TP53 mutations from 12 countries/geographic areas. For food availabilities, we relied on data extracted from the Food Balance Sheets of the Food and Agriculture Organization of the United Nations. Dendrograms for mutation sites, mutation types and food patterns were constructed through Ward's hierarchical clustering algorithm and their stability was assessed evaluating silhouette values. Feature selection used entropy-based measures for similarity between clusterings, combined with principal component analysis by exhaustive and heuristic approaches. CONCLUSION/SIGNIFICANCE: Mutations clustered in two major geographic groups, one including only Western countries, the other Asia and parts of Europe. This was determined by variation in the frequency of transitions at CpGs, the most common mutation type. Higher frequencies of transitions at CpGs in the cluster that included only Western countries mainly reflected higher frequencies of mutations at CpG codons 175, 248 and 273, the three major TP53 hotspots. Pearson's correlation scores, computed between the principal components of the datamatrices for mutation types, food availability and mutation sites, demonstrated statistically significant correlations between transitions at CpGs and both mutation sites and availabilities of meat, milk, sweeteners and animal fats, the energy-dense foods at the basis of

  3. Polymorphisms of the pri-miR-34b/c promoter and TP53 codon 72 are associated with risk of colorectal cancer.

    Science.gov (United States)

    Oh, Jisu; Kim, Jong Woo; Lee, Bo Eun; Jang, Moon Ju; Chong, So Young; Park, Pil Won; Hwang, Seong Gyu; Oh, Doyeun; Kim, Nam Keun

    2014-02-01

    The microRNA (miR)-34 family is a direct transcriptional target of tumor-suppressor TP53 and loss of miR-34 function may impair TP53-mediated cell cycle arrest and apoptosis. In the present study, we investigated whether the single nucleotide polymorphisms (SNPs) rs4938723 (T>C) in the promoter region of miR-34b/c and Arg72Pro (G>C) in codon 72 of TP53 are independently or complementarily associated with the risks and clinical outcomes of colorectal cancer (CRC) and whether the combined effect of these SNPs and metabolic risk factors are related to CRC. We evaluated the SNPs in 545 CRC patients and 428 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequence analysis. We found that the GC and GC/CC genotypes of TP53 Arg72Pro were associated with decreased risk of CRC (adjusted OR = 0.727 for GC; OR = 0.735 for GC/CC). The combined genotypes of TT-GC and CC-GG were significantly associated with reduced CRC risk (adjusted OR = 0.628 for TT-GC; OR = 0.381 for CC-GG, respectively). The SNP rs4938723 and diabetes mellitus (DM) together were associated with an increased CRC risk, but the SNP TP53 Arg72Pro CC with DM showed a protective effect against CRC. These findings indicate that rs4938723 in the promoter region of pri-miR-34b/c and the SNP in TP53 codon 72 were related to decreased risk of CRC in the population studied and those metabolic diseases and genetic variants influence each other with regard to CRC susceptibility.

  4. BRCA1 tumor suppressor network: focusing on its tail

    Directory of Open Access Journals (Sweden)

    Wang Bin

    2012-02-01

    Full Text Available Abstract Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine. The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.

  5. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...... instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation...... carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...

  6. TP53基因多态与中国人群结直肠癌遗传易感性的相关性%TP53 gene polymorphisms and colorectal cancer risk in Chinese population

    Institute of Scientific and Technical Information of China (English)

    贾杭若; 何向蕾; 朱忠政; 金夏祥; 王爱忠; 黄海燕; 褚炯; 俞国冰; 朱冠山

    2007-01-01

    目的 探讨TP53基因C-8343G、C-1863T及第72密码子(CGC/CCC,其编码氨基酸分别为精氨酸R和脯氨酸P,R72P)单核苷酸多态(SNP)与中国人群结直肠癌(CRC)遗传易感性的关系.方法 采用TaqMan和聚合酶链反应-限制性片段长度多态方法,检测345例CRC患者与670名对照SNP的基因型分布及差异.结果 C-8343G和C-1863T基因型分布在CRC、对照两组人群间差异无统计学意义(P>0.05).R72P在两组人群中的基因型及等位基因分布差异有统计学意义(P<0.01).与RR纯合子相比,RP杂合子和PP纯合子的CRC风险分别增加至1.60倍(95%CI=1.17~2.18,P<0.01)和2.37倍(95% CI=1.61~3.47,P<0.01).饮酒可进一步增加R72P多态的CRC风险效应:以RR饮酒者为参照,RP和PP饮酒者的CRC风险分别为3.01倍(95% CI=1.48~6.12)和4.71倍(95% CI=1.90~11.68).结论 TP53基因C-8343G和C-1863T多态与CRC风险无关;R72P多态增加中国人群,特别是饮酒人群的CRC发病风险.

  7. BRCA1/2 associated hereditary breast cancer

    Institute of Scientific and Technical Information of China (English)

    Li-song TENG; Yi ZHENG; Hao-hao WANG

    2008-01-01

    Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

  8. A nonsense mutation (Arg-196-Term) in exon 6 of the human TP53 gene identified in small cell lung carcinoma

    NARCIS (Netherlands)

    Hayes, VM; Oosthuizen, CJJ; Kotze, MJ; Marx, MP; Buys, CHCM

    1996-01-01

    In a search for mutations of the TP53 tumour suppressor gene in lung cancer samples from gold miners from the Witwatersrand, South Africa, using heteroduplex and single strand conformation polymorphism (SSCP) analysis, a nonsense mutation was found in exon 6, consisting of a C to T transition and re

  9. Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil.

    Science.gov (United States)

    de Carvalho, Fernanda Magri; de Almeida Pereira, Thiago; Gonçalves, Patrícia Lofego; Jarske, Robson Dettmann; Pereira, Fausto Edmundo Lima; Louro, Iuri Drumond

    2013-08-01

    The close relationship between aflatoxins and 249ser TP53 gene mutation (AGG to AGT, Arg to Ser) in hepatocellular carcinoma (HCC) makes this mutation an indirect indicator of dietary contamination with this toxin. We have examined the prevalence of codon 249 TP53 mutation in 41 HCC and 74 liver cirrhosis (without HCC) cases diagnosed at the HUCAM University Hospital in Vitoria, Espírito Santo State, Brazil. DNA was extracted from paraffin sections and from plasma. The mutation was detected by DNA amplification, followed by restriction endonuclease digestion and confirmed by direct sequencing. DNA restriction showed 249ser mutation in 16 HCC and 13 liver cirrhosis, but sequencing confirmed mutations in only 6 HCC and 1 liver cirrhosis. In addition, sequencing revealed 4 patients with mutations at codon 250 (250ser and 250leu) in HCC cases. The prevalence of TP53 mutation was 10/41 (24.3%) in HCC and 1/74 (1.4%) in liver cirrhosis. No relationship between the presence of mutations and the etiology of HCC was observed. TP53 exon 7 mutations, which are related to aflatoxins exposure, were found at 14.6% (249ser), 7.3% (250leu) and 2.4% (250ser) in 41 cases of HCC and 1.4% in 74 liver cirrhosis (without HCC) cases, suggesting a moderate dietary exposure to aflatoxins in the Espírito Santo State, Brazil.

  10. Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes' C colon cancer

    NARCIS (Netherlands)

    Bleeker, W A; Hayes, V M; Karrenbeld, A; Hofstra, R M; Hermans, J; Buys, C C; Plukker, J T

    2000-01-01

    OBJECTIVE: It has been suggested that KRAS and TP53 mutated tumors might influence the phenotypic behavior of left- and right-sided colon tumors. We investigated the incidence of these mutations in left- and right-sided colon tumors and their possible influence on survival in a homogeneous group of

  11. The association between the TP53 Arg72Pro polymorphism and colorectal cancer: An updated meta-analysis based on 32 studies

    Science.gov (United States)

    Tian, Xin; Dai, Shundong; Sun, Jing; Jiang, Shenyi; Jiang, Youhong

    2017-01-01

    Several previous studies evaluated the association between the Arg72Pro (rs1042522) polymorphism in the TP53 tumor suppressor gene and colorectal cancer (CRC). However, the results are conflicting. This meta-analysis aimed to shed new light on the precise association between TP53 variants and CRC. We analyzed 32 published case-control studies involving 8,586 cases and 10,275 controls using crude odd ratios (ORs) with 95% confidence intervals (CIs). The meta-analysis was performed using a fixed-effect or random-effects model, as appropriate. We found that the TP53 Arg72Pro polymorphism was not significantly associated with CRC risk in the overall population. However, subgroup analysis based on ethnicity revealed an increased risk of CRC among Asians (CC vs. GC+GG: OR=1.22, 95% CI: 1.02-1.45), and similar results were found for rectal cancer (CC vs. GC+GG: OR=1.34, 95% CI: 1.120-1.62). These results suggest that the TP53 Arg72Pro polymorphism CC genotype may contribute to an increased risk of CRC, especially for rectal cancer and among Asians. PMID:27901479

  12. MUTATION SPECTRA OF SMOKY COAL COMBUSTION EMMISSIONS IN SALMONELLA REFLECTS THE TP53 AND KRAS MUTATIONS IN LUNG TUMORS FROM SMOKY COAL EXPOSED INDIVIDUALS

    Science.gov (United States)

    Mutation Spectra of Smoky Coal Combustion Emissions in Salmonella Reflect the TP53and KRAS Mutations in Lung Tumors from Smoky Coal-Exposed Individuals Abstract Nonsmoking women in Xuan Wei County, Yunnan Province, China who use smoky coal for cooking and h...

  13. Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett's esophagus progression prediction : A prospective follow-up study

    NARCIS (Netherlands)

    Davelaar, Akueni L.; Calpe, Silvia; Lau, Liana; Timmer, Margriet R.; Visser, Mike; ten Kate, Fiebo J.; Parikh, Kaushal B.; Meijer, Sybren L.; Bergman, Jacques J.; Fockens, Paul; Krishnadath, Kausilia K.

    2015-01-01

    Barrett's esophagus (BE) goes through a sequence of low grade dysplasia (LGD) and high grade dysplasia (HGD) to esophageal adenocarcinoma (EAC). The current gold standard for BE outcome prediction, histopathological staging, can be unreliable. TP53 abnormalities may serve as prognostic biomarkers. T

  14. Prognostic significance of K-ras and TP53 mutations in the role of adjuvant chemotherapy on survival in patients with Dukes C colon cancer

    NARCIS (Netherlands)

    Bleeker, W A; Hayes, V M; Karrenbeld, A; Hofstra, R M; Verlind, E; Hermans, J; Poppema, S; Buys, C H; Plukker, J T

    2001-01-01

    PURPOSE: Mutations in K-ras and TP53 genes are common in colorectal cancer. They affect biologic behavior and might influence chemotherapy susceptibility in these tumors. We investigated whether the survival of patients with Dukes C colon cancer treated with adjuvant chemotherapy is influenced by K-

  15. HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53

    NARCIS (Netherlands)

    Meulendijks, D.; Tomasoa, N. B.; Dewit, L.; Smits, P.H.M.; Bakker, R.; Van Velthuysen, M. L F; Rosenberg, E. H.; Beijnen, J. H.; Schellens, J. H M; Cats, A.

    2015-01-01

    Background:Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic s

  16. 利用明星基因TP53设计分子生物学开放实验的构思%A Design Concept of Experimental Molecular Biology by Utilizing Superstar TP53

    Institute of Scientific and Technical Information of China (English)

    吴燕华; 乔守怡

    2014-01-01

    为适应迅猛发展的分子生物学技术及理论,高校的分子生物学实验课程应与时俱进,不断进行改革和提高.笔者结合自身科研背景及教学经验,以明星基因TP53为研究对象,设计了一项分子生物学开放实验.一方面紧密联系流行的学术前沿,糅合新颖的分子生物学实验技术,另一方面以开放实验为载体指引学生思考和解决科学问题.这一改革构思旨在提高分子生物学实验教学质量的同时,为培养真正的生物科学研究型人才创造条件.

  17. Pri-Mir-34b/C and Tp-53 Polymorphisms are Associated With The Susceptibility of Papillary Thyroid Carcinoma: A Case-Control Study.

    Science.gov (United States)

    Chen, Peng; Sun, Ruifen; Pu, Yan; Bai, Peng; Yuan, Fang; Liang, Yundan; Zhou, Bin; Wang, Yanyun; Sun, Yinghe; Zhu, Jingqiang; Zhang, Lin; Gao, Linbo

    2015-09-01

    Tumor suppressor p53 directly regulated the abundance of the miR-34b/c. The interaction might contribute to certain cancer. We hypothesized that rs4938723 in the promoter region of pri-miR-34b/c and TP-53 Arg72Pro may be related to the risk of papillary thyroid carcinoma (PTC). A total of 784 patients with PTC and 1006 healthy controls were recruited to participate in this study. The variants were discriminated using a polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Additionally, the relative expression levels of miR-34b/c and TP-53 in 44 paired samples were revealed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A significantly increased risk of PTC was observed in the miR-34b/c rs4938723 CT, CC, and CT/CC genotypes compared with the TT genotype (CT vs TT: adjusted odds ratio [OR] = 1.51, 95%confidence interval [CI] = 1.23-1.85; CC vs TT: adjusted OR = 1.89, 95%CI = 1.39-2.63; CT/CC vs TT: adjusted OR = 1.59, 95%CI = 1.30-1.92, respectively). Significantly increased PTC susceptibility was also associated with the TP-53 Arg72Pro CC and CG/CC genotypes compared with the GG genotype (CC vs GG: adjusted OR = 2.04, 95%CI = 1.54-2.70; CG/CC vs GG: adjusted OR = 1.35, 95%CI = 1.11-1.67, respectively). Stratification analysis revealed that patients carrying the TP-53 Arg72Pro C allele and CC genotype had a significantly increased risk for developing N1 (C vs. G: OR = 1.27, 95%CI = 1.03-1.56; CC vs. GG: OR = 1.62, 95%CI = 1.07-2.46, respectively). Combined analysis showed that the genotypes of rs4938723 CT/CC + TP-53CG/CC increased the risk of PTC compared with rs4938723TT + TP-53GG (OR = 2.25, 95%CI = 1.67-3.03). Additionally, level of miR-34b was significantly upregulated in PTC patients.These findings indicate that the miR-34b/c rs4938723 and TP-53 Arg72Pro polymorphisms may contribute to the susceptibility of PTC.

  18. Survival in Norwegian BRCA1 mutation carriers with breast cancer

    Directory of Open Access Journals (Sweden)

    Hagen Anne

    2009-04-01

    Full Text Available Abstract Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers. One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival. BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls. Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis.

  19. Expression levels of the apoptotic inhibition molecules BIRC5 in non-small cell lung cancer and its correlation with Tp53 expression%BIRC5在非小细胞肺癌中的表达及与Tp53的关系

    Institute of Scientific and Technical Information of China (English)

    梁红玲; 黄健清; 李洪胜; 张绪超; 谢至

    2013-01-01

    Objective:To investigate the expression level of the apoptotic inhibition molecule BIRC5 in non-small cell lung cancer (NSCLC) and adjacent non-cancerous tissues and its correlation with Tp53 expression and clinicopathologic parameters.Methods:Cancer versus adjacent non-cancerous tissues,formalin-fixed paraffin-embedded,of NSCLC were collected and made into tissue microarray (TMA).Immunohistochemistry (IHC) was performed to analyze the expression levels of BIRC5 and Tp53.Results:In the analysis of non-paired 139 cases of cancers versus 25 adjacent tissues,non-parametric rank test showed that BIRC5 were expressed in cancers at a higher level than that in adjacent tissues (P < 0.01).Expression levels of BIRC5 were higher in male than in female patients,smokers than non-smokers patients,and squamous than non-squamous tumors (P < 0.001).BIRC5 and Tp53 expressions had negative correlation (r =-0.311,P =0.011) ; Mann-Whiteney test showed BIRC5 expressed higher in patients with low levels of Tp53 than in patients with high levels of Tp53 (P < 0.05).In NSCLC patients with either stages Ⅰ-Ⅳ or stages Ⅲ-Ⅳ,there was no significant difference of overall survival (OS) in patients with high levels of BIRC5 versus low levels of BIRC5.Conclusion:BIRC5 was significantly up-regulated at a higher expression level in lung cancer tissues than adjacent non-cancerous tissues and had negative correlation with Tp53 expression.The prognostic role of BIRC5 expression and its regulatory mechanisms by Tp53 warrant further investigation.%目的:探讨凋亡信号分子BIRC5在肺癌与癌旁组织中的表达差异,并分析BIRC5与Tp53和临床病理资料之间的关系.方法:制备非小细胞肺癌患者的癌与癌旁组织石蜡标本的组织芯片.采用免疫组织化学方法检测分析BIRC5、Tp53凋亡分子在组织中的蛋白表达水平.结果:BIRC5表达水平在癌组织中(n=139)较癌旁组织(n=25)显著升高(P<0.01);BIRC5在男性患者表达水平

  20. Characteristics of Yak Tumor Protein p53 Gene (Tp53)and Its Expression in Different Periods of Estrus Ovaries%牦牛Tp53基因特征分析及其在不同发情时期卵巢中的表达

    Institute of Scientific and Technical Information of China (English)

    郑红飞; 潘阳阳; 刘鹏刚; 彭秀梅; 崔燕; 余四九

    2015-01-01

    为研究牦牛肿瘤抑制蛋白Tp53(Tumor protein p53)的基因序列特征及其在牦牛卵巢中的表达情况,采集不同发情时期牦牛卵巢.根据黄牛的基因序列设计5'到3'端特异性引物,RT-PCR扩增基因克隆得到Tp53基因,并对其基因结构等其他生物信息进行分析.采用Real-time PCR方法分析牦牛不同发情时期卵巢中Tp53基因的表达差异.结果显示:牦牛Tp53基因序列的编码区为1 161 bp,编码386个氨基酸.相似性与进化分析显示,与瘤牛Tp53基因的相似性最高,达到98.4%,与家猫的相似性最低,为80.7%,表明Tp53基因在进化中具有高度保守性;Real-timePCR检测结果显示,Tp53基因在各个发情时期卵巢中均有表达,且表达量差异显著(P<0.05).Tp53基因的表达量出现差异可能是由于在不同发情时期卵巢细胞DNA损伤程度及内分泌等因素的不同所致.牦牛Tp53基因的成功克隆及生物信息学分析为该基因的进一步研究奠定了一定基础.

  1. Frequent mutations in EGFR, KRAS and TP53 genes in human lung cancer tumors detected by ion torrent DNA sequencing.

    Directory of Open Access Journals (Sweden)

    Xin Cai

    Full Text Available Lung cancer is the most common malignancy and the leading cause of cancer deaths worldwide. While smoking is by far the leading cause of lung cancer, other environmental and genetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive lung cancer molecular profile is essential for developing more effective, tailored therapies. Until recently, personalized DNA sequencing to identify genetic mutations in cancer was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 76 human lung cancer samples. The sequencing analysis revealed missense mutations in KRAS, EGFR, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations.

  2. PIK3CA and TP53 gene mutations in human breast cancer tumors frequently detected by ion torrent DNA sequencing.

    Directory of Open Access Journals (Sweden)

    Xusheng Bai

    Full Text Available Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5-10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations.

  3. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH, and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5, clear cell (n = 4, or low grade serous (n = 2 carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic, BRCA1 loss (epigenetic, and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  4. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  5. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  6. The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations.

    Science.gov (United States)

    Lee, Shin Yup; Jeon, Hyo-Sung; Hwangbo, Yup; Jeong, Ji Yun; Park, Ji Young; Lee, Eun Jin; Jin, Guang; Shin, Kyung Min; Yoo, Seung Soo; Lee, Jaehee; Lee, Eung Bae; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2015-02-01

    A large number of studies have evaluated the impact of TP53 mutations on the prognosis of patients with non-small cell lung cancer (NSCLC); however, the results of these studies are still controversial. Recently, considerable intratumor heterogeneity for genetic alterations has been demonstrated in various human cancers, including lung cancer. In the present study, we evaluated TP53 mutations in NSCLCs by direct sequencing and observed remarkable variation in the values of relative intensity (RI, the height of the peak of mutated allele/the height of the peak of non-mutated allele) of the mutations. We also examined whether the RI values were associated with intratumor heterogeneity of TP53 mutations. In addition, we evaluated the relationship between TP53 mutations and survival outcome. The patients with a TP53 mutation did not have significantly worse survival compared to those without the mutation. However, when tumors with a TP53 mutation were categorized into two groups, those with a low and those with a high RI, the latter group had significantly worse survival compared to those with wild-type TP53 (adjusted hazard ratio = 2.58, 95% confidence interval = 1.21-5.48, P = 0.01), whereas the former group did not. These results suggest that intratumor genetic heterogeneity may be an important factor in determining the role of TP53 mutations on the prognosis of NSCLC patients.

  7. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...

  8. Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population.

    Science.gov (United States)

    Yang, Jie; Zhu, Ji-Min; Wu, Song; Li, Jing; Wang, Ming-Rui; Wang, Ting-Ting; Lu, Yu-Wei

    2017-04-01

    Tumour suppressor protein 53 (p53) plays a central role in apoptosis, cell proliferation and death. Previously studies found contribution of functional p53 Arg72Pro polymorphism (TP53 rs1042522G/C polymorphism) in the development of systemic lupus erythematosus (SLE) remains controversial. In this study, for the first time, we evaluated its association with SLE in a Chinese Han population. This case-control study enrolled 1470 SLE patients and 2283 healthy controls. The genotyping of TP53 rs1042522 polymorphism was determined by Sequenom Mass ARRAY technology. Statistical analysis was conducted by Chi-square test (χ (2) test). Odds ratio (OR) with 95% confidence interval (CI) was calculated using unconditional logistic regression with adjusting age and sex. Allele and genotype frequencies of TP53 rs1042522G/C polymorphism showed statistically significant difference between the SLE patients and the normal controls (C vs. G: OR = 0.89, 95% CI 0.89-0.97, p = 0.01; (GC + CC) vs. GG using recessive model: OR = 0.84, 95% CI 0.73-0.96, p = 0.01; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.04; CC vs. GG using co-dominant model: OR = 0.80, 95% CI 0.66-0.96, p = 0.02; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.02). In addition, there was weak association between discoid rash and distribution of TP53 rs1042522G/C polymorphism in SLE patients (C vs. G: OR = 1.25, 95% CI 1.00-1.55, p = 0.04; CC vs. GG using co-dominant model: OR = 1.54, 95% CI 1.10-2.36, p = 0.04). Our finding suggests a significant relationship between the TP53 rs1042522G/C polymorphism and SLE. TP53 rs1042522G/C polymorphism would be promising as an indicator of SLE as well as the therapeutic target if its functions and mechanisms could be further investigated.

  9. 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.

  10. 肿瘤抑制蛋白基因Tp53在牦牛体外受精早期胚胎中的表达%The Expression of Tumor Protein p53 Gene (Tp53) in Yak (Bos grunneins) In vitro Fertilization (IVF) Early Embryos During Developmental Process

    Institute of Scientific and Technical Information of China (English)

    郑红飞; 潘阳阳; 李秦; 张译夫; 吕鹏; 崔燕; 余四九

    2015-01-01

    本研究旨在探讨肿瘤抑制蛋白基因(tumor protein p53,Tp53)在牦牛(Bos grunneins)早期不同发育时期体外受精胚胎中的表达情况及其与体外受精胚胎发育的关系.本实验采集牦牛卵巢,收集牦牛卵丘-卵母细胞复合体(cumulus-oocyte complexes,COCs)进行体外成熟培养及对成熟卵母细胞体外受精后进行培养.采用RT-PCR、实时荧光定量PCR(quantitative Real-time PCR,qRT-PCR)和间接免疫荧光方法检测不同时期体外受精胚胎发育过程中Tp53在基因和蛋白水平的表达动态.结果表明,在不同发育时期体外受精胚胎中均有Tp53基因的表达,并且Tp53在2~4细胞期和囊胚期表达量相对较低,组间差异不显著(P>0.05);Tp53在5~8细胞期和9~16期表达量相对较高,组间差异不显著(P>0.05);在2~4细胞期和囊胚期表达量与在4~8细胞期和9~l6期表达量相比差异显著(P<0.05).本研究表明,Tp53在调节牦牛早期胚胎发育中也起着非常重要的作用.Tp53的表达量与胚胎发育阻断的发生几率成正相关.间接免疫荧光显示Tp53蛋白主要存在于细胞核中,少量存在于细胞质中,其作用和DNA的损伤有关.

  11. 249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients

    Directory of Open Access Journals (Sweden)

    Paranaguá-Vezozzo Denise C

    2009-06-01

    Full Text Available Abstract Background Ser-249 TP53 mutation (249Ser is a molecular evidence for aflatoxin-related carcinogenesis in Hepatocellular Carcinoma (HCC and it is frequent in some African and Asian regions, but it is unusual in Western countries. HBV has been claimed to add a synergic effect on genesis of this particular mutation with aflatoxin. The aim of this study was to investigate the frequency of 249Ser mutation in HCC from patients in Brazil. Methods We studied 74 HCC formalin fixed paraffin blocks samples of patients whom underwent surgical resection in Brazil. 249Ser mutation was analyzed by RFLP and DNA sequencing. HBV DNA presence was determined by Real-Time PCR. Results 249Ser mutation was found in 21/74 (28% samples while HBV DNA was detected in 13/74 (16%. 249Ser mutation was detected in 21/74 samples by RFLP assay, of which 14 were confirmed by 249Ser mutant-specific PCR, and 12 by nucleic acid sequencing. All HCC cases with p53-249ser mutation displayed also wild-type p53 sequences. Poorly differentiated HCC was more likely to have 249Ser mutation (OR = 2.415, 95% CI = 1.001 – 5.824, p = 0.05. The mean size of 249Ser HCC tumor was 9.4 cm versus 5.5 cm on wild type HCC (p = 0.012. HBV DNA detection was not related to 249Ser mutation. Conclusion Our results indicate that 249Ser mutation is a HCC important factor of carcinogenesis in Brazil and it is associated to large and poorly differentiated tumors.

  12. BRCA1 interaction of centrosomal protein Nlp is required for successful mitotic progression.

    Science.gov (United States)

    Jin, Shunqian; Gao, Hua; Mazzacurati, Lucia; Wang, Yang; Fan, Wenhong; Chen, Qiang; Yu, Wei; Wang, Mingrong; Zhu, Xueliang; Zhang, Chuanmao; Zhan, Qimin

    2009-08-21

    Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability.

  13. Análise do polimorfismo no códon 72 do gene TP53 em mulheres inférteis com e sem endometriose

    OpenAIRE

    Bianco, Bianca; Christofolini, Denise Maria [UNIFESP; Brandes,Ariel; Lerner, Tatiana Goberstein; Gonçalves-Filho,Rubens Paulo; Souza,Angela Mara Bentes de; Barbosa,Caio Parente

    2011-01-01

    OBJETIVO: avaliar a frequência do polimorfismo no códon 72 do gene TP53 em mulheres inférteis com endometriose, mulheres com infertilidade idiopática, Grupo Controle e sua associação com a doença. MÉTODOS: estudo caso-controle que incluiu 198 mulheres inférteis com endometriose, 70 mulheres com infertilidade idiopática e 169 mulheres férteis sem endometriose como controles. O polimorfismo no códon 72 do gene TP53 (rs1042522, Arg/C:Pro/G), que promove uma troca de C/G na sequência codante, foi...

  14. Investigation of single-strand conformational polymorphism of the TP53 gene in women with a family history of breast cancer

    Directory of Open Access Journals (Sweden)

    R.R. Burbano

    2000-11-01

    Full Text Available Breast cancer in families with germ line mutations in the TP53 gene has been described in the medical literature. Mutation screening for susceptibility genes should allow effective prophylactic and preventive measures. Using single-strand conformational polymorphism, we screened for mutations in exons 5, 6, 7 and 8 of gene TP53 in the peripheral blood of 8 young non-affected members (17 to 36 years old of families with a history of breast cancer. Studies of this type on young patients (mean age, 25 years are very rare in the literature. The identification of these mutations would contribute to genetic counseling of members of families with predisposition to breast cancer. The results obtained did not show any polymorphism indicating mutation. In our sample, the familial tumorigenesis is probably related to other gene etiologies.

  15. BRCA1 founder mutations compared to ovarian cancer in Belarus.

    Science.gov (United States)

    Savanevich, Alena; Oszurek, Oleg; Lubiński, Jan; Cybulski, Cezary; Dębniak, Tadeusz; Narod, Steven A; Gronwald, Jacek

    2014-09-01

    In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.

  16. 抑制突变TP53增强胶质母细胞瘤细胞替莫唑胺敏感性及其相关机制%Down Regulating Mutant TP53 Enhances Temozolomide Sensitivity in Glioblastoma cells

    Institute of Scientific and Technical Information of China (English)

    王翔; 陈锦秀; 毛庆; 刘艳辉; 游潮

    2011-01-01

    背景与目的:胶质瘤化疗耐药是胶质瘤治疗效果差的一个瓶颈.导致化疗耐药的分子机制目前尚未完全清楚.突变TP53的“获得功能”被认为是决定肿瘤发生及发展中的重要因素.本研究目的在于探讨突变TP53“获得功能”在多形性胶质母细胞瘤化疗耐药中的作用及其相关机制.方法:对人脑胶质瘤母细胞株T98G细胞进行mRNA测序,确定其TP53基因是否突变及突变位点.采用脂质体法包裹化学合成的突变TP53干扰小RNA片段(siRNA)转染T98G细胞.运用RT-PCR方法在转染后的第1天至第5天检测肿瘤中突变TP53在mRNA水平的表达,及相应时点6-氧甲基鸟嘌呤-DNA甲基转移酶(MGMT)mRNA的表达.将转染siRNA的T98G细胞接种于96孔板中,加入梯度浓度(10~1000μmol/L)的替莫唑胺.模拟人体用药,替莫唑胺组在头5天内每天更换培养基,加入替莫唑胺;对照组加入司莫司汀.用MTT法观察各组在突变TP53沉默前后的化疗敏感性变化.结果:T98G细胞的237号密码子发生突变,且高表达突变TP53及MGMT mRNA.设计的siRNA可以有效地沉默T98G细胞株内突变TP53基因,使其在mRNA水平不表达或者低表达,沉默作用时间可达5天.沉默突变TP53基因后,T98G细胞株对替莫唑胺的敏感性增加4倍,对司莫司汀的敏感性无明显改变.沉默突变TP53基因后,可使MGMT的表达降低,两者呈正相关.结论:突变型TP53能增强胶质母细胞瘤细胞对替莫唑胺化疗的耐药性,其耐药机制可能是通过上调MGMT的表达实现的.

  17. Adrenocortical carcinoma with extension to the inferior vena cava and right atrium: 20-month-old girl with TP53 mutation

    Directory of Open Access Journals (Sweden)

    Terry L. Levin, MD

    2015-01-01

    Full Text Available A 20-month-old female presented with respiratory distress and a right adrenal mass extending into the inferior vena cava and right atrium. The mass was initially thought to be neuroblastoma. Pathology later revealed adrenocortical carcinoma. Inferior vena cava extension is far more common in adrenocortical carcinoma than neuroblastoma, and its presence should prompt clinical and laboratory evaluation for an adrenocortical tumor. The genetic findings in TP53 associated with this disease are discussed.

  18. Methylation levels of P16 and TP53 that are involved in DNA strand breakage of 16HBE cells treated by hexavalent chromium.

    Science.gov (United States)

    Hu, Guiping; Li, Ping; Li, Yang; Wang, Tiancheng; Gao, Xin; Zhang, Wenxiao; Jia, Guang

    2016-05-13

    The correlations between methylation levels of p16 and TP53 with DNA strand breakage treated by hexavalent chromium [Cr(VI)] remain unknown. In this research, Human bronchial epithelial cells (16HBE cells) in vitro and bioinformatics analysis were used to analyze the epigenetic role in DNA damage and potential biomarkers. CCK-8 and single cell gel electrophoresis assay were chosen to detect the cellular biological damage. MALDI-TOF-MS was used to detect the methylation levels of p16 and TP53. qRT-PCR was used to measure their expression levels in different Cr(VI) treatment groups. The transcription factors with target sequences of p16 and TP53 were predicted using various bioinformatics software. The findings showed that the cellular toxicity and DNA strand damage were Cr(VI) concentration dependent. The hypermethylation of CpG1, CpG31 and CpG32 of p16 was observed in Cr(VI) treated groups. There was significant positive correlation between the CpG1 methylation level of p16 and cell damage. In Cr(VI) treated groups, the expression level of p16 was lower than that in control group. The expression level of TP53 increased when the Cr(VI)concentration above 5μM. About p16, there was significant negative correlation between the CpG1 methylation levels with its expression level. A lot of binding sites for transcription factors existed in our focused CpG islands of p16. All the results suggested that the CpG1 methylation level of p16 could be used as a biomarker of epigenetic effect caused by Cr(VI) treatment, which can enhance cell damage by regulating its expression or affecting some transcription factors to combine with their DNA strand sites.

  19. The use of FISH-comet to detect c-Myc and TP 53 damage in extended-term lymphocyte cultures treated with terbuthylazine and carbofuran.

    Science.gov (United States)

    Mladinic, Marin; Zeljezic, Davor; Shaposhnikov, Sergey A; Collins, Andrew R

    2012-05-20

    Terbuthylazine and carbofuran are suspected to cause non-Hodgkin's lymphoma and lung cancer. We evaluated the effects of prolonged exposure to low concentrations on primary DNA damage by comet assay, and on the structural integrity of c-Myc and TP 53 genes by FISH-comet. Another novelty in studying these pesticides' genotoxicity is the use of 14-day extended-term human lymphocyte cultures. Concentrations corresponded to values of ADI and OEL: for terbuthylazine 0.58 ng/ml and 8 ng/ml; for carbofuran 8 ng/ml and 21.6 ng/ml, respectively. A possible effect of metabolic activation (S9) was also considered. Carbofuran treatment induced a significant migration of DNA into the tail in a concentration-dependent manner, while for terbuthylazine the effect was significant only at the higher concentration. Terbuthylazine caused migration of both c-Myc signals into the comet tail. A significant occurrence of TP 53 signals in the tail was observed at 8 ng/ml. Prolonged carbofuran treatment significantly elevated the migration of a single c-Myc signal into the tail in a concentration-dependent manner. With S9, distribution of signals shifted toward increased presence of both signals in tail. Our results showed impaired structural integrity of c-Myc and TP 53 due to prolonged exposure to terbuthylazine and carbofuran.

  20. 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...... treatment times of 6.5 and 5.5 weeks according to the DAHANCA-guidelines. Endpoints were local control at T-site, disease-specific and crude survival. RESULTS: 125 of 180 carcinomas (69%) carried in total 176 mutations. 72 carcinomas were WT (40%) and 108 carcinomas (60%) carried mutations giving...... dysfunctional p53. Overall, mutations in TP53 were not associated with the endpoints. However, when dichotomising according to TP53 status and evaluating the effect of the overall treatment time then tumours with mutant TP53 did benefit from 6 instead of 5fx/wk regarding local control, P=0.005; RR: 0.33 (C.I 95...

  1. Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome

    Directory of Open Access Journals (Sweden)

    de la Cruz-Hernández Erick

    2009-12-01

    Full Text Available Abstract Background Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors. Methods Mutation analysis was based on Denaturing high performance liquid chromatography (DHPLC screening of exons 2-11 of the TP53 gene, sequencing, and cloning of DNA obtained from peripheral blood lymphocytes. Results We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4. The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150. With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain. Conclusion To our knowledge, this specific alteration has not been reported previously, but we believe it is the cause of the Li-Fraumeni syndrome in this family.

  2. EBV-negative monomorphic B-cell post-transplant lymphoproliferative disorders are pathologically distinct from EBV-positive cases and frequently contain TP53 mutations.

    Science.gov (United States)

    Courville, Elizabeth L; Yohe, Sophia; Chou, David; Nardi, Valentina; Lazaryan, Aleksandr; Thakral, Beenu; Nelson, Andrew C; Ferry, Judith A; Sohani, Aliyah R

    2016-10-01

    Monomorphic post-transplant lymphoproliferative disorder commonly resembles diffuse large B-cell lymphoma or Burkitt lymphoma, and most are Epstein-Barr virus (EBV) positive. We retrospectively identified 32 cases of monomorphic post-transplant lymphoproliferative disorder from two institutions and evaluated EBV in situ hybridization; TP53 mutation status; p53, CD30, myc, and BCL2 expression by immunohistochemistry; proliferation index by Ki67; and germinal center vs non-germinal center immunophenotype by Hans criteria. Post-transplant lymphoproliferative disorder arose after hematopoietic stem cell transplant in five and solid organ transplant in 27 patients, a median of 4 and 96 months after transplant, respectively (overall median latency 71 months, range 2-295). The most common morphology was diffuse large B-cell lymphoma (28 cases), with three cases of Burkitt lymphoma, and one case of plasmablastic lymphoma. Ten cases (31%) were EBV negative. Of those with the morphology of diffuse large B-cell lymphoma, the EBV-negative cases were more frequently TP53-mutated (Pnegative (Ppost-transplant lymphoproliferative disorder were older with a longer latency from time of transplant to diagnosis (Ppost-transplant setting and underscores differences between EBV-positive and EBV-negative post-transplant lymphoproliferative disorder in terms of immunophenotype and TP53 mutation frequency, supporting an alternative pathogenesis for EBV-negative post-transplant lymphoproliferative disorder.

  3. MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation.

    Science.gov (United States)

    Tang, Guilin; DiNardo, Courtney; Zhang, Liping; Ravandi, Farhad; Khoury, Joseph D; Huh, Yang O; Muzzafar, Tariq; Medeiros, L Jeffrey; Wang, Sa A; Bueso-Ramos, Carlos E

    2015-01-01

    MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent -5/del(5q), -18, and -17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course.

  4. A comparison among HER2, TP53, PAI-1, angiogenesis, and proliferation activity as prognostic variables in tumours from 408 patients diagnosed with early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Alsner, Jan; Ege Olsen, Karen;

    2008-01-01

    BACKGROUND: The prognostic potential of HER2, TP53 mutations, PAI-1 protein levels, angiogenesis and proliferation were investigated in tumours from 408 patients with early breast cancer followed >10 years. One hundred and sixty seven patients (41%) died from breast cancer. MATERIALS AND METHODS...... receptor (p prognosis. In multivariate analysis, metastatic nodes (1-3 positive: RR 1.56 95% CI 1.02-2.38; >3 positive: RR 3.70 95% CI 2.54-5.38), HER2+ (RR 1.91, 95% CI 1.35-2.70), mutated TP53 (RR 1.70, 95% CI 1.21-2.38), PAI-1 (RR 1.04, 95% CI 1.......01-1.07) and grade 3 (RR 1.96, 95% CI 1.83-3.22) were independent markers of poor outcome. CONCLUSION: Compared to PAI-1 protein levels, Chalkley counts and MIB-1, HER2+ and mutations of TP53 were the strongest independent markers of poor prognosis irrespective of nodal status....

  5. Kinetic profiles by topographic compartments in muscle-invasive transitional cell carcinomas of the bladder: role of TP53 and NF1 genes.

    Science.gov (United States)

    Blanes, Alfredo; Rubio, Javier; Martinez, Armando; Wolfe, Hubert J; Diaz-Cano, Salvador J

    2002-07-01

    We evaluated 71 muscle-invasive transitional cell carcinomas (TCCs) of the bladder by tumor compartments. Kinetic parameters included mitotic figure counting, Ki-67 index, proliferation rate (DNA slide cytometry), and apoptotic index (in situ end labeling [ISEL] of fragmented DNA using digoxigenin-labeled deoxyuridine triphosphate and Escherichia coli DNA polymerase [Klenow fragment]). At least 50 high-power fields per compartment were screened from the same tumor areas; results are expressed as percentage of positive neoplastic cells. Mean and SD were compared by tumor compartment. DNA was extracted from microdissected samples (superficial and deep) and used for microsatellite analysis of TP53 and NF1 by polymerase chain reaction-denaturing gradient gel electrophoresis. Significantly higher marker scores were revealed in the superficial compartment than in the deep compartment. An ISEL index of less than 1% was revealed in 63% (45/71) of superficial compartments and 86% (61/71) of deep compartments. Isolated NF1 alterations were observed mainly in superficial compartments, whereas isolated TP53 abnormalities were present in deep compartments. Lower proliferation and down-regulation of apoptosis define kinetically the deep compartment of muscle-invasive TCC of the bladder and correlate with the topographic heterogeneity, NF1-defective in superficial compartments and TP53-defective in deep compartments.

  6. TP53*P72 allele influences negatively female life expectancy in a population of central Italy: cross-sectional study and genetic-demographic approach analysis.

    Science.gov (United States)

    Di Pietro, Fabio; Dato, Serena; Carpi, Francesco M; Corneveaux, Jason J; Serfaustini, Simona; Maoloni, Sebastiano; Mignini, Fiorenzo; Huentelman, Matthew J; Passarino, Giuseppe; Napolioni, Valerio

    2013-05-01

    The association of TP53 P72R (rs1042522) with longevity remains uncertain and varies with ethnicity. Here, we tested its association with longevity in a cross-sectional population of Central Italy (18-106 years, N = 1,072), by integrating demographic information and frequency data to account for the different survival rates between sexes through the application of a genetic-demographic approach. rs1042522 affects females longevity, showing significant associations in Comparison 2 (Age Class 3 [>91 years] vs Age Class 2 [73-91 years]) under both additive (odds ratio [OR] 0.574; p = .006) and dominant (OR 0.513; p = .006) models. The TP53*P72 allele is significantly underrepresented in Age Class 3 only in women (OR 0.575; p = .008). The genetic-demographic approach demonstrated that the frequency of female TP53*P72 carriers underwent a significant reduction after 82 years (OR 0.586; p = .002). The same analyses gave nonsignificant results in men. The discrepancies among the results obtained on rs1042522 for longevity could result from the pleiotropic effects of p53 and the potential ethnic variation of its functional variants.

  7. NORTHERN BLOT ANALYSIS OF nm23 GENE EXPRESSION IN HUMAN LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    LIU Lun-xu; ZHOU Qing-hua; SHI Ying-kang; QIN Yang; SUN Zhi-lin; SUN Ze-fang

    1999-01-01

    Objective: To investigate the role of nm23 gene expression in human lung cancer. Methods: Forty human lung cancer tissues and 19 non-cancer pulmonary tissues were studied for their nm23-H1 and nm23-H2 mRNA expression with non-radioactive Northern blot hybridization. The correlation of nm23 mRNA expression with clinical features of lung cancer was analyzed. Results: The mRNA expression of nm23-H2 gene in poorly differentiated squamous cell carcinoma was significantly decreased compared to that in moderate-high differentiated squamous cell carcinoma. The mRNA expression of nm23-H1 and nm23-H2 gene in small cell lung cancer was significantly decreased compared to that in squamous cell carcinoma. No significant difference in nm23 mRNA expression was observed between lung cancer with and without lymph node metastasis, nor was there significant difference between tumor stage. Conclusion: The mRNA expression of nm23 gene is correlated with the degree of differentiation of lung cancer, but there is no evidence of metastasis suppression effect by nm23 gene.

  8. Combined analysis of pri-miR-34b/c rs4938723 and TP53 Arg72Pro with cervical cancer risk.

    Science.gov (United States)

    Yuan, Fang; Sun, Ruifen; Chen, Peng; Liang, Yundan; Ni, Shanshan; Quan, Yi; Huang, Juan; Zhang, Lin; Gao, Linbo

    2016-05-01

    miR-34 family members can form a p53-miR-34 positive feedback loop and induce apoptosis, DNA repair, angiogenesis, and cell cycle arrest. We conducted a case-control study to examine whether two polymorphisms (i.e., rs4938723 in the promoter of pri-miR-34b/c and TP53 Arg72Pro) were linked to the carcinogenesis of cervical cancer among Chinese Han women. Genotypes of the two polymorphisms in 328 cervical cancer patients and 568 control subjects were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. We found a significantly increased cervical cancer risk in the pri-miR-34b/c rs4938723 under dominant and overdominant model (CT/CC vs. TT: adjusted OR = 1.34, 95 % CI = 1.01-1.77; CT vs. TT/CC: adjusted OR = 1.37, 95 % CI = 1.05-1.80, respectively). Increased cervical cancer risks were also found in the TP53 Arg72Pro under a heterozygous comparison and overdominant model (CG vs. GG: adjusted OR = 1.44, 95 % CI = 1.06-1.95; CG vs. GG/CC: adjusted OR = 1.47, 95 % CI = 1.12-1.94, respectively). Stratification analysis showed that patients carrying the pri-miR-34b/c rs4938723 CT genotype had a significantly increased risk for developing poorly differential status and clinical stage I. Moreover, increased cancer risks were observed for the TP53 Arg72Pro polymorphism in patients with poorly differential status, clinical stage II, and without lymph node metastasis. Combined analysis revealed that the genotypes of rs4938723 CT/CC and TP53 Arg72Pro CG/CC had an increased cervical cancer risk (OR = 2.21, 95 % CI = 1.38-3.53). These findings suggest that the pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the genesis of cervical cancer.

  9. 抑癌基因TP53及新家族成员TP63和TP73的研究新进展

    Institute of Scientific and Technical Information of China (English)

    陈中; 张嘉玲; 杨歆萍; 吕海; CARTER Van Waes

    2013-01-01

    抑癌基因TP53在调控细胞周期、细胞凋亡和维持基因组稳定的过程中发挥着重要作用。TP63和TP73是TP53家族中包含的另外两个成员,均具有多种亚型,这些亚型通过自身家族或与其它转录因子家族之间的相互作用,从而对广泛的基因群发挥调控作用。本文将综述TP53及其家族成员TP63、TP73的功能学研究上的最新进展,并将重点介绍我们NIH/NIDCD头颈外科实验室的近期的研究工作所取得的新发现。我们近期的研究结果揭示了在肿瘤炎症的微环境中,存在着一种新的可逆转的动态机制为促炎症细胞因子TNF-α诱导NF—κBc—REL/△Np63ct相互作用,协同促进细胞增殖、生存、炎症和迁移相关基因群的调控。并在有突变的TP53肿瘤中,这些相互作用同时使肿瘤抑制基因TAp73的功能失活,促进肿瘤对TNF—α的抗药性和细胞生存。我们的研究阐述了炎症与肿瘤发生、发展的新机制,其中NF—κB和TP53两大转录因子家族基因的相互作用起到了关键性作用。这一新发现或许可为肿瘤的诊断、治疗和预防提供新的策略。

  10. Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients.

    Science.gov (United States)

    Molina, Vicente; Papiol, Sergi; Sanz, Javier; Rosa, Araceli; Arias, Bárbara; Fatjó-Vilas, Mar; Calama, Julia; Hernández, Ana I; Bécker, Joemir; Fañanás, Lourdes

    2011-05-01

    Abnormalities in white matter (WM) volumes and integrity in schizophrenia, together with post-mortem studies showing reduced expression of oligodendrocyte/myelination genes and apoptotic processes taking place in oligodendrocytes, suggest the interest of major regulators of apoptosis as candidate genes for some features related to myelin integrity in schizophrenia. Protein p53, encoded by TP53 gene, has a central role in the control of apoptosis and is involved in oligodendrocyte development. TP53 gene polymorphisms may account for variability in WM features, metabolic activity and biochemical markers of neuronal integrity and membrane turnover. Pro72Arg and Ins16bp polymorphisms at TP53 gene were analyzed in 20 DSM-IV schizophrenia patients. T1/T2-weighted sequences of these patients were acquired using a 1.5T Philips Gyroscan system. Scans were transformed into Talairach space and segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using Statistical Parametric Mapping under a ROI approach. Likewise dorsolateral prefrontal cortex (DLPFC) metabolic activity was measured using a procedure based on MRI/PET image fusion. In 13 of these patients proton magnetic resonance spectroscopy was used to examine N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) levels in dorsolateral-medial prefrontal cortex (DLMPFC). MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n=45). Patients Pro/Arg heterozygous (Pro72Arg polymorphism) showed a generalized deficit in whole-brain WM that was especially prominent in frontal lobe and a lower metabolic activity in the DLPFC as compared to Pro/Pro homozygous. Pro/Arg subjects also showed decreased NAA/Cho and increased Cho/Cr ratios in right DLMPFC. TP53 genetic variability influences WM volumes in frontal lobes and it seems to modulate the metabolic activity in this region. Our results suggest that TP53 might influence aspects of myelin and white matter integrity

  11. Correlative Research between the Expression of Myc, TP53 and Clinical Pathological Factors in Esophageal Cancer of Xinjiang Area%新疆食管癌中Myc、TP53表达及其与临床病理因素相关性研究

    Institute of Scientific and Technical Information of China (English)

    郭琼; 李卉; 沙亚哈提·别尔克哈之; 谌宏鸣; 李惠武

    2015-01-01

    目的:检测Myc和TP53在食管癌组织和远端无癌组织的表达情况,并分析其与临床病理因素之间的关系,初步探讨Myc和TP53在新疆食管癌发生发展中可能存在的特点.方法:经Trizol一步法提取88例新疆地区食管癌组织及其远端无癌组织标本总RNA,mRNA逆转录为cDNA,经聚合酶链式反应生成产物,运用光密度值即半定量RT-PCR技术检测88例新疆地区食管癌组织、远端无癌组织中Myc和TP53的mRNA表达情况及二者阳性表达率,并分析Myc和TP53的表达与临床病理因素之间的相关性.结果:①Myc的mRNA相对表达量在食管癌组织中高于远端无癌组织,差异有显著性(P<0.01);TP53的mRNA相对表达量在远端无癌组织中高于癌组织(P<0.05);②Myc的阳性表达率在88例食管癌组织中高于远端无癌组织(P<0.05);TP53的阳性表达率在远端无癌组织中高于癌组织(P<0.05);③Myc的表达与分化程度(P<0.01)、TNM分期(P<0.01)、淋巴结转移(P<0.05)、侵犯深度(P<0.05)和族别(P<0.05)有关,与性别无关;TP53的表达与侵犯程度(P<0.01)有关,与性别、分化程度、TNM分期、淋巴结转移和族别均无关;④88例食管癌组织中,Myc和TP53的表达呈现负相关(r=-0.501,P<0.0 1).结论:Myc在新疆地区食管癌组织中表达上调,TP53则表达减弱.说明Myc参与食管癌的发生和发展,而TP53则可能保护正常组织不发生癌变.

  12. 全反式维甲酸联合顺铂对A549细胞增殖及PDCD5和TP53 mRNA表达的影响%Effects of ATRA combined with cisplatin on A549 cell proliferation and expression of PDCD5 and TP53 mRNA

    Institute of Scientific and Technical Information of China (English)

    刘红; 李海燕; 李伟国; 康燕; 陈红杰; 黄永杰; 王静

    2013-01-01

    目的 观察全反式维甲酸(ATRA)联合顺铂对肺癌A549细胞增殖的影响,探索ATRA应用的最适浓度,研究各组肺癌A549细胞PDCD5、TP53基因表达情况.方法 以不同浓度的ATRA(10-5 mol/L、10-6 mol/L、10-7 mol/L)与顺铂(10-2 μmol/L)联合作用于肺癌A549细胞,采用MTT法检测细胞增殖情况.利用RT-PCR检测ATRA、顺铂作用于肺癌细胞A549细胞后,凋亡相关基因PDCD5、TP53 mRNA的表达.结果 ①MTT研究可观察到,在24 h、48 h、72 h各时间点,ATRA组、顺铂组及两药联合组A549细胞增殖率与阴性对照组比较明显降低(P<0.05);在同一时间点,ATRA不同的浓度间,抑制率随浓度的增加而增加(P<0.05).②与阴性对照组相比,药物干预组PDCD5、TP53mRNA含量明显增加(P<0.05).结论 ATRA对肺癌A549的生长具有抑制作用,有明显的浓度和时间依赖性;ATRA及其与顺铂联用,可以诱导PDCD5及TP53的mRNA的表达.PDCD5与TP53的表达呈正相关.%Objective To observe the functions of all-trans retinoic acid (ATRA) combined with cisplatin on proliferation of A549 cells and to explore the optimal concentration of ATRA and the expressions of PDCD5,TP53 genes of A549 cells in different groups.Methods A549 cells were treated by different concentrations of ATRA (10-5 mol/L,10-6 mol/L,10-7 mol/L) and cisplatin (10-2 μmol/L).MTT assay was used to detect cell proliferation in different groups.The expressions of PDCD5 and TP53 mRNA were detected by RT-PCR.Results ①MTT assay showed the cell proliferation rate in ATRA group,cisplatin group,and two-drug group was lower than that in control group (P <0.05) in 24 h,48 h,and 72 h after treatment.At the same time-point,cell inhibition rate increased with the increase of the concentration of ATRA (P <0.05).②Compared with control group,mRNA of PDCD5 and TP53 in groups treated with drugs increased (P <0.05).Conclusions The growth of lung cancer A549 cells can be inhibited by ATRA in a concentration

  13. gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair

    Science.gov (United States)

    Chevrier, Sandy; Boidot, Romain

    2014-01-01

    The widespread use of Next Generation Sequencing has opened up new avenues for cancer research and diagnosis. NGS will bring huge amounts of new data on cancer, and especially cancer genetics. Current knowledge and future discoveries will make it necessary to study a huge number of genes that could be involved in a genetic predisposition to cancer. In this regard, we developed a Nextera design to study 11 complete genes involved in DNA damage repair. This protocol was developed to safely study 11 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD80, and TP53) from promoter to 3'-UTR in 24 patients simultaneously. This protocol, based on transposase technology and gDNA enrichment, gives a great advantage in terms of time for the genetic diagnosis thanks to sample multiplexing. This protocol can be safely used with blood gDNA. PMID:25350069

  14. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Nilbert, Mef; Petersen, Janne

    2016-01-01

    Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk...... in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk...... was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G...

  15. "Ring-fencing" BRCA1 tumor suppressor activity.

    Science.gov (United States)

    Patel, Ketan J; Crossan, Gerry P; Hodskinson, Michael R G

    2011-12-13

    BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis.

  16. 温州地区原发性肝细胞癌TP53基因249密码子突变研究%Analysis of mutation of TP53 gene codon 249 in primary hepatocellular carcinoma in Wenzhou area

    Institute of Scientific and Technical Information of China (English)

    胡伟建; 郑亦胡; 鲍海力; 朱椰凡; 张启瑜

    2016-01-01

    目的 检测温州地区原发性肝细胞癌的TP53基因249密码子突变情况,并探讨其在肝细胞癌中所起的作用及其临床意义.方法 收集石蜡包埋的原发性肝细胞癌组织120例,应用Sanger测序技术检测突变情况.运用Spearman检验分析肿瘤组织中TP53基因249密码子突变与原发性肝细胞癌患者临床病理特征之间的相关性.结果 TP53基因249密码子在120例肝癌组织中总突变率为3.33% (4/120),进一步分析显示TP53基因249密码子突变与肝细胞癌患者的临床病理因素未发现存在相关性(P> 0.05).结论 在温州地区,TP53基因249密码子突变为非高发事件,未发现其与原发性肝细胞癌的进展相关.

  17. nm23H1 expression and its role in the evolution of non-gastrointestinal malignancies

    Institute of Scientific and Technical Information of China (English)

    Shailendra Kapoor

    2009-01-01

    The role of nm23H1 genetic instability is not limited to gastrointestinal malignancies. A similar close relationship exists between nm23H1 genetic instability and other non gastrointestinal systemic malignancies. For instance, in oral malignant melanomas with lymphoid metastasis, the nm23H1 expression is significantly lower in contrast to tumors with no lymphoid metastasis.Similarly, increased metastasis is seen in non small cell lung cancers following down regulation of nm23H1 in conjunction with KAI-1 down regulation.There is an inverse relationship between tumor stage and metastasis and nm23H1 expression in individuals with prostate carcinomas and a similar relationship exists between microsatellite instability of the nm23H1 gene and ovarian carcinogenesis. For instance, nearly 70.5% of stageⅠ-Ⅱ ovarian tumors express nm23H1 in sharp contrast to only 25% of stage Ⅲ-Ⅳ ovarian tumors. As is clearly evident, nm23H1 has a major role in gastrointestinal and non-gastrointestinal carcinogenesis.The coming few years will hopefully see the development of new strategies by virtue of which we can alter nm23H1 expression and thus decrease the risk of metastasis in malignant tumors.

  18. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bernstein, Jonine L; Thomas, Duncan C; Shore, Roy E

    2013-01-01

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with ra...

  19. File list: Oth.ALL.10.BRCA1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.10.BRCA1.AllCell hg19 TFs and others BRCA1 All cell types SRX182682,SRX1506...31,SRX150596,SRX150457,SRX150688,SRX481566,SRX359987 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.10.BRCA1.AllCell.bed ...

  20. File list: Oth.ALL.05.BRCA1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.05.BRCA1.AllCell hg19 TFs and others BRCA1 All cell types SRX182682,SRX1506...31,SRX150596,SRX150457,SRX150688,SRX481566,SRX359987 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.05.BRCA1.AllCell.bed ...

  1. File list: Oth.ALL.20.BRCA1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.20.BRCA1.AllCell hg19 TFs and others BRCA1 All cell types SRX182682,SRX1506...31,SRX150596,SRX150457,SRX150688,SRX481566,SRX359987 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.20.BRCA1.AllCell.bed ...

  2. File list: Oth.ALL.50.BRCA1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.50.BRCA1.AllCell hg19 TFs and others BRCA1 All cell types SRX182682,SRX1506...31,SRX150596,SRX150457,SRX150688,SRX481566,SRX359987 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.50.BRCA1.AllCell.bed ...

  3. Identification of colorectal cancer patients with tumors carrying the TP53 mutation on the codon 72 proline allele that benefited most from 5-fluorouracil (5-FU based postoperative chemotherapy

    Directory of Open Access Journals (Sweden)

    Tsuchiya Eiju

    2009-12-01

    Full Text Available Abstract Background Although postoperative chemotherapy is widely accepted as the standard modality for Dukes' stage C or earlier stage colorectal cancer (CRC patients, biomarkers to predict those who may benefit from the therapy have not been identified. Previous in vitro and clinical investigations reported that CRC patients with wild-type p53 gene (TP53-tumors benefit from 5-fluorouracil (5-FU based chemotherapy, while those with mutated TP53-tumors do not. However, these studies evaluated the mutation-status of TP53 by immunohistochemistry with or without single-strand conformation polymorphism, and the mutation frequency was different from study to study. In addition, the polymorphic status at p53 codon 72, which results in arginine or proline residues (R72P and is thought to influence the function of the protein significantly, was not examined. Methods To evaluate the significance of the TP53 mutation as a molecular marker to predict the prognosis of CRC patients, especially those who received postoperative chemotherapy, we examined the mutation by direct sequencing from fresh CRC tumors and evaluated the R72P polymorphism of the mutated TP53 by a combined mutant allele- and polymorphic allele-specific polymerase chain reaction (PCR. Results The TP53 mutation occurred in 147 (70% of 211 Japanese CRC tumors. The mutation was observed in 93 (63% tumors on the R72 allele and in 54 (37% tumors on the P72 allele. Although the alterations to TP53 have no prognostic significance for CRC patients overall, we found that Dukes' stage C CRC patients who did not receive postoperative chemotherapy and carried the mutated TP53-R72 showed significantly longer survival times than those with the mutated TP53-P72 when evaluated by overall survival (p = 0.012. Conclusion Using a combined mutant allele- and polymorphic allele-specific PCR, we defined the codon 72 polymorphic status of the TP53 mutated allele in Japanese CRC patients. We raised a possibility

  4. EVALUATION OF THE PROGNOSTIC VALUE OF nm23 GENE EXPRESSION IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    刘红; 毛慧生; 傅西林; 方志沂; 冯玉梅; 范宇; 李树玲

    2002-01-01

    Objective: To investigate the expression of nm23 gene and evaluate its prognostic value in breast cancer. Methods: nm23 expressions were detected in 101 breast cancer patients (group 1) by immunohistochemistry. RT-PCR and immunohistochemistry were used to measure expressions of nm23 gene in another 68 patients with breast cancer (group 2). Results: nm23 gene expression in group 1 was inversely associated with distant metastasis and lymph node metastasis (P<0.05). In 44 patients with negative lymph node, 9 cases progressed to distant metastasis, 7 of them (77.8%) showed low expression of nm23 gene (P<0.05). In 57 patients with positive lymph node, 24 our of 29 patients who had no distant metastasis (82.8%) expressed nm23 gene at high level (P<0.05). Meanwhile, there were 6 patients with distant metastasis in the group 2, all of thenm expressed nm23 gene mRNA at low level. Conclusion: The results showed that nm23 gene might play an independent role in predicting prognosis of breast cancer.

  5. 胶质瘤IDH1和TP53突变与LOH1p/19q的表达及意义%Expression and significance of IDH1, TP53 mutation and LOH 1p/19q in glioma

    Institute of Scientific and Technical Information of China (English)

    王君祥; 姜华; 褚荣涛; 曹芳; 赵富文; 周幽心; 冯鸣

    2015-01-01

    目的 探讨胶质瘤异柠檬酸脱氢酶1 (IDH1)突变、TP53突变和1p/19q联合性缺失(LOH 1p/19q)的表达及其意义.方法 病理组织学证实的Ⅱ-Ⅲ级胶质瘤136例,采用基因片段测序检测IDH1突变,免疫组织化学检测TP53突变,荧光原位杂交法检测LOH 1p/19q的表达.结果 136例中,IDH1突变107例,TP53突变59例,LOH 1p/19q 36例.其中,同时存在IDH1突变和TP53突变共有55例(弥漫性细胞瘤24例,间变性星形细胞瘤26例,少突星形细胞瘤3例,间变性少突星形细胞瘤2例).同时存在IDH1突变和LOH 1p/19q共有26例(少突胶质细胞瘤13例,间变性少突胶质细胞瘤9例,少突星形细胞瘤2例,间变性少突星形细胞瘤2例).无一例同时存在TP53突变和LOH1p/19q.结论 联合检测IDH1突变、TP53突变和LOH1p/19q能有利于明确肿瘤分子病理分型和预后判断,可能成为未来胶质瘤基因治疗的新靶点.

  6. The association between exposure to aflatoxin, mutation in TP53, infection with hepatitis B virus, and occurrence of liver disease in a selected population in Hyderabad, India.

    Science.gov (United States)

    Anitha, S; Raghunadharao, D; Waliyar, F; Sudini, H; Parveen, M; Rao, Ratna; Kumar, P Lava

    2014-05-15

    Aflatoxin B1 is a carcinogen produced by Aspergillus flavus and a few related fungi that are often present in many food substances. It interacts synergistically with Hepatitis B or C virus (HBV, HBC) infection, thereby increasing the risk of hepatocellular carcinoma (HCC). The G to T transversion at the third position of codon 249 (AGG) of the TP53 gene, substituting arginine to serine, is the most common aflatoxin-induced mutation linked to HCC. This study examined mutations in TP53 by PCR-RFLP analysis and by measurement of an aflatoxin-albumin adduct as a biomarker for human exposure of aflatoxin B1 by indirect-competitive ELISA, in samples collected from healthy controls as well as patients with hepatitis in Hyderabad, Andhra Pradesh, India. A total of 238 blood samples were analyzed the presence of the G to T mutation. Eighteen of these samples were from HBV-positive subjects, 112 of these were from subjects who had HBV-induced liver cirrhosis, and 108 samples were taken from subjects without HBV infection or liver cirrhosis (control group). The G to T mutation was detected in 10 samples, 8 of which were from subjects positive to both HBV and aflatoxin-albumin adduct in blood (p=0.07); whilst two were from individuals who were HBV-negative, but positive for the aflatoxin-albumin adduct (p=0.14). The aflatoxin-albumin adduct was detected in 37 of 238 samples, 29 samples were from HBV-positive subjects and eight were from individuals who were positive for both HBV and the TP53 mutation (p=0.07). The concentration of aflatoxin-albumin adduct ranged from 2.5 to 667pg/mg albumin. Despite low incidence of the G to T mutation, its detection in subjects positive to aflatoxin-adducts is indicative of a strong association between the mutation and aflatoxin exposure in India.

  7. EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma.

    Science.gov (United States)

    Chen, Qian; Zheng, Peng-Sheng; Yang, Wen-Ting

    2016-06-14

    Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53.

  8. TP53 mutations, human papilloma virus DNA and inflammation markers in esophageal squamous cell carcinoma from the Rift Valley, a high-incidence area in Kenya

    Directory of Open Access Journals (Sweden)

    Martel-Planche Ghislaine

    2011-10-01

    Full Text Available Abstract Background Squamous Cell Carcinoma of Esophagus is one of the most common malignancies in both men and women in eastern and south-eastern Africa. In Kenya, clinical observations suggest that this cancer is frequent in the Rift Valley area. However, so far, there has been no report on the molecular characteristics of esophageal squamous cell carcinoma (ESCC in this area. Results We have analyzed TP53 mutations, the presence of human papilloma virus (HPV DNA and expression of inflammation markers Cyclooxygenase 2 (Cox-2 and Nitrotyrosine (NTyR in 28 cases (13 males and 15 females of archived ESCC tissues collected at the Moi Teaching and Referral Hospital in Eldoret, Kenya. Eleven mutations were detected in TP53 exons 5 to 8 (39%. All ESCC samples were negative for HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82. Immunohistochemical analysis of Cox-2 and NTyR showed a low proportion of positive cases (17.4% and 39.1%, respectively. No association between the above markers and suspected risk factors (alcohol or tobacco use, hot tea drinking, use of charcoal for cooking was found. Conclusion Our findings suggest that mechanisms of esophageal carcinogenesis in eastern Africa might be different from other parts of the world. Low prevalence of TP53 mutation compared with other intermediate or high incidence areas of the world highlights this hypothesis. Our data did not support a possible ole of HPV in this series of cases. Further studies are needed to assess and compare the molecular patterns of ESCC from Kenya with those of high-incidence areas such as China or Central Asia.

  9. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Mansouri, Larry; Grabowski, Pawel; Degerman, Sofie;

    2013-01-01

    Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic...... markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P...

  10. A New Cell-Free System to Study BRCA1 Function

    Science.gov (United States)

    2015-05-01

    suppress genome instability by promoting homologous recombination , which it does in part by helping to recruit BRCA2 and the RAD51 recombinase to...BRCA1S1379F-BARD1, BRCA1I26A-BARD1, or BRCA1ΔCC-BARD1 and measure the effects on ICL repair. Re-addition of recombinant wild type BRCA1-BARD1 to...has been assumed that BRCA1’s primary role in ICL repair is to support homologous recombination . However, our data strongly support the novel concept

  11. Effect of the BRCA1-SIRT1-EGFR axis on cisplatin sensitivity in ovarian cancer.

    Science.gov (United States)

    Li, Da; Wu, Qi-Jun; Bi, Fang-Fang; Chen, Si-Lei; Zhou, Yi-Ming; Zhao, Yue; Yang, Qing

    2016-01-01

    There is accumulating evidence that breast cancer 1 (BRCA1), sirtuin 1 (SIRT1), and epidermal growth factor receptor (EGFR) help to modulate cisplatin cytotoxicity. The role of dynamic crosstalk among BRCA1, SIRT1, and EGFR in cisplatin sensitivity remains largely unknown. We found that BRCA1, SIRT1, and EGFR levels were increased in cisplatin-resistant ovarian cancers compared with those in cisplatin-sensitive ovarian cancers. Hypomethylation in the BRCA1 promoter was associated with BRCA1 activation, significantly elevated SIRT1 levels, decreased nicotinamide adenine dinucleotide (NAD)-mediated SIRT1 activity, and decreased EGFR levels. Treatment with 5 and 10 μg/ml cisplatin induced a gradual increase in BRCA1 and SIRT1 levels and a gradual decrease in NAD levels and NAD-mediated SIRT1 activity, whereas EGFR levels were increased or decreased by treatment with 5 or 10 μg/ml cisplatin, respectively. The overexpression of SIRT1 or the enhancement of SIRT1 activity synergistically enhanced the BRCA1-mediated effects on EGFR transcription. In contrast, the knockdown of SIRT1 or the inhibition of SIRT1 activity inhibited the BRCA1-mediated effects on EGFR transcription. BRCA1 regulates EGFR through a BRCA1-mediated balance between SIRT1 expression and activity. Those results improve our understanding of the basic molecular mechanism underlying BRCA1-related cisplatin resistance in ovarian cancer.

  12. Ispartada meme kanserli hastalarda BRCA1 ve BRCA2 ekspresyonu

    OpenAIRE

    Çandır, Özden; Karahan, Nermin; Bülbül, Mahmut; Kılınç, Fahriye; Başpınar, Şirin

    2009-01-01

    SüleymanDemirel Üniversitesi TIP FAKÜLTESİ DERGİSİ: 2005 Haziran; 12(2) Ispartada meme kanserli hastalarda BRCA1 ve BRCA2 ekspresyonu Özden Çandır, Nermin Karahan, Mahmut Bülbül, Fahriye Kılınç, Şirin Başpınar, Özet Amaç: BRCA1 ve BRCA2 genlerindeki mutasyonlar, kalıtımsal meme kanserlerinde predispozan faktördür. Sporadik meme kanserlerinde de BRCA proteini ekpresyonunda kayıp olduğu görülmektedir. Bu çalışmada amacımız, Isparta'da meme kanserleri...

  13. BP1, an Isoform of DLX4 Homeoprotein, Negatively Regulates BRCA1 in Sporadic Breast Cancer

    Directory of Open Access Journals (Sweden)

    Brian J. Kluk, Yebo Fu, Trina A. Formolo, Lei Zhang, Anne K. Hindle, Yan-gao Man, Robert S. Siegel, Patricia E. Berg, Chuxia Deng, Timothy A. McCaffrey, Sidney W. Fu

    2010-01-01

    Full Text Available Introduction: Several lines of evidence point to an important role for BP1, an isoform of DLX4 homeobox gene, in breast carcinogenesis and progression. BRCA1 is a well-known player in the etiology of breast cancer. While familial breast cancer is often marked by BRCA1 mutation and subsequent loss of heterozygosity, sporadic breast cancers exhibit reduced expression of wild type BRCA1, and loss of BRCA1 expression may result in tumor development and progression.Methods: The Cister algorithm and Genomatix program were used to identify potential BP1 binding sites in BRCA1 gene. Real-time PCR, Western blot and immunohistochemistry analysis were performed to verify the expression of BRCA1 and BP1 in cell lines and breast cancer tissues. Double-stranded siRNA transfection was carried out for silencing BP1 expression. ChIP and EMSA were used to confirm that BP1 specifically binds to BRCA1.Results: A putative BP1 binding site was identified in the first intron of BRCA1, which was confirmed by chromatin immunoprecipiation and electrophoresis mobility shift assay. BP1 and BRCA1 expression were inversely correlated in breast cancer cell lines and tissues, suggesting that BP1 may suppress BRCA1 transcription through consensus sequence binding.Conclusions: BP1 homeoprotein represses BRCA1 expression through direct binding to its first intron, which is consistent with a previous study which identified a novel transcriptional repressor element located more than 500 base pairs into the first intron of BRCA1, suggesting that the first intron plays an important role in the negative regulation of BRCA1. Although further functional studies are necessary to confirm its repressor activity towards BRCA1, the elucidation of the role of BP1 in breast tumorigenesis holds great promise in establishing BP1 as a novel target for drug therapy.

  14. Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers.

    Science.gov (United States)

    Burga, Laura N; Tung, Nadine M; Troyan, Susan L; Bostina, Mihnea; Konstantinopoulos, Panagiotis A; Fountzilas, Helena; Spentzos, Dimitrios; Miron, Alexander; Yassin, Yosuf A; Lee, Bernard T; Wulf, Gerburg M

    2009-02-15

    Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1-positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n = 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERalpha; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploinsufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers.

  15. Determination of TP53 Mutation for the Prediction of Disease-Free Survival in Adjuvant-Treated Stage Ⅲ Colon Cancer Patients%TP53基因突变检测预测Ⅲ期结肠癌患者的无病生存期

    Institute of Scientific and Technical Information of China (English)

    郑树; 黄凌

    2006-01-01

    @@ 1 文献类型 预测. 2 证据水平 1b. 3 文献来源 Westra JL, Schaapveld M, Hollema H, et al.Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage Ⅲ colon cancer patients [J]. J Clin Oncol, 2005,23(24): 5635-5643.

  16. 延边地区TP53基因-72密码子多态性与宫颈癌预后的相关性%The relationship between TP53-codon 72 polymorphism and prognosis of patients with cervical cancer

    Institute of Scientific and Technical Information of China (English)

    俞星; 金昱

    2015-01-01

    [目的]探讨延边地区TP53基因-72密码子多态性位点(TP53-rs1042522 C>G)与宫颈癌预后的相关性.[方法]选择在延边大学附属医院和延边肿瘤医院接受治疗的宫颈癌患者403例(Ⅰ期21例、Ⅱ期245例、Ⅲ期132例、Ⅳ期3例、分期不详2例),给予抗癌治疗前采集外周静脉血,提取基因组DNA,利用聚合酶链反应-限制性片段长度多态性方法对TP53-rs1042522 C>G进行分型.[结果]CC,CG和GG基因型在宫颈癌中的频率分别为23.3%,54.4%和22.3%,CC基因型总生存率显著低于GG,CG和CC+ CG基因型(P=0.001,P=0.000 1).无病生存率分析结果显示,CC基因型总生存率显著低于GG,CG和CC+ CG基因型(P=0.017,P=0.003),提示CC变异型宫颈癌患者总生存率和无病生存率显著低于其他基因型.[结论] TP53-rs1042522 C>G可作为宫颈癌治疗后预测总生存率和无病生存率的生物标志物.

  17. Study on associations of genetic polymorphisms of vitamin D receptor,pepsinogen C and Tp53 with the risk of breast cancer%维生素D受体基因、胃蛋白酶原C基因及TP53基因多态性与乳腺癌相关研究

    Institute of Scientific and Technical Information of China (English)

    张海超; 刘德权; 王茂华; 王建逵; 梁英; 叶挺; 程思俊; 张卓尼

    2011-01-01

    乳腺癌的发病往往是外界各种不良因素及个体基因长期共同作用的结果,在众多因素中基因多态性是造成个体差异非常重要的一方面.通过国内外的病例对照研究我们发现维生素D受体基因、胃蛋白酶原C基因及TP53基因多态性与乳腺癌相关研究是目前国外的研究热点.通过对维生素D受体基因、胃蛋白酶原C基因及TP53基因多态性的研究可使我们进一步了解乳腺癌的病因.%Breast carcinoma is a multifactor disorder, that is thought to result from an interaction between genetic background and environmental factors, among the many factors contributing to the individual difference, gene polymorphism is a matter of special importance. With the present situation and development of study of gene polymorphism, we find that the case-control study on the associations of genetic polymorphisms of vitamin D receptor, pepsinogen C and TP53 with the risk of breast cancer, which is becoming a hot point. Advance study on gene polymorphism of vitamin D receptor, pepsinogen C and TP53 can throw new light on the cause of the disease.

  18. Association of polymorphism in TP53 gene with susceptibility and radiation sensitivity of non-small-cell-lung cancer in Chinese population%TP53基因多态性与非小细胞肺癌易感性及辐射敏感性的关系

    Institute of Scientific and Technical Information of China (English)

    邵国光; 刘林林; 许传杰

    2005-01-01

    目的:研究中国北方人非小细胞肺癌(NSCLC)的易感性和放疗敏感性与TP53基因多态性的关系.方法:采用病例对照研究方法,通过合成序列特异性引物(PCR-RFLP)方法检测88例NSCLC患者及112例健康对照者的TP53基因的基因型,观察不同基因型患者的放射治疗效果,筛检与辐射敏感性相关的基因型.结果:NSCLC组的C/C等位基因频率明显高于对照组(χ2=5.65,P=0.017),NSCLC组的C/C基因型频率明显高于对照组(χ2=9.33,P=0.0023),C/C纯合子患非小细胞肺癌的相对危险度为2.43(1.32~4.51),G/G纯合子患肺癌的相对危险度为0.90(0.46~1.75).TP53基因多态性与非小细胞肺癌患者的辐射敏感性无关联.结论:TP53基因的C/C基因型为非小细胞肺癌的易感基因,但尚未发现该基因型与NSCLC的辐射敏感性相关.

  19. Mutation analysis of genes that control the G1/S cell cycle in melanoma: TP53, CDKN1A, CDKN2A, and CDKN2B

    Directory of Open Access Journals (Sweden)

    López-Nevot Miguel

    2005-04-01

    Full Text Available Abstract Background The role of genes involved in the control of progression from the G1 to the S phase of the cell cycle in melanoma tumors in not fully known. The aim of our study was to analyse mutations in TP53, CDKN1A, CDKN2A, and CDKN2B genes in melanoma tumors and melanoma cell lines Methods We analysed 39 primary and metastatic melanomas and 9 melanoma cell lines by single-stranded conformational polymorphism (SSCP. Results The single-stranded technique showed heterozygous defects in the TP53 gene in 8 of 39 (20.5% melanoma tumors: three new single point mutations in intronic sequences (introns 1 and 2 and exon 10, and three new single nucleotide polymorphisms located in introns 1 and 2 (C to T transition at position 11701 in intron 1; C insertion at position 11818 in intron 2; and C insertion at position 11875 in intron 2. One melanoma tumor exhibited two heterozygous alterations in the CDKN2A exon 1 one of which was novel (stop codon, and missense mutation. No defects were found in the remaining genes. Conclusion These results suggest that these genes are involved in melanoma tumorigenesis, although they may be not the major targets. Other suppressor genes that may be informative of the mechanism of tumorigenesis in skin melanomas should be studied.

  20. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations.

    Science.gov (United States)

    Pujals, Anaïs; Favre, Loëtitia; Pioche-Durieu, Catherine; Robert, Aude; Meurice, Guillaume; Le Gentil, Marion; Chelouah, Sonia; Martin-Garcia, Nadine; Le Cam, Eric; Guettier, Catherine; Raphaël, Martine; Vassilev, Lyubomir T; Gaulard, Philippe; Codogno, Patrice; Lipinski, Marc; Wiels, Joëlle

    2015-01-01

    The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy.

  1. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations.

    Science.gov (United States)

    Liu, Xiao-Yang; Gerges, Noha; Korshunov, Andrey; Sabha, Nesrin; Khuong-Quang, Dong-Anh; Fontebasso, Adam M; Fleming, Adam; Hadjadj, Djihad; Schwartzentruber, Jeremy; Majewski, Jacek; Dong, Zhifeng; Siegel, Peter; Albrecht, Steffen; Croul, Sidney; Jones, David T W; Kool, Marcel; Tonjes, Martje; Reifenberger, Guido; Faury, Damien; Zadeh, Gelareh; Pfister, Stefan; Jabado, Nada

    2012-11-01

    Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

  2. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the path...

  3. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers : Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    NARCIS (Netherlands)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Amanda; Robson, Mark; Sherman, Mark; Mulligan, Anna Marie; Couch, Fergus J.; Engel, Christoph; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O'Malley, Frances; John, Esther M.; Janavicius, Ramunas; Tihomirova, Laima; Hansen, Thomas V. O.; Nielsen, Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benitez, Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; Peshkin, Beth N.; Caldes, Trinidad; de la Hoya, Miguel; Canadas, Carmen; Heikkinen, Tuomas; Heikkila, Paivi; Aittomaki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques; Montagna, Marco; Agata, Simona; D'Andrea, Emma; Yan, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; Henriksson, Karin; Steele, Linda; Neuhausen, Susan L.; Nussbaum, Robert; Beattie, Mary; Odunsi, Kunle; Sucheston, Lara; Gayther, Simon A.; Nathanson, Kate; Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2012-01-01

    Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the patholo

  4. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Ake; Karlsson, Per; Askmalm, Marie Stenmark; Bustinza, Gisela Barbany; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benitez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M. W.; Ausems, Margreet G. E. M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J. J. P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnes; Berthet, Pascaline; Sobol, Hagay; Eisinger, Francois; de Paillerets, Brigitte Bressac; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V. O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly in

  5. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

    NARCIS (Netherlands)

    Mavaddat, N.; Barrowdale, D.; Andrulis, I.L.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Spurdle, A.; Robson, M.; Sherman, M.; Mulligan, A.M.; Couch, F.J.; Engel, C.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Southey, M.C.; Terry, M.B.; Goldgar, D.; O'Malley, F.; John, E.M.; Janavicius, R.; Tihomirova, L.; Hansen, T.V.; Nielsen, F.C.; Osorio, A.; Stavropoulou, A.; Benitez, J.; Manoukian, S.; Peissel, B.; Barile, M.; Volorio, S.; Pasini, B.; Dolcetti, R.; Putignano, A.L.; Ottini, L.; Radice, P.; Hamann, U.; Rashid, M.U.; Hogervorst, F.B.L.; Kriege, M.; Luijt, R.B. van der; Peock, S.; Frost, D.; Evans, D.G.; Brewer, C.; Walker, L.; Rogers, M.T.; Side, L.E.; Houghton, C.; Weaver, J.; Godwin, A.K.; Schmutzler, R.K.; Wappenschmidt, B.; Meindl, A.; Kast, K.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Preisler-Adams, S.; Varon-Mateeva, R.; Schonbuchner, I.; Gevensleben, H.; Stoppa-Lyonnet, D.; Belotti, M.; Barjhoux, L.; Isaacs, C.; Peshkin, B.N.; Caldes, T.; Hoya, M. de la; Canadas, C.; Heikkinen, T.; Heikkila, P.; Aittomaki, K.; Blanco, I.; Lazaro, C.; Brunet, J.; Agnarsson, B.A.; Arason, A.; Barkardottir, R.B.; Dumont, M.; Simard, J.; Montagna, M.; Agata, S.; D'Andrea, E.; Yan, M.; Fox, S.; Rebbeck, T.R.; Rubinstein, W.; Tung, N.; Garber, J.E.; Wang, X.; Fredericksen, Z.; Pankratz, V.S.; Lindor, N.M.; Szabo, C.; Offit, K.; Sakr, R.; Gaudet, M.M.; Singer, C.F.; Tea, M.K.; Rappaport, C.; Mai, P.L.; Greene, M.H.; Sokolenko, A.; Imyanitov, E.; Toland, A.E.; Senter, L.; Sweet, K.; Thomassen, M.; Gerdes, A.M.; Kruse, T.; Caligo, M.; Aretini, P.; Rantala, J.; Wachenfeld, A. von; Henriksson, K.; Steele, L.; Neuhausen, S.L.; Nussbaum, R.; Beattie, M.; Odunsi, K.; Sucheston, L.; Gayther, S.A.; Nathanson, K.; Gross, J.; Walsh, C.; Karlan, B.; Chenevix-Trench, G.; Easton, D.F.; Antoniou, A.C.; Ligtenberg, M.J.L.; Hoogerbrugge, N.

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the patholo

  6. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics.

    Science.gov (United States)

    Wagner, T M; Möslinger, R A; Muhr, D; Langbauer, G; Hirtenlehner, K; Concin, H; Doeller, W; Haid, A; Lang, A H; Mayer, P; Ropp, E; Kubista, E; Amirimani, B; Helbich, T; Becherer, A; Scheiner, O; Breiteneder, H; Borg, A; Devilee, P; Oefner, P; Zielinski, C

    1998-07-29

    We identified 17 BRCA1 mutations in 86 Austrian breast and ovarian cancer families (20%) that were screened for mutations by denaturing high-performance liquid chromatography (DHPLC) and the protein truncation test (PTT). Eleven distinct mutations were detected, 4 of them (962del4, 2795del4, 3135del4 and L3376stop) not previously reported in families of non-Austrian origin. In addition, 6 rare missense mutations (allele frequency Cys61Gly (3 times) 5382insC (2 times) and Q1806stop (2 times). Haplotype analysis of the 4 recurrent mutations suggested a common ancestor for each of these. Thirty-four breast cancer cases from 17 families with BRCA1 mutations were further analyzed. We observed a low median age of onset (39.5 years). Sixty-eight percent of all BRCA1 breast cancer cases had negative axillary lymph nodes. This group showed a significant prevalence of a negative estrogen and progesterone receptor status and stage I tumors compared with an age-related, node-negative control group. The prevalence of grade III tumors was marginally significant. Survival analysis either with a control group matched for age (within 5 years), grade, histologic subtype and estrogen receptor status, or with an age-related, node-negative comparison group, showed no statistical difference.

  7. Possible Mechanism of TP53 Accumulation in Nasopharyngeal Carcinoma by Atlas Human Cancer cDNA Expression Array%用 cDNA Array 探讨鼻咽癌组织 TP53积聚的可能原因

    Institute of Scientific and Technical Information of China (English)

    李虹; 韩为农; 张玲; 谢鹭; 姚开泰

    2001-01-01

    目的:用 cDNA Array 比较鼻咽癌组织及正常组织基因表达谱,寻找鼻咽癌组织 TP53积聚的可能原因。方法:( 1) Atlas Human Cancer cDNA Expression Array 7742 1滤膜杂交。( 2) AtlasImage 1.01a分析滤膜杂交结果。( 3) RT PCR反应验证滤膜杂交结果。( 4)免疫组化证实基因在蛋白质水平的表达改变。结果:( 1) 588个肿瘤相关基因中,共有 134个基因表达上调, 88个基因表达下调。( 2)膜上有 TP53调节基因 32种。其中 13种显示差异表达,有 11个表达上调, 2个表达下调。( 3) TP53上游的蛋白激酶基因 ATM和 JNK2表达呈上调趋势。( 4)泛素降解系统的两个基因 ubiquitin conjugating enzyme E2( M74524) ubiquitin conjugating enzyme E2 ( L22005) mRNA在鼻咽癌和正常鼻咽组织内的表达没有明显改变。结论:( 1)在鼻咽癌组织内, TP53的功能失控。( 2) ATM和 JNK极有可能是 TP53积聚的重要原因。

  8. THE RESEARCH PROGRESSION OF TUMOR SUPPRESSOR TP53 AND THE NEW FAMILY MEMBERS TP63 AND TP73%抑癌基因TP53及新家族成员TP63和TP73的研究新进展

    Institute of Scientific and Technical Information of China (English)

    陈中; 张嘉玲; 杨歆萍; 吕海; CARTER Van Waes

    2013-01-01

    抑癌基因TP53在调控细胞周期、细胞凋亡和维持基因组稳定的过程中发挥着重要作用.TP63和TP73是TP53家族中包含的另外两个成员,均具有多种亚型,这些亚型通过自身家族或与其它转录因子家族之间的相互作用,从而对广泛的基因群发挥调控作用.本文将综述TP53及其家族成员TP63、TP73的功能学研究上的最新进展,并将重点介绍我们NIH/NIDCD头颈外科实验室的近期的研究工作所取得的新发现.我们近期的研究结果揭示了在肿瘤炎症的微环境中,存在着一种新的可逆转的动态机制为促炎症细胞因子TNF-α诱导NF-kB c-REL/ANp 63α相互作用,协同促进细胞增殖、生存、炎症和迁移相关基因群的调控.并在有突变的TP53肿瘤中,这些相互作用同时使肿瘤抑制基因TAp73的功能失活,促进肿瘤对TNF-α的抗药性和细胞生存.我们的研究阐述了炎症与肿瘤发生、发展的新机制,其中NF-kB和TP53两大转录因子家族基因的相互作用起到了关键性作用.这一新发现或许可为肿瘤的诊断、治疗和预防提供新的策略.

  9. The Correlations between MGMT Promoter Methylation, NF-κB, TP53 and MGMT Protein Expression in Human Primary Glioblastomas%人原发胶质母细胞瘤组织中NF-κB、TP53及MGMT甲基化与MGMT蛋白表达的相关性研究

    Institute of Scientific and Technical Information of China (English)

    张钧; 滕颖; 齐雪岭; 李岩; 于春江; 张俊平

    2013-01-01

    背景与目的:胶质瘤化疗敏感性与一些分子表达相关.本研究检测和分析原发性胶质母细胞瘤(glioblastoma multiforme,GBM)患者肿瘤组织中核因子κB(NF-κB)、突变型P53(TP53)及O6甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)基因启动子区甲基化与MGMT蛋白表达的相关性,以探讨调控MGMT蛋白表达的作用机制.方法:采用甲基化特异性PCR方法(methylation specific PCR,MSP)检测我院收治的120例原发性GBM患者肿瘤组织标本MGMT基因启动子区甲基化;采用免疫组化方法检测NF-κB、TP53、MGMT蛋白表达情况.采用SPSS17.0软件及Spearman相关系数分析方法进行统计学分析.结果:免疫组化表明NF-κB、TP53表达与MGMT表达呈正相关(r=-0.244,r=-0.271,P均<0.05),NF-κB与TP53表达亦呈正相关(r=0.329,P<0.05).MSP结果显示MGMT基因启动子区甲基化率与MGMT蛋白表达强度无相关性.结论:转录因子NF-κB与TP53对原发性GBM肿瘤组织中MGMT蛋白表达可能存在正调控作用,而MGMT基因启动子区甲基化率与MGMT蛋白表达强度无相关性.

  10. 口腔鳞癌浸润前沿、中心和癌间质TP53、RPS6基因变化的研究%The TP53 and RPS6 alterations at the invasive tumor front, center and stroma of oral squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    王新红; 樊明文; 孙志军; 陈新明; 王丽; 李原

    2007-01-01

    目的 检测微卫星位点TP53、RPS6在口腔鳞癌浸润前沿、中心及癌间质细胞中的基因变化,揭示口腔鳞癌的生物学行为.方法 运用激光捕获显微切割分别获取同一肿瘤浸润前沿、中心及癌间质足量的细胞,提取DNA,PCR-变性PAGE电泳检测TP53和RPS6位点的基因变化.结果 浸润前沿、中心和癌间质中TP53和RPS6存在杂合性缺失(loss of heterozygosity,LOH)和微卫星不稳定(microsatellite instability,MI),发生率从23.5%(4/17)到64.7%(11/17),且LOH和(或)MI的模式存在不同.上皮TP53和RPS6的LOH和MI发生率分别为70.6%(12/17)和64.7%(11/17),间质为43.8%(7/16)和23.5%(4/17),癌实质较间质发生率高,差异有统计学意义(P<0.05).浸润前沿TP53的LOH发生率为64.7%(11/17),中心为60.0%(9/15).RPS6在浸润前沿的LOH和MI为58.8%(10/17),中心为29.4%(5/17).两位点总发生率分别为62.5%(20/32)和44.1%(15/34),差异有统计学意义(P<0.05).结论 部分口腔鳞癌样本浸润前沿、中心和肿瘤间质的基因变化不同,癌实质基因变化率与肿瘤分化程度有关.

  11. Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

    Science.gov (United States)

    Chen, Kuan-Hui Ethan; Walker, Ameae M

    2016-06-01

    Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21.

  12. The role of the breast cancer susceptibility gene 1 (BRCA1 in sporadic epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Mueller Christopher R

    2003-10-01

    Full Text Available Abstract Mutations within the BRCA1 tumor suppressor gene occur frequently in familial epithelial ovarian carcinomas but they are a rare event in the much more prevalent sporadic form of the disease. However, decreased BRCA1 expression occurs frequently in sporadic tumors, and the magnitude of this decrease has been correlated with increased disease progression. The near absence of somatic mutations consequently suggests that there are alternative mechanisms that may contribute to the observed loss of BRCA1 in sporadic tumors. Indeed, both allelic loss at the BRCA1 locus and epigenetic hypermethylation of the BRCA1 promoter play an important role in BRCA1 down-regulation; yet these mechanisms alone or in combination do not always account for the reduced BRCA1 expression. Alternatively, misregulation of specific upstream factors that control BRCA1 transcription may be a crucial means by which BRCA1 is lost. Therefore, determining how regulators of BRCA1 expression may be co-opted during sporadic ovarian tumorigenesis will lead to a better understanding of ovarian cancer etiology and it may help foster the future development of novel therapeutic strategies aimed at halting ovarian tumor progression.

  13. BRCA1 and its phosphorylation involved in caffeine-inhibitable event upstream of G2 checkpoint

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Caffeine,which specifically inhibits ATM/ATR kinases,efficiently abrogates the ionizing radiation(IR)-induced G2 arrest and increases the sensitivity of various tumor cells to IR.Mechanisms for the effect of caffeine remain to be elucidated.As a target of ATM/ATR kinases,BRCA1 becomes activated and phosphorylated in response to IR.Thus,in this work,we investigated the possible role of BRCA1 in the effect of caffeine on G2 checkpoint and observed how BRCA1 phosphorylation was regulated in this process.For these purposes,the BRCA1 protein level and the phosphorylation states were analyzed by Western blotting by using an antibody against BRCA1 and phospho-specific antibodies against Ser-1423 and Ser-1524 residues in cells exposed to a combination of IR and caffeine.The results showed that caffeine down-regulated IR-induced BRCA1 expression and specifically abolished BRCA1 phosphorylation of Ser-1524,which was followed by an override of G2 arrest by caffeine.In addition,the ability of BRCA1 to transactivate p21 may be required for MCF-7 but not necessary for Hela response to caffeine.These data suggest that BRCA1 may be a potential target of caffeine.BRCA1 and its phosphorylation are most likely to be involved in the caffeine-inhibitable event upstream of G2 arrest.

  14. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng, E-mail: zhanglf@cnilas.org

    2013-10-15

    The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21{sup waf1}/cip1 and p57{sup kip2}, which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21{sup waf1}/cip1 and p57{sup kip2}. - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21{sup waf1/cip1} and p57{sup kip2}.

  15. Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations.

    Science.gov (United States)

    Yao, Lu; Sun, Jie; Zhang, Juan; He, Yingjian; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-04-01

    BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

  16. Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells.

    Science.gov (United States)

    Busschots, Steven; O'Toole, Sharon; O'Leary, John J; Stordal, Britta

    2015-08-01

    A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients.

  17. Expression of the novel gene NM23-H1B in ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    LI Wen; LIU Yan; JIN Zhi-Jun; FENG You-ji; XU Ling-ling

    2005-01-01

    Objective:To study the expression of the human novel gene NM23-H1B in ovarian cancer. Methods: Totally 24 samples from patients with epithelial ovarian tumor at different clinical stages and 4 from normal ovaries were examined for NM23-H1B mRNA expression by RT-PCR and Northern blot. Results: All samples expressed NM23-H1B mRNA through RT-PCR, while the level of expression in ovarian tumor was higher than that of normal ovary. The results of Northern blot showed that NM23-H1B was overexpressed in ovarian cancer while lowexpressed in normal ovary or low malignant potential (LMP). The level of expression at early stage cancer(stageⅠand Ⅱ) was higher than those in advanced cancer(stage Ⅲ and Ⅳ). In early stage carcinoma, the expression level was involved in the differentiation of tumor cell, and well-differentiated cancer expressed NM23-H1B mRNA in comparatively higher level. Conclusion: The novel gene NM23-N1B is closely correlated with the ovarian cancer.

  18. Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes.

    Science.gov (United States)

    Svobodova, Karla; Zemanova, Zuzana; Lhotska, Halka; Novakova, Milena; Podskalska, Lucie; Belickova, Monika; Brezinova, Jana; Sarova, Iveta; Izakova, Silvia; Lizcova, Libuse; Berkova, Adela; Siskova, Magda; Jonasova, Anna; Cermak, Jaroslav; Michalova, Kyra

    2016-03-01

    Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and

  19. Differential expression of ID4 and its association with TP53 mutation, SOX2, SOX4 and OCT-4 expression levels.

    Directory of Open Access Journals (Sweden)

    Thais Fernanda de Almeida Galatro

    Full Text Available Inhibitor of DNA Binding 4 (ID4 is a member of the helix-loop-helix ID family of transcription factors, mostly present in the central nervous system during embryonic development, that has been associated with TP53 mutation and activation of SOX2. Along with other transcription factors, ID4 has been implicated in the tumorigenic process of astrocytomas, contributing to cell dedifferentiation, proliferation and chemoresistance. In this study, we aimed to characterize the ID4 expression pattern in human diffusely infiltrative astrocytomas of World Health Organization (WHO grades II to IV of malignancy (AGII-AGIV; to correlate its expression level to that of SOX2, SOX4, OCT-4 and NANOG, along with TP53 mutational status; and to correlate the results with the clinical end-point of overall survival among glioblastoma patients. Quantitative real time PCR (qRT-PCR was performed in 130 samples of astrocytomas for relative expression, showing up-regulation of all transcription factors in tumor cases. Positive correlation was found when comparing ID4 relative expression of infiltrative astrocytomas with SOX2 (r = 0.50; p<0.005, SOX4 (r = 0.43; p<0.005 and OCT-4 (r = 0.39; p<0.05. The results from TP53 coding exon analysis allowed comparisons between wild-type and mutated status only in AGII cases, demonstrating significantly higher levels of ID4, SOX2 and SOX4 in mutated cases (p<0.05. This pattern was maintained in secondary GBM and further confirmed by immunohistochemistry, suggesting a role for ID4, SOX2 and SOX4 in early astrocytoma tumorigenesis. Combined hyperexpression of ID4, SOX4 and OCT-4 conferred a much lower (6 months median survival than did hypoexpression (18 months. Because both ID4 alone and a complex of SOX4 and OCT-4 activate SOX2 transcription, it is possible that multiple activation of SOX2 impair the prognosis of GBM patients. These observational results of associated expression of ID4 with SOX4 and OCT-4 may be used as a

  20. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.

    Science.gov (United States)

    Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Geyer, Felipe C; De Filippo, Maria R; Eberle, Carey A; Akram, Muzaffar; Fusco, Nicola; Ichihara, Shu; Sakr, Rita A; Yatabe, Yasushi; Vincent-Salomon, Anne; Rakha, Emad A; Ellis, Ian O; Wen, Y Hannah; Weigelt, Britta; Schnitt, Stuart J; Reis-Filho, Jorge S

    2016-04-01

    Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute

  1. BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer.

    Science.gov (United States)

    Gorski, Julia J; James, Colin R; Quinn, Jennifer E; Stewart, Gail E; Staunton, Kieran Crosbie; Buckley, Niamh E; McDyer, Fionnuala A; Kennedy, Richard D; Wilson, Richard H; Mullan, Paul B; Harkin, D Paul

    2010-08-01

    Expression profiling of BRCA1-deficient tumours has identified a pattern of gene expression similar to basal-like breast tumours. In this study, we examine whether a BRCA1-dependent transcriptional mechanism may underpin the link between BRCA1 and basal-like phenotype. In methods section, the mRNA and protein were harvested from a number of BRCA1 mutant and wild-type breast cancer cell lines and from matched isogenic controls. Microarray-based expression profiling was used to identify potential BRCA1-regulated transcripts. These gene targets were then validated (by in silico analysis of tumour samples) by real-time PCR and Western blot analysis. Chromatin immunoprecipitation (ChIP) assays were used to confirm recruitment of BRCA1 to specific promoters. In results, we demonstrate that functional BRCA1 represses the expression of cytokeratins 5(KRT5) and 17(KRT17) and p-Cadherin (CDH3) in HCC1937 and T47D breast cancer cell lines at both mRNA and protein level. ChIP assays demonstrate that BRCA1 is recruited to the promoters of KRT5, KRT17 and CDH3, and re-ChIP assays confirm that BRCA1 is recruited independently to form c-Myc and Sp1 complexes on the CDH3 promoter. We show that siRNA-mediated inhibition of endogenous c-Myc (and not Sp1) results in a marked increase in CDH3 expression analogous to that observed following the inhibition of endogenous BRCA1. The data provided suggest a model whereby BRCA1 and c-Myc form a repressor complex on the promoters of specific basal genes and represent a potential mechanism to explain the observed overexpression of key basal markers in BRCA1-deficient tumours.

  2. BRCA1在胃癌中的研究进展%Progress in research of the BRCA1 gene in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    钟国栋; 余英豪

    2013-01-01

    Chemotherapy occupies an important position in the treatment of gastric cancer.Platinum drugs are commonly chemotherapy drugs for gastric cancer; however,sensitivity to these drugs varies among different patients.The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene that is associated with sensitivity to platinum drugs.At present,the research on the BRCA1 gene is mainly focused on breast cancer,and there have been fewer studies on gastric cancer.This paper will give an overview of the structure and function of the BRCA1 gene and the relationship between BRCA1 and gastric cancer.%化疗在胃癌的治疗中占有重要地位,铂类药物是常用的胃癌化疗药物之一,不同个体对铂类药物的敏感性差异很大.乳腺癌易感基因l(breast cancer susceptibility gene 1,BRCA1)是一种抑癌基因,与铂类药物的敏感性有关.目前针对BRCA1的研究多集于乳腺癌方面,而在胃癌中的研究很少.本文就BRCA1的结构与功能,BR CA1与胃癌关系的相关研究进展进行综述.

  3. NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

    Directory of Open Access Journals (Sweden)

    Ambs Stefan

    2010-05-01

    Full Text Available Abstract Background A recent genome-wide association study (GWAS has identified a single nucleotide polymorphism (SNP rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER+ versus ER- cancer. Results We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059. In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG of rs11249433 when compared to the non-risk AA genotype (p = 0.0062. Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015, but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.

  4. Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bastide, K.; Guilly, M.N.; Lectard, B.; Levalois, C.; Chevillard, S. [CEA, DSV, IRCM, SREIT, Laboratoire de Cancerologie Experimentale, BP6, Fontenay-aux-Roses Cedex F-92265 (France); Bernaudin, J.F. [Service d' Histologie-Biologie Tumorale, Unite Propre de Recherche de l' Enseignement Superieur EA 3499, Universite Paris 6, Hopital Tenon, Paris F-75020 (France); Joubert, Ch. [CEA, DSV, I2BM, MIRCEN, Laboratoire de Biologie Appliquee, BP6, Fontenay-aux-Roses Cedex F-92265 (France); Malfoy, B. [Institut Curie, Centre de Recherche, Paris F-75248 (France); CNRS, UMR 7147, Paris F-75248 (France); Universite Paris VI, Paris F-75248 (France)

    2009-07-01

    Inhalation of radon is closely associated with an increased risk of lung cancers. While the involvement of Ink4a in lung tumor development has been widely described, the tumor suppressor gene has not been studied in radon-induced lung tumors. In this study, loss of heterozygosity (LOH) analysis of the Cdkn2a locus, common to the Ink4a and Arf genes, was performed on 33 radon-induced rat lung tumors and showed a DNA loss in 50% of cases. The analysis of p16Ink4a protein expression by immunohistochemistry revealed that 50% of the tumors were negative for this protein. Looking for the origin of this lack of expression, we observed a low frequency of homozygous deletion (6%), a lack of mutation, an absence of correlation between promoter methylation and Ink4a mRNA expression and no correlation between LOH and protein expression. However, a tendency for an inverse correlation between p16Ink4a and pRb protein expression was observed. The expressions of p19Arf, Mmd2 and Mdm4 were not deregulated and only 14% of the tumors were mutated for Tp53. These results indicated that Ink4a/Cdk4/Rb1 pathway deregulation, more than Arf/Mdm2/Tp53 pathway, has a major role in the development of these tumors through p16Ink4a deregulation. However, all known mechanisms of inactivation of the pathway do not play a recurrent role in these tumors and the actual origin of the lack of p16Ink4a protein expression remains to be established. (author)

  5. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F

    2007-01-01

    oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk...... was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk...

  6. Reduced NM23 Protein Level Correlates With Worse Clinicopathologic Features in Colorectal Cancers

    Science.gov (United States)

    Yang, Tian; Chen, Bo-Zan; Li, Dan-Feng; Wang, Huai-Ming; Lin, Xiao-Sheng; Wei, Hong-Fa; Zeng, Yong-Ming

    2016-01-01

    Abstract The clinical value of a prominent metastasis suppressor, nonmetastatic protein 23 (NM23), remains controversial. In this study, we examined the correlation between NM23 protein levels and the clinicopathologic features of colorectal cancers (CRC), and assessed the overall prognostic value of NM23 for CRC. Embase, PubMed, Web of Science, and other scientific literature databases were exhaustively searched to identify relevant studies published prior to June 31, 2015. The methodological qualities of selected studies were scored based on the critical appraisal skills program (CASP) criteria, as independently assessed by 2 reviewers. NM23 protein levels in tumor tissues of CRC patients were examined in relation to Dukes stage, differentiation grade, T-stage, lymph node metastasis status, and overall survival (OS). STATA software version 12.0 (Stata Corp, College Station, TX) was used for statistical analysis of data pooled from selected studies. Nineteen cohort studies met the inclusion criteria for present study and contained a combined total of 2148 study subjects. Pooled odd ratios (ORs) for NM23 expression revealed that reduced NM23 protein levels in CRC tumor tissues correlated with Dukes stage C and D (OR = 1.89, 95% CI: 1.06–3.39, P = 0.032), poor differentiation grades (OR = 1.41, 95% CI: 1.03–1.94, P = 0.032), and positive lymph node metastasis status (OR = 3.21, 95% CI: 1.95–5.29, P < 0.001). On the other hand, no such correlations were evident with T-stage T3-4 (OR = 1.56, 95% CI: 0.60–4.06, P = 0.367) or OS (OR = 0.79, 95% CI: 0.58–1.08, P = 0.138). Our analysis of pooled data found that NM23 expression is reduced in CRC tissues and low NM23 levels tightly correlate with higher Dukes stages, poorer differentiation grade, and positive lymph node metastases. However, NM23 levels did not influence the OS in CRC patients. PMID:26825905

  7. BRCA1 Gene Mutations in Chinese Families with Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Yurong Shi; Chenbin Li; Ruifang Niu; Xishan Hao; Xiangcheng Zhi; Liansheng Ning

    2005-01-01

    OBJECTIVE To investigate the frequency of BRCA1 gene mutations in breast cancer families in China.METHODS Genomic DNA was obtained by conventional techniques from the peripheral blood mononuclear cells collected from 94 persons derived from 45 breast cancer families. All participants gave written informed consent. The mutations in the BRCA1 gene were detected by the polymerase chain reaction and single stranded conformation polymorphism(PCR-SSCP). Then , the samples of interest were sent for direct DNA sequencing.RESULTS No mutation sites were found in exon 2 or 20 by DNA sequencing.Eight sites were found in exon 11 such as 2201C>T (Ser694Ser),3232A>G(Glu 1038Gly), 2201C >A/G (Ser694Arg), 2731C >T (Pro871Leu),2086A >T(Asn591lle) and three sites of 1584G>T (Glu424Stop). Three mutation sites were found in exon 16 which included 5106A >G (Met1663Val),5208delT(Stop 1639) and 4956A>G (Ser 1613Gly).CONCLUSION These mutation sites may be related to breast cancer, but more investigation is needed to determine whether the mutation sites are hot spots of mutations in Chinese familial breast cancer patients.

  8. Founder mutations in BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Ferla, R; Calò, V; Cascio, S; Rinaldi, G; Badalamenti, G; Carreca, I; Surmacz, E; Colucci, G; Bazan, V; Russo, A

    2007-06-01

    BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance.

  9. The Research and Application of TP53 Family mRNA Sequences Based on the Fuzzy Comprehensive Evaluation%基于模糊综合评价方法对TP53家族的mRNA序列的分析及应用

    Institute of Scientific and Technical Information of China (English)

    孔娟娟; 王其强; 朱平

    2012-01-01

    p53 protein plays an important role in the human body of tumor. It has become the current focus of cancer treatment. This paper uses the mathematical method of fuzzy comprehensive evaluation by establishing membership functions to analyze TP53, TP63 and TP73 mRNA sequences and the protein sequence. And it discusses the different-bases (a,c,g, u(t)) condons of the end which have effects on the hydrophobicity of amino acids of human p53, p63 and p73 tumor proteins. The result shows that the codon ending with c has the greatest influence on the hydrophobicity of ammo acids in human TP53, TP63 and TP73 mRNA sequences, the codon ending with u(t) has the relatively greater influence, the codon ending with g has the moderate influence and the codon ending with a has the weakest influence.%p53蛋白在人体肿瘤当中具有重要作用,它已成为癌症治疗的焦点.本文利用数学中模糊综合评价的方法通过建立隶属函数,对人类TP53、TP63以及TP73的mRNA序列及其蛋白质序列进行了分析,讨论了以不同碱基(a,c,g'u(t))结尾的密码子对它们的氨基酸亲疏水性的影响程度.结果表明:以碱基c结尾的密码子对TP53、TP63和TP73的氨基酸的亲疏水性的影响程度为非常强,以碱基u(t)结尾的密码子对其影响程度为强,以碱基g结尾的密码子对其影响程度为中,以碱基a结尾的密码子对其影响程度为弱.

  10. Molecular analysis of TP53, D9S1747, D9S162 and RPS6 in oral squamous cell carcinoma%微卫星位点TP53、D9S1747、D9S162及RPS6的杂合性缺失与口腔鳞状细胞癌的关系

    Institute of Scientific and Technical Information of China (English)

    王新红; 张颖颖; 陈新明; 孙志军

    2011-01-01

    Objective To investigate the correlation between the frequency of molecular abnormalities of 4 loci at chromosomal 9p21 (D9S1747 ,D9S162, RPS6) and 17p13 (TP53) and the clinical characteristics and prognosis. Methods The oral squamous cell carcinoma(OSCC) lesions in 71 patients were manually microdessected. Genomic DNA from these lesions and normal lymphnode tissu or peripheral blood of the same patients were extracted using the Watson's tissue kit. The loss of heterozygosity(LOH) and microsatellite instability (MI) of 17p13 and 9p21 were analyzed by PCR-page electrophoresis after DNA extraction. Results LOH and MI were detected in the OSCC of 48 patients (68%). The LOH and MI frequency at chromosomes 17p13 and 9P21 were 56% (35/63) and 59% (40/68) respectively. The LOH and MI frequency at 9p21 was significantly associated with WHO grading ( P < 0.01 ) and lymphonode metastasis (P <0.01 ). The LOH and MI frequency at 17p13 was significantly associated with clinical stage (P < 0.05 ). TP53 genetic aberration and 9p21 genetic aberration were significant prognostic factors for OSCC. The prognosis was poor in the LOH and MI positive group of chromosome 17p13 and 9p21. The frequency of LOH and MI at TP53 was the only independent factor for overall survival ( P < 0.05 ).Conclusions The LOH and MI of 17p13 and 9p21 were related to clinical stage and lymphonode metastasis. LOH of TP53 was an independent prognostic factor for OSCC.%目的 检测微卫星位点TP53(位于17p13区)、D9S1747、D9S162、RPS6(均位于9p21区)在口腔鳞状细胞癌中的杂合性缺失(1oss of heterozygosity,LOH)和微卫星不稳定(microsatellite instability,MI)与临床病理因素及预后的关系.方法 取71例符合纳入标准的口腔鳞状细胞癌病变组织,用基因组DNA快速提取纯化试剂盒提取肿瘤组织及对应正常淋巴结或外周血的DNA,聚合酶链反应(PCR)变性电泳检测上述位点的基因变化.结果 所有位点在癌组

  11. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: a.jha@plymouth.ac.uk [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)

    2016-02-15

    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  12. BRCA1/2-negative hereditary triple-negative breast cancers exhibit BRCAness.

    Science.gov (United States)

    Domagala, Pawel; Hybiak, Jolanta; Cybulski, Cezary; Lubinski, Jan

    2017-04-01

    BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2-associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs.

  13. Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

    Directory of Open Access Journals (Sweden)

    Angela Toss

    2015-01-01

    Full Text Available More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

  14. Should we screen BRCA1 mutation carriers only with MRI? A multicenter study

    NARCIS (Netherlands)

    Obdeijn, I.-M.; Winter-Warnars, G.A.O.; Mann, R.M.; Hooning, M.J.; Hunink, M.G.M.; Tilanus-Linthorst, M.M.

    2014-01-01

    BRCA1 mutation carriers are offered screening with MRI and mammography. Aim of the study was to investigate the additional value of digital mammography over MRI screening. BRCA1 mutation carriers, who developed breast cancer since the introduction of digital mammography between January 2003 and Marc

  15. Promoter mutation and reduced expression of BRCA1 in canine mammary tumors.

    Science.gov (United States)

    Qiu, H B; Sun, W D; Yang, X; Jiang, Q Y; Chen, S; Lin, D G

    2015-12-01

    Breast cancer 1, early onset (BRCA1) is one of the most important genes in human familial breast cancer, which also plays an important role in canine mammary tumors. The objectives of this study were to determine the promoter sequence of canine BRCA1, to investigate its promoter mutation status and to describe BRCA1 expression pattern in canine mammary tumors. The promoter sequence of canine BRCA1 was acquired by aligning human BRCA1 promoter sequence with canine genomic sequence and confirmed by standard promoter activity analysis. Same as human BRCA1 promoter, the CAAT box and G/C box were found in canine BRCA1 promoter. In order to explore the mutation status of the promoter region and to investigate the expression pattern of this gene, 10 normal canine mammary tissues, 15 benign mammary tumors and 15 malignant mammary tumors were used. By sequencing, 46.7% of the malignant mammary tumors were found with a deletion of one cytosine in the promoter region. The mRNA expression of BRCA1 was significantly reduced in benign and malignant mammary tumors (Ppromoter sequence and to describe the promoter mutation status in canine mammary tumors.

  16. Relationship between BRCA1 Expression and Efifcacy of Platinum-based Chemotherapy in Colorectal Cancer

    Institute of Scientific and Technical Information of China (English)

    Xu Guanghui; Li Yu; Liu Yi

    2014-01-01

    Objective:To explore the expression of breast cancer susceptibility gene 1 (BRCA1) in human colorectal cancer and its correlation with efifcacy of platinum-based chemotherapy. Methods:A total of 78 samples from patients with colorectal cancer and receiving platinum-based chemotherapy were selected, and meanwhile 14 cases of normal colonic mucosa samples were selected as a normal control, 12 cases of non-cancerous tissue in colorectal cancer samples were selected as a pericarcinorma control. The expression of BRCA1 in these tissues was detected using immunohistochemical S-P method, and all patients treated with drugs were followed-up for survival time. Results: The positive rate of BRCA1 expression in colorectal cancer tissue was 52.6%, signiifcantly lower than that in the control groups. BRCA1 expression was closely associated with histological differentiation degrees (χ2=14.16,P=0.001), but not with the age, gender, local inifltration, lymph node metastasis and TNM staging. Comparing with those with positive BRCA1 expression, the patients with negative BRCA1 expression after oxaliplatin-based chemotherapy had signiifcantly longer disease-free survival (DFS) (P=0.032). Conclusion:Application of oxaliplatin-based chemotherapy in the patients with negative BRCA1 expression can obtain the survival beneift, and the level of BRCA1 expression can be useful in the selection of chemotherapy regimens and evaluation of prognosis for patients with colorectal cancer after surgery.

  17. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs...

  18. BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage

    NARCIS (Netherlands)

    Nieuwenhuis, B.; Van Assen-Bolt, AJ; van Waarde-Verhagen, Maria; Sijmons, R.J.; van der Hout, A.H.; Bauch, T; Streffer, C; Kampinga, H.H.

    2002-01-01

    Purpose: Up to 90% of hereditary breast cancer cases are linked to germ-line mutations in one of the two copies of the BRCA1 or BRCA2 genes. Brca1 and Brca2 proteins are both involved in the cellular defence against DNA damage, although the precise function of the proteins is still not known. Some s

  19. EGFR Expression Predicts BRCA1 Status in Patients with Breast Cancer

    NARCIS (Netherlands)

    Diest, P.J. van; Groep, P. van der; Wall, E. van der

    2006-01-01

    In their article, Lakhani et al. (1) report on the value of basal phenotype markers for the prediction of BRCA1 status. One of the useful features pointing to ‘‘BRCA1-ness’’ appeared to be high expression of the epidermal growth factor receptor (EGFR). No rationale is given by the authors for includ

  20. Scientists find a new function for breast cancer gene BRCA1

    Science.gov (United States)

    Scientists at the National Cancer Institute (NCI) have uncovered a new function for BRCA1, a gene most commonly associated with hereditary breast and ovarian cancer. Working on mouse cells in the lab, they discovered that BRCA1 suppresses the expression o

  1. BRCA1-Associated Triple-Negative Breast Cancer and Potential Treatment for Ruthenium-Based Compounds.

    Science.gov (United States)

    Hongthong, Khwanjira; Ratanaphan, Adisorn

    2016-01-01

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). The clinicopathological characteristics of TNBC include a high grading, a high rate of cell proliferation and a greater degree of chromosomal rearrangement. Patients with triple-negative breast cancer are more likely to be drug resistant and more difficult to treat, and are also frequently BRCA1 mutants. Methylation of the BRCA1 promoter region is associated with a reduction of the BRCA1 mRNA level. TNBC patients with a methylated BRCA1 had a better disease-free survival compared with those with non-methylated BRCA1. From a therapeutic perspective, the expression level of BRCA1 has been a major determinant of the responses to different classes of chemotherapy. BRCA1-dysfunctional tumors are hypersensitive to DNA damaging chemotherapeutic agents like platinum drugs. Although platinum based drugs are currently widely used as conventional chemotherapeutic drugs in breast cancer chemotherapy, their use has several disadvantages. It is therefore of interest to seek out alternative therapeutic metal-based compounds that could overcome the limitations of these platinum based drugs. Ruthenium-based compounds could be the most promising alternative to the platinum drugs. This review highlights the use of BRCA1 as a predictive marker as well as for a potential drug target for anticancer ruthenium compounds.

  2. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie;

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs aris...

  3. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A;

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  4. BRCA1--conductor of the breast stem cell orchestra: the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer.

    Science.gov (United States)

    Buckley, Niamh E; Mullan, Paul B

    2012-09-01

    Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups.

  5. Tp53 polymorphism and clinical response to platinum-based chemotherapy in advanced non-small cell lung cancer%Tp53单核苷酸多态与晚期NSCLC对铂类药物化疗敏感性关系

    Institute of Scientific and Technical Information of China (English)

    孙宁; 陈宝安; 孙新臣; 成红艳; 冯继锋; 程璐; 陆祖宏

    2010-01-01

    目的 探讨Tp53基因单核苷酸多态性(SNP)与非小细胞型肺癌(NSCLC)患者对铂类药物为主的化疗方案敏感性的关系.方法 用新型三维DNA微阵列检测芯片进行基因分型,测序法验证该芯片结果,比较不同基闪型对化疗敏感性的影响.结果 携带杂合基因型和突变纯合型对化疗敏感性的影响趋势不同;但多种因素校正、分析差异无统计学意义.结论 Tp53 Pro72Arg位点基因状态可能对NSCLC患者化疗敏感性有影响.

  6. Research progress of vitamin D receptor, pepsinogen C, and TP53 gene and its polymorphisms in breast cancer%维生素D受体、胃蛋白酶原C与TP53基因及其多态性与乳腺癌的研究进展

    Institute of Scientific and Technical Information of China (English)

    叶挺; 郑阿莲; 刘德权

    2012-01-01

    维生素D受体(VDR)是类固醇激素和甲状腺受体超家族成员,具有抑制增殖、诱导乳腺癌细胞凋亡的功能;蛋白水解酶是胃蛋白酶原C(PGC)或胃亚蛋白酶的前体,是反映乳腺癌早期复发和死亡的新型预后因素;而TP53基因突变及其过表达见于乳腺癌的早期阶段,是乳腺癌发生的早期事件.基因多态性将会为乳腺癌的治疗提供新的治疗方向.%The vitamin D receptor ( VDR) is a member of the steroid hormones and thyroid hormone receptor super family, can inhibit proliferation and induce apoptosis of breast function; proteolytic enzyme is pepsinogen C (PGC) or gastricsin precursors, a new prognostic factor that reflect the early breast cancer recurrence and death. TP53 gene mutation and over expression can be seen in the early stages of breast cancer and is an early event in breast cancer. Gene polymorphism will provide a new therapeutic direction for the treatment of breast cancer.

  7. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Directory of Open Access Journals (Sweden)

    Sokolenko Anna P

    2009-01-01

    Full Text Available Abstract Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.

  8. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Science.gov (United States)

    Sokolenko, Anna P; Voskresenskiy, Dmitry A; Iyevleva, Aglaya G; Bit-Sava, Elena M; Gutkina, Nadezhda I; Anisimenko, Maxim S; Yu Sherina, Nathalia; Mitiushkina, Nathalia V; Ulibina, Yulia M; Yatsuk, Olga S; Zaitseva, Olga A; Suspitsin, Evgeny N; Togo, Alexandr V; Pospelov, Valery A; Kovalenko, Sergey P; Semiglazov, Vladimir F; Imyanitov, Evgeny N

    2009-01-01

    Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele. PMID:19338681

  9. Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

    DEFF Research Database (Denmark)

    Rattenborg, Thomas; Gjermandsen, Irene; Bonefeld-Jørgensen, Eva Cecilie

    2002-01-01

    in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter...... the expression of BRCA1. METHODS: Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153...... and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals. RESULTS: All three polychlorinated...

  10. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine;

    2009-01-01

    BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated...... in a small number of studies. METHODS: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox...... proportional hazards framework. RESULTS: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had...

  11. Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark

    DEFF Research Database (Denmark)

    Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe;

    2006-01-01

    Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations......, but BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested...... negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which...

  12. ANALYSIS OF A METASTASIZING TESTICULAR MIXED GONADAL STROMAL TUMOR WITH OSTEOSARCOMA COMPONENTS SUGGESTS THAT A MALIGNANT-TUMOR WITH THE HISTOLOGY OF OSTEOSARCOMA MAY DEVELOP WITHOUT PRIMARY INVOLVEMENT OF RB1 AND TP53

    NARCIS (Netherlands)

    REUVEKAMP, PTW; STULP, RP; KOOPS, HS; OOSTERHUIS, JW; SCHEFFER, H; BUYS, CHCM

    1992-01-01

    A malignant stromal tumor of the testis with an osteosarcoma component and five of its metastases mainly containing osteosarcoma have been analyzed for RB1 and TP53 abnormalities. Whereas in the primary tumor and in some of the metastases loss of heterozygosity could not be detected for RB1 or for t

  13. Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer.

    Science.gov (United States)

    Steinmann, D; Bremer, M; Rades, D; Skawran, B; Siebrands, C; Karstens, J H; Dörk, T

    2001-09-14

    Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations.

  14. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain: delimitation and mechanism of three novel BRCA1 rearrangements.

    Directory of Open Access Journals (Sweden)

    Laura Fachal

    Full Text Available In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC that lack point mutations and small indels. In Galicia (Northwest Spain, the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22 seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013 and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014.

  15. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements.

    Science.gov (United States)

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014).

  16. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Marquart, Louise; McGuffog, Lesley;

    2011-01-01

    Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies.......Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies....

  17. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei

    2015-01-01

    IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained...

  18. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Whiley, Phillip J; Thompson, Bryony

    2012-01-01

    Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional...

  19. Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study.

    NARCIS (Netherlands)

    Chang-Claude, J.; Andrieu, N.; Rookus, M.A.; Brohet, R.M.; Antoniou, A.C.; Peock, S.; Davidson, R.; Izatt, L.; Cole, T.; Nogues, C.; Luporsi, E.; Huiart, L.; Hoogerbrugge, N.; Leeuwen, F.E. van; Osorio, A.; Eyfjord, J.; Radice, P.; Goldgar, D.E.; Easton, D.F.

    2007-01-01

    BACKGROUND: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. METHODS: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2

  20. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    NARCIS (Netherlands)

    R. Rebbeck (Timothy); N. Mitra (Nandita); F. Wan (Fei); O. Sinilnikova (Olga); S. Healey (Sue); L. McGuffog (Lesley); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); K.L. Nathanson (Katherine); Y. Laitman (Yael); A. Kushnir (Anya); S. Paluch-Shimon (Shani); R. Berger (Raanan); J. Zidan (Jamal); E. Friedman (Eitan); H. Ehrencrona (Hans); M. Stenmark-Askmalm (Marie); Z. Einbeigi (Zakaria); N. Loman (Niklas); K. Harbst (Katja); J. Rantala (Johanna); B. Melin (Beatrice); D. Huo (Dezheng); O.I. Olopade (Olofunmilayo); J.L. Seldon (Joyce); P.A. Ganz (Patricia); R.L. Nussbaum (Robert L.); S. Chan (Salina); K. Odunsi (Kunle); S.A. Gayther (Simon); S.M. Domchek (Susan); B.K. Arun (Banu); K.H. Lu (Karen); G. Mitchell (Gillian); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); A.K. Godwin (Andrew); S.S. Pathak; E.B. Ross (Eric); M.J. Daly (Mark); A.S. Whittemore (Alice); E.M. John (Esther); A. Miron (Alexander); M.B. Terry (Mary Beth); W.K. Chung (Wendy K.); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); T.V.O. Hansen (Thomas); T. Ramon Y Cajal; A. Osorio (Ana); J. Benítez (Javier); J. Godino (Javier); M.I. Tejada; M. Duran (Mercedes); J.N. Weitzel (Jeffrey); K.A. Bobolis (Kristie A.); S.R. Sand (Sharon); A. Fontaine (Annette); A. Savarese (Antonella); B. Pasini (Barbara); B. Peissel (Bernard); B. Bonnani (Bernardo); D. Zaffaroni (Daniela); F. Vignolo-Lutati (Francesca); G. Scuvera (Giulietta); G. Giannini (Giuseppe); L. Bernard (Loris); M. Genuardi (Maurizio); P. Radice (Paolo); R. Dolcetti (Riccardo); S. Manoukian (Siranoush); V. Pensotti (Valeria); V. Gismondi (Viviana); D. Yannoukakos (Drakoulis); F. Fostira (Florentia); J. Garber (Judy); D. Torres (Diana); M.U. Rashid (Muhammad); U. Hamann (Ute); S. Peock (Susan); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); R. Eeles (Rosalind); R. Davidson (Rosemarie); D. Eccles (Diana); T. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); S. Hodgson (Shirley); P.J. Morrison (Patrick); L.J. Walker (Lisa); M.E. Porteous (Mary); M.J. Kennedy (John); L. Izatt (Louise); L. Adlard; A. Donaldson (Alan); S.D. Ellis (Steve); P. Sharma (Priyanka); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Becker (Alexandra); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); S. Engert (Stefanie); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); C. Mundhenke (Christoph); D. Niederacher (Dieter); M.C. Fleisch (Markus); C. Sutter (Christian); C.R. Bartram; N. Dikow (Nicola); S. Wang-Gohrke (Shan); D. Gadzicki (Dorothea); D. Steinemann (Doris); K. Kast (Karin); M. Beer (Marit); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); B.H.F. Weber (Bernhard); D. Stoppa-Lyonnet (Dominique); M. Belotti (Muriel); M. Gauthier-Villars (Marion); F. Damiola (Francesca); N. Boutry-Kryza (N.); C. Lasset (Christine); H. Sobol (Hagay); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); M.-A. Collonge-Rame; I. Mortemousque (Isabelle); C. Nogues (Catherine); E. Rouleau (Etienne); C. Isaacs (Claudine); A. de Paepe (Anne); B. Poppe (Bruce); K. Claes (Kathleen); K. De Leeneer (Kim); M. Piedmonte (Marion); G. Rodriguez (Gustavo); K. Wakely (Katie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); K.-A. Phillips (Kelly-Anne); T. Caldes (Trinidad); M. de La Hoya (Miguel); A. Romero (Atocha); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A.H. van der Hout (Annemarie); F.B.L. Hogervorst (Frans); S. Verhoef; J.M. Collee (Margriet); C.M. Seynaeve (Caroline); J.C. Oosterwijk (Jan); J.J. Gille (Johan); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); C.M. Kets; M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); P. Devilee (Peter); A.R. Mensenkamp (Arjen); A. Kwong (Ava); E. Olah; J. Papp (Janos); O. Díez (Orland); C. Lazaro (Conxi); E. Darder (Esther); I. Blanco (Ignacio); M. Salinas; A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); G. Sukiennicki (Grzegorz); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); A. Toloczko-Grabarek (Aleksandra); E. Złowocka-Perłowska (Elzbieta); J. Menkiszak (Janusz); A. Arason (Adalgeir); R.B. Barkardottir (Rosa); J. Simard (Jacques); R. Laframboise (Rachel)

    2015-01-01

    textabstractImportance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere asce

  1. Expression and significance of heparanase and nm23-H1 in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ying-Bin Liu; Jian-Wei Wang; Gui-Long Deng; Hai-Jun Li; Xue-Dong Feng; Hao-Ran Qian; Shun-Liang Gao; Xiao-Peng Chen; Shu-You Peng; He-Qing Fang; Yu-Lian Wu; Cheng-Hong Peng; Zhe Tang; Bin Xu

    2005-01-01

    AIM: To explore the relation between heparanase (HPA)and nm23-H1 in hepatocellular carcinoma (HCC), and whether they could be used as valuable markers in predicting post-operative metastasis and recurrence of HCC.METHODS: Reverse transcription-polymerase chain reaction and immunohistochemistry (S-P method) were used to measure the expressions of HPA mRNA and nm23-H1protein in primary tumor tissue and paracancerous tissue of 33 cases of HCC. Paracancerous tissues of 9 cases of benign liver tumor were used as normal controls. The results were analyzed in combination with the results of clinicopathological examination and follow-up.RESULTS: The positive expression of HPA gene was significantly higher in primary tumor tissues of HCC (48.5%,L6/33) as compared to the paracancerous tissues of HCC and normal controls (3.03%, 1/33) (P<0.01). HPA expression was not related with the size of tumor, envelope formation, AFP level, HBsAg state and cirrhosis of liver.The positive rates of HPA mRNA in the group with high tendency to metastasis or recurrence and in the group with metastasis or recurrence during the follow-up were significantly higher than those in the group with low tendency to metastasis or recurrence (62.5% vs 37.5%,P<0.05) and in the group without metastasis or recurrence (78.6% vs 21.4%, P<0.01). The poorly differentiated tumor and tumor of TNM stages Ⅲ-Ⅳ had a higher positive rate of HPA gene expression than the well differentiated tumor and tumor of TNM stages Ⅰ-Ⅱ (66.7% vs 33.3%, P<0.05). The positive expression rate of nm23-H1 protein in HCC tissue was significantly lower than that in corresponding non-cancerous or normal liver tissue (45.5, 72.7, 88.9%, P<0.05). nm23-H1 expression was not related with the size of tumor, envelope formation,AFP level, HBsAg state, cirrhosis of liver, Edmondson grade,and TNM stage (P>0.05). The positive rates of nm23-H1 in the group with high tendency to metastasis and recurrence and in patients with

  2. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis

    Directory of Open Access Journals (Sweden)

    Walter Arancio

    2015-01-01

    Full Text Available It has been suggested that cancer stem cells (CSC may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2, in the control cell cycle (TP53, CCND1, and in mitochondrial activity (COX8A. The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated.

  3. Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data

    Science.gov (United States)

    Wang, Zhaoming; Rajaraman, Preetha; Melin, Beatrice S.; Chung, Charles C.; Zhang, Weijia; McKean-Cowdin, Roberta; Michaud, Dominique; Yeager, Meredith; Ahlbom, Anders; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E.; Buring, Julie E.; Butler, Mary Ann; Carreón, Tania; Feychting, Maria; Gapstur, Susan M.; Gaziano, J. Michael; Giles, Graham G.; Hallmans, Goran; Henriksson, Roger; Hoffman-Bolton, Judith; Inskip, Peter D.; Kitahara, Cari M.; Le Marchand, Loic; Linet, Martha S.; Li, Shengchao; Peters, Ulrike; Purdue, Mark P.; Rothman, Nathaniel; Ruder, Avima M.; Sesso, Howard D.; Severi, Gianluca; Stampfer, Meir; Stevens, Victoria L.; Visvanathan, Kala; Wang, Sophia S.; White, Emily; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Hartge, Patricia; Chanock, Stephen J.

    2016-01-01

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10−11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. PMID:25907361

  4. Deletions of N33, STK11 and TP53 Are Involved in the Development of Lymph Node Metastasis in Larynx and Pharynx Carcinomas

    Directory of Open Access Journals (Sweden)

    Marta Alonso Guervós

    2007-01-01

    Full Text Available Background: Lymph node metastasis is the mayor cause of mortality in patients with head and neck squamous cell carcinomas (45%. The genetic changes underlying metastasis are still largely unknown and genetic markers to predict lymph node positivity still need to be found. The aim of this study was to search such markers by using Multiplex Ligation-dependent Probe Amplification (MLPA, a semi-quantitative PCR technique to detect gene copy number alterations. Methods: Thirty-seven genes were analysed by MLPA in 34 larynx and 22 pharynx carcinomas. Results: Losses of CDKN2A (9p21 and MLH1 (3p22 and gains of CCND1, EMS1 (both at 11q13, RECQL4 and PTP4A3 (both at 8q24 were the most frequent aberrations in both larynx and pharynx carcinomas. Amplifications were detected at EMS1, CCND1 and ERBB2 (17q21. A correlation between loss of N33 (8p22 and poor survival was found (p=0.02. Gain of EMS1 had the same relation with survival but not significant (p=0.08. Lymph node positive tumors presented a specific pattern of genetic alterations, with losses of N33, STK11 (19p13 and TP53 (17p13, the latter especially in larynx tumors. Conclusion: We propose that these 3 genes might play a role in the development of metastasis in larynx and pharynx squamous cell carcinomas.

  5. Mutational pattern of TP53 tumor suppressor gene in human lung cells exposed to air pollution PM{sub 2.5}; Spectre mutationnel de TP53 en reponse a une exposition in vitro a un aerosol atmospherique particulaire PM{sub 2,} {sub 5}

    Energy Technology Data Exchange (ETDEWEB)

    Billet, Sylvain; Paget, Vincent [Universite Lille Nord de France, Lille (France); Unite de Chimie Environnementale et Interactions sur le Vivant, Maison de la Recherche en Environnement Industriel, Universite du Littoral Cote d' Opale, Dunkerque (France); GRECAN, Universite de Caen Basse-Normandie et Centre Regional de Lutte Contre le Cancer Francois Baclesse, Caen (France); Garcon, Guillaume; Verdin, Anthony; Shirali, Pirouz [Universite Lille Nord de France, Lille (France); Unite de Chimie Environnementale et Interactions sur le Vivant, Maison de la Recherche en Environnement Industriel, Universite du Littoral Cote d' Opale, Dunkerque (France); Andre, Veronique; Heutte, Natacha; Sichel, Francois [GRECAN, Universite de Caen Basse-Normandie et Centre Regional de Lutte Contre le Cancer Francois Baclesse, Caen (France)

    2012-01-15

    Environmental exposure to fine airborne particulate matter (PM 2.5) is thought to be responsible for cardiopulmonary diseases, including lung cancer. However, the mechanisms of action potentially involved in PM{sub 2.5} toxicity are not yet fully described. Mutations in the TP53 gene are the most common alterations in human solid tumors. TP53 mutational patterns have sometimes been linked to carcinogen exposure. The purpose of this study was to determine the mutations that alter the functionality of this transcription factor in a model of human epithelial lung cells (A549) exposed to the fine particulate fraction (PM{sub 2.5}) of an atmospheric aerosol sampled under urban and industrial influences. PM{sub 2.5} was collected in Dunkerque City by cascade impaction. Its physicochemical characterization revealed the presence of many inorganic and organic compounds, including some that are known for their toxicity. The search for mutations altering the functionality of the P53 protein was performed 72 h after exposure of A549 cells to PM{sub 2.5} at its lethal concentration at 50% (LC{sub 50}, 118.60 {mu}g/mL = 31.63 {mu}g/cm{sup 2}), using the Functional Analysis of Separated Alleles in Yeast (FASAY). Sixteen mutations altering P53 function were detected after A549 cells exposure to the collected PM{sub 2.5}: eight deletions of one or two nucleotides and eight nucleotide substitutions, mainly transitions A > G and G > A. These mutations are described in the literature as possibly caused by endogenous mechanisms, such as oxidative stress. This kind of alteration can be induced by metal content of the PM{sub 2.5}, as well as by metabolic activation of the organic compounds coated onto its surface. Involvement of oxidative stress in TP53 mutations was confirmed by the detection of an oxidative DNA adduct, 8-hydroxy-2'-deoxyguanosine (8-OHdG), in A549 cells exposed to the collected PM. (authors)

  6. Deletion of tumor suppressor P53 gene in diffuse large B-cell lymphoma with heterogeneous immunophenotype%不同免疫表型弥漫大B细胞淋巴瘤的抑癌基因TP53缺失分析

    Institute of Scientific and Technical Information of China (English)

    姚玉华; 史伟峰; 戴丽; 曹祥山

    2012-01-01

    目的 探讨不同免疫表型的弥漫大B细胞淋巴瘤(diffuse large B-cell 1 ymphoma,DLBCL)抑癌基因TP53缺失情况的差异.方法 根据淋巴瘤细胞免疫标志物CD10、Bcl-6及MUM-1的表达情况,将57例DLBCL石蜡包埋组织标本分为GCB(生发中心样B细胞)与non-GCB(非生发中心样B细胞)淋巴瘤两类,用荧光原位杂交(FISH)技术检测GCB与non-GCB类中TP53缺失情况.结果 24例GCB类中有4例(16.7%) TP53缺失,33例non-GCB类中有14例(42.4%) TP53缺失.二者TP53缺失率差异有统计学意义(P<0.05).结论 non-GCB类患者TP53缺失发生率较高,TP53缺失是non-GCB类预后差的可能原因之一.FISH可以快速、准确、灵敏地检测出TP53的缺失.

  7. Evolutionary constraint helps unmask a splicing regulatory region in BRCA1 exon 11.

    Directory of Open Access Journals (Sweden)

    Michela Raponi

    Full Text Available BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis.

  8. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    Directory of Open Access Journals (Sweden)

    Wang Jufang

    2011-08-01

    Full Text Available Abstract Background Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Methods Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Results Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. Conclusions The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

  9. RANKL/RANK control Brca1 mutation-driven mammary tumors.

    Science.gov (United States)

    Sigl, Verena; Owusu-Boaitey, Kwadwo; Joshi, Purna A; Kavirayani, Anoop; Wirnsberger, Gerald; Novatchkova, Maria; Kozieradzki, Ivona; Schramek, Daniel; Edokobi, Nnamdi; Hersl, Jerome; Sampson, Aishia; Odai-Afotey, Ashley; Lazaro, Conxi; Gonzalez-Suarez, Eva; Pujana, Miguel A; Cimba, For; Heyn, Holger; Vidal, Enrique; Cruickshank, Jennifer; Berman, Hal; Sarao, Renu; Ticevic, Melita; Uribesalgo, Iris; Tortola, Luigi; Rao, Shuan; Tan, Yen; Pfeiler, Georg; Lee, Eva Yhp; Bago-Horvath, Zsuzsanna; Kenner, Lukas; Popper, Helmuth; Singer, Christian; Khokha, Rama; Jones, Laundette P; Penninger, Josef M

    2016-07-01

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.

  10. Bcl-2 inhibits nuclear homologous recombination by localizing BRCA1 to the endomembranes.

    Science.gov (United States)

    Laulier, Corentin; Barascu, Aurélia; Guirouilh-Barbat, Josée; Pennarun, Gaëlle; Le Chalony, Catherine; Chevalier, François; Palierne, Gaëlle; Bertrand, Pascale; Verbavatz, Jean Marc; Lopez, Bernard S

    2011-05-15

    Genetic stability requires coordination of a network of pathways including DNA repair/recombination and apoptosis. In addition to its canonical anti-apoptotic role, Bcl-2 negatively impacts genome stability. In this study, we identified the breast cancer tumor suppressor BRCA1, which plays an essential role in homologous recombination (HR), as a target for Bcl-2 in the repression of HR. Indeed, ionizing radiation-induced BRCA1 foci assembly was repressed when Bcl-2 was expressed ectopically, in human SV40 fibroblasts, or spontaneously, in lymphoma t(14:18) cells and in HeLa and H460 cancer cell lines. Moreover, we showed that the transmembrane (TM) domain of Bcl-2 was required for both inhibition of BRCA1 foci assembly and the inhibition of HR induced by a double-strand break targeted into an intrachromosomal HR substrate by the meganuclease I-SceI. Fluorescence confocal microscopy, proximity ligation assay, and electron microscopy analyses as well as Western blot analysis of subcellular fractions showed that Bcl-2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of Bcl-2. Targeting BRCA1 to the endomembranes depletes BRCA1 from the nucleus and, thus, accounts for the inhibition of HR. Furthermore, our findings support an apoptosis-stimulatory role for the cytosolic form of BRCA1, suggesting a new tumor suppressor function of BRCA1. Together, our results reveal a new mode of BRCA1 regulation and for HR in the maintenance of genome stability.

  11. Mutational Screening of BRCA1 in Breast Cancer Patients%乳腺癌BRCA1基因突变的筛查研究

    Institute of Scientific and Technical Information of China (English)

    张海添; 陆云飞; 曾健; 廖清华; 林坚

    2005-01-01

    目的研究BRCA1基因在散发性乳腺癌中的突变情况,探讨BRCA1基因突变与乳腺癌的关系.方法应用PCP-SSCP(single-strand conformation polymorphism analysis)分析和DNA直接测序法,检测65例散发性乳腺癌BRCA1第2,3,5,8,10,12,13,14,15,16,17,18,19,20和21外显子基因突变情况.结果65例中共检测出4例突变,其中1例为5外显子的错义突变(287 A>T),1例为12外显子的错义突变(4 285 G>A),1例为17外显子的错义突变(5 115 T>C),1例为18外显子的错义突变(5 206 T>A).乳腺癌BRCA1的基因突变率为6.2%(4/65).结论BRCA1基因突变与散发性乳腺癌有密切关系.

  12. rs78378222 polymorphism in the 3'-untranslated region of TP53 contributes to development of age-associated cataracts by modifying microRNA-125b-induced apoptosis of lens epithelial cells.

    Science.gov (United States)

    Zhao, Yang; Li, Xiao; Zhu, Siquan

    2016-09-01

    MicroRNAs (miRNAs) negatively regulate the expression of the target genes by binding to 'seed sequences' in the 3'‑untranslated region (3'‑UTR) mRNA transcripts, and the variants within or nearby 'seed sequences' may compromise or enhance miRNA/mRNA interaction leading to either 'loss‑of‑function' or 'gain‑of‑function' effects. Cataracts are the leading cause of blindness worldwide and are characterized by progressive aggregation and precipitation of lens proteins, and the development of age‑related cataracts is associated with dysregulated cellular activities of lens epithelial cells. Luciferase assays and online miRNA databases were used to validate that tumor protein p53 (TP53) is the target gene of miR‑125b. Furthermore, reverse transcription‑quantitative polymerase chain reaction and western blotting were conducted to detect expression levels of miR‑125b and TP53 in different groups of cells transfected with miR‑125b mimics or inhibitors. In addition, flow cytometry analysis and the MTT assay were conducted to detect the effects of miR‑125b on apoptosis and cell viability. The current study demonstrated that the rs78378222 polymorphism minor allele introduces a novel potential miR‑125b binding site in the TP53 3'‑UTR with a consecutive 8‑bp perfect match, creating a 'gain‑of‑function' variant and affecting the regulation of TP53 expression. A luciferase assay demonstrated that transfection of lens epithelial cells with wild type TP53 3'‑UTR significantly reduced the luciferase activity of the miR‑125b overexpressing cells compared with scramble controls. In addition, the luciferase activity of miR‑125b overexpressing cells transfected with the construct containing the rs78378222 polymorphism minor allele was also reduced compared with cells transfected with the wild type 3'‑UTR. Furthermore, it was demonstrated that the expression level of miR‑125 was comparable in epithelial cells from patients with age

  13. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene.

    Science.gov (United States)

    Snouwaert, J N; Gowen, L C; Latour, A M; Mohn, A R; Xiao, A; DiBiase, L; Koller, B H

    1999-12-20

    BRCA1 is a nuclear phosphoprotein that has been classified as a tumor suppressor based on the fact that women carrying a mutated copy of the BRCA1 gene are at increased risk of developing breast and ovarian cancer. The association of BRCA1 with RAD51 has led to the hypothesis that BRCA1 is involved in DNA repair. We describe here the generation and analysis of murine embryonic stem (ES) cell lines in which both copies of the murine homologue of the human BRCA1 gene have been disrupted by gene targeting. We show that exogenous DNA introduced into these BRCA1 deficient cells by electroporation is randomly integrated into the genome at a significantly higher rate than in wild type ES cells. In contrast, integration of exogenous DNA by homologous recombination occurs in BRCA1 deficient cells at a significantly lower rate than in wild type controls. When BRCA1 expression is re-established at 5-10% of normal levels by introduction of a Brca1 transgene into BRCA1 deficient ES cells, the frequency of random integration is reduced to wild type levels, although the frequency of homologous recombination is not significantly improved. These results suggest that BRCA1 plays a role in determining the response of cells to double stranded DNA breaks.

  14. BRCA1 Accelerates CtIP-Mediated DNA-End Resection

    Directory of Open Access Journals (Sweden)

    Andrés Cruz-García

    2014-10-01

    Full Text Available DNA-end resection is a highly regulated and critical step in the response and repair of DNA double-strand breaks. In higher eukaryotes, CtIP regulates resection by integrating cellular signals via its posttranslational modifications and protein-protein interactions, including cell-cycle-controlled interaction with BRCA1. The role of BRCA1 in DNA-end resection is not clear. Here, we develop an assay to study DNA resection in higher eukaryotes at high resolution. We demonstrate that the BRCA1-CtIP interaction, albeit not essential for resection, modulates the speed at which this process takes place.

  15. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

    DEFF Research Database (Denmark)

    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders

    2017-01-01

    BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient...

  16. NM23-H1在结直肠癌中的表达

    Institute of Scientific and Technical Information of China (English)

    石光锋; 王晓霜; 丁宇

    2002-01-01

    @@ 本研究应用免疫组织化学LSAB(labelled streptavidin biotin method)法检测结直肠正常粘膜、管状腺瘤、绒毛状腺瘤、癌 NM23-H1的表达,探讨其与结直肠癌的转移及生物学行为的关系.

  17. Microdissecção e captura a laser na investigação do gene TP53 em tecidos incluídos em parafina Laser-capture microdissection for TP53 gene analysis in paraffin-embedded tissues

    Directory of Open Access Journals (Sweden)

    Shadia Muhammad Ihlaseh

    2007-02-01

    Full Text Available INTRODUÇÃO: Microdissecção e captura a laser (MCL é uma técnica de desenvolvimento recente que permite a coleta de células individuais ou pequeno conjunto de células para análise molecular. Atualmente, no Brasil, há raros microscópios para MCL, de modo que a divulgação dos procedimentos inerentes a essa técnica é oportuna para destacar seu amplo potencial para diagnóstico e investigação. OBJETIVO: Este trabalho descreve a padronização dos procedimentos de MCL e de extração de DNA de material fixado em formalina e incluído em parafina. MATERIAL E MÉTODOS: Foram estudados o éxon 8 do gene TP53 e o gene da ciclofilina em amostras de tecido normal e de neoplasias de fígado e rim provenientes de modelo de carcinogênese química induzida em rato. A extração do DNA foi comprovada por reação em cadeia da polimerase (nested-PCR. RESULTADOS: Foram padronizados os procedimentos de preparo dos cortes histológicos, de microdissecção e captura a laser e de obtenção de seqüências gênicas pela reação de nested-PCR para tecidos incluídos em parafina. Obtivemos amplificação de 48,3% das amostras para o éxon 8 do gene TP53 e 51,7% para o gene da ciclofilina. Considerando pelo menos um dos dois segmentos gênicos, foram amplificadas 79,3% das amostras. DISCUSSÃO E CONCLUSÃO: A extração de DNA de tecidos fixados em formalina e incluídos em parafina e a técnica de nested-PCR foram adequadamente padronizadas para produtos gênicos de interesse, obtidos de material coletado por MCL. Esses procedimentos podem ser úteis para a obtenção de seqüências de DNA de arquivos para análise molecular.BACKGORUND: Laser-capture micro-dissection (LCM is a recently developed procedure that provides single cells or specific cell groups for molecular analysis. Currently, there are few LCM systems in Brazil, in such a way that it is necessary to disseminate the technical procedures inherent to the methodology, and also to

  18. Localization of human BRCA1 and BRCA2 in non-inherited colorectal carcinomas and matched normal mucosas.

    Science.gov (United States)

    Bernard-Gallon, D J; Peffault de Latour, M; Hizel, C; Vissac, C; Cure, H; Pezet, D; Dechelotte, P J; Chipponi, J; Chassagne, J; Bignon, Y J

    2001-01-01

    We characterized the expression of BRCA1 and BRCA2 in 38 sporadic colorectal carcinomas and matched normal mucosas with 9 anti-BRCA1 antibodies and 4 anti-BRCA2 antibodies, raised against several different epitopes, using immunohistochemical technique. We demonstrated an increased BRCA1 and BRCA2 staining in the apical cell pole of epithelial malignant cells and we also revealed a significant increase in BRCA1 and BRCA2 nuclear foci in tumor colorectal specimens in comparison with corresponding normal tissues. These increases in BRCA1 and BRCA2 expression may be explained by the fact that colorectal tissue is subject to very active proliferation and differentiation.

  19. TP53 and ovarian cancer

    NARCIS (Netherlands)

    M. Schuijer (Monique); P.M.J.J. Berns (Els)

    2003-01-01

    textabstractOvarian cancer represents the fourth most frequent type of cancer among females and is the leading cause of death from gynecological cancer in the western world. This review describes gene alterations in ovarian cancer. Specific emphasis is placed on genetic alterations and the prevalenc

  20. Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations

    Science.gov (United States)

    Communal, Laudine; Courtin, Aurélie; Mourra, Najat; Lahlou, Najiba; Le Guillou, Morwenna; de Jotemps, Muriel Perrault; Chauvet, Marie-Pierre; Chaouat, Marc; Pujol, Pascal; Feunteun, Jean; Delaloge, Suzette; Forgez, Patricia; Gompel, Anne

    2016-01-01

    Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy. PMID:27246982

  1. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  2. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders;

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian...... cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15 patients with 7 different genomic rearrangements, including a BRCA1 exon 5-7 deletion with a novel breakpoint, a BRCA1...... exon 13 duplication, a BRCA1 exon 17-19 deletion, a BRCA1 exon 3-16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17-18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations...

  3. Genomic aberrations of BRCA1-mutated fallopian tube carcinomas.

    Science.gov (United States)

    Hunter, Sally M; Ryland, Georgina L; Moss, Phillip; Gorringe, Kylie L; Campbell, Ian G

    2014-06-01

    Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.

  4. 胃癌17号染色体异倍体改变及TP53和拓扑异构酶Ⅱα蛋白过表达与病理诊断的相关性%Correlation between aneuploidy of chromosome 17,over-expression of TP53 and TOP Ⅱα,and the clinicopathoiogical features and diagnosis of gastric adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    鲁海珍; 吴玉鹏; 罗巍; 韩亚玲; 蔡岩; 徐昕; 梁晶; 刘尚梅; 王明荣

    2009-01-01

    Objective The purpose of this study was to investigate the markers which can be used in auxiliary diagnosis of gastric adenocarcinoma (GAC),and their correlation with their clinicopathological features.Methods 122 surgical specimens including 99 gastric adenocarcinoma (GAC),18 adjacent mucosa and 5 distal normal mucosa were collected,and analyzed by in situ hybridization (FISH).The centromere probe cen17,specific for chromosome 17,which was reported to be frequently amplified in GAC,was selected for the FISH analysis.The clinicopathological features of the 99 GAC cases were reviewed,and the level of TP53 and TOP Ⅱα gene expression,located in chromosome 17,was detected using tissue microarray (TMA),compared with that of corresponding adjacent normal mucosa.Data were analyzed with SPSS 11.5 for Windows.Results The statistical results of FISH and TMA showed that 58.6% of cen17 in tumor tissues were aneuploid,and 45.5% of TP53 and 84.7% of TOP Ⅱα were over-expressed in GAC samples,significantly higher than those in non-tumor gastric mucosa (0,12.1% and 14.1%,respectively) (P =0.000).58 GAC tissues were aneuploid of cen 17,including 26 cases TP53-positive and 49 cases TOP Ⅱα-positive.The expression of TP53 in non-tumor gastric mucosa with dysplasia was significantly higher than that in the mucosa without dysplasia (P=0.009).Aneuploidy of cen17 was more frequent in grade 1 or 2 than in grade 3 GAC(P<0.05).Higher frequency of aneuploidy of cen17 was also observed in the gastric cardia than in pylorus (P<0.05),while no correlation was found between aneuploidy of cen17 and age,sex of patients,lymph node metastasis,and clinical stage of tumors.Over-expression of TP53 protein was associated with the size of tumors (P<0.05).In addition,a negative correlation was observed between over-expression of TOP Ⅱα and lymph node metastasis (LNM) as well as TNM classification (P<0.05).Conclusion Detection of aneuploidy of cen17 as well as over-expression of TP53 and

  5. Lymphatic metastasis and nm23H1 genetic instability in Chinese colon cancer patients

    Institute of Scientific and Technical Information of China (English)

    Zhi-Hong Su; Ji-Cheng Li

    2004-01-01

    AIM: To investigate the pathogenic mechanism of colon cancer at the molecular level and to elucidate the relationship between intercellular adhesion molecule-1 (ICAM-1) and nm23H1 genes and Chinese patients with colon cancer.METHODS: DNA was extracted from paraffin-embedded materials. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to analyze MSI and LOH. Expression of ICAM-1 was detected by Envision immunohistochemistry. Experimental results were analyzed with Leica-Qwin computer imaging techniques and SPSS software of statistics.RESULTS: ICAM-1 expression of lymphatic endothelium was negative in normal colon and positive in colon cancer respedively.The number of lymphatics positive for ICAM-1 was gradually increased with degree of cancer invasion (P<0.01). In the group with metastasis of colon cancer, the number of lymphatics positive for ICAM-1 in lymph nodes was more than that in the group with no metastasis (P<0.01). The frequency of MSI, LOH and nm23H1 protein was 26.67%, 20.00% and 53.33% in colon cancer, respectively. In TNM staging, MSI (43.75%) and nm23H1 protein (81.25%) in stages Ⅰ+Ⅱ were detected more easily than the corresponding indexes (MSI:7.14%, P<0.05 and nm23H1: 21.43%, P<0.01) in stages Ⅲ+Ⅳ. By comparison, the frequency of LOH (35.71%) in stages Ⅲ+Ⅳ was more than that of LOH (6.25%, P<0.05)in stages Ⅰ+Ⅱ. LOH exhibited a rising trend along with the Duke's staging. nm23H1 protein in the group of tubular adenocarcinoma (60.00%) was higher expressed than that in the group of mucoid adenocarcinoma (20.00%) (P<0.01),and exhibited a rising trend with the differentiation degrees of tubular adenocarcinoma. nm23H1 protein in MSI positive group was higher expressed (75%) than that in MSI negative group (45.45%, P<0.05).CONCLUSION: The expression of ICAM-1 in lymphatic vessels is beneficial to the judgement of the invasion and metastasis ability of colon cancer and the anti-tumor immunity

  6. Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.

    Science.gov (United States)

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Bp, Manasa; Minhas, Sachin; Shokeen, Yogender; Aggarwal, Shyam

    2017-02-01

    Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

  7. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  8. Mutation Analysis in the BRCA1 Gene in Chinese Breast Cancer Families

    Institute of Scientific and Technical Information of China (English)

    WUZhengyan; ZHENLinlin; FANPing

    2003-01-01

    Objective: To study the mutation of BRCA1 gene in Chinese breast cancer families. Methods:Fifteen families were selected, involving 41 members, consisting of 23 breast cancer patients. Using poly-merase chain reaction and single stranded conformation polymorphism (PCR-SSCP), and subsequent DNA sequencing, the mutation of BRCA1 genes were analyzed. Results: Four mutations were found in all fam-ilies, and the proportion of mutation was 26.7% (4/15) in breast cancer families. One of the 4 mutations was 2228 insC, resulting in chain termination at codon 711. The remaining 3 mutations were 1884A→T and 3232A→G, resulting in single amino acid change respectively. Conclusion: BRCA1 is a breast cancer susceptibility gene. The relatively low proportion and frequency of BRCA1 mutations in our study hints additional BRCA genes existed.

  9. Analysis of BRCA1 involvement in breast cancer in Indian women

    Indian Academy of Sciences (India)

    P H Pestonjamasp; I Mittra

    2000-03-01

    The involvement of the familial breast-ovarian cancer gene (BRCA1) in the molecular pathogenesis of breast cancer among Indian women is unknown. We have used a set of microsatellite polymorphisms to examine the frequency of allele loss at the BRCA1 region on chromosome 17q21, in a panel of 80 human breast tumours. Tumour and blood leukocyte/normal tissue DNA from a series of 80 patients with primary breast cancer was screened by PCR-amplified microsatellite length polymorphisms to detect deletions at three polymorphic BRCA1 loci. PCR-allelotype was valuable in examining allele losses from archival and small tumour samples. Loss of alleles at BRCA1 in the patient set, confirmed a noteworthy role of this gene in the molecular pathogenesis of breast cancer and was in accordance with its well-documented tumour suppressive function.

  10. High SINE RNA Expression Correlates with Post-Transcriptional Downregulation of BRCA1

    Directory of Open Access Journals (Sweden)

    Giovanni Bosco

    2013-04-01

    Full Text Available Short Interspersed Nuclear Elements (SINEs are non-autonomous retrotransposons that comprise a large fraction of the human genome. SINEs are demethylated in human disease, but whether SINEs become transcriptionally induced and how the resulting transcripts may affect the expression of protein coding genes is unknown. Here, we show that downregulation of the mRNA of the tumor suppressor gene BRCA1 is associated with increased transcription of SINEs and production of sense and antisense SINE small RNAs. We find that BRCA1 mRNA is post-transcriptionally down-regulated in a Dicer and Drosha dependent manner and that expression of a SINE inverted repeat with sequence identity to a BRCA1 intron is sufficient for downregulation of BRCA1 mRNA. These observations suggest that transcriptional activation of SINEs could contribute to a novel mechanism of RNA mediated post-transcriptional silencing of human genes.

  11. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.

    Science.gov (United States)

    Xu, Xingzhi; Lee, Juhie; Stern, David F

    2004-08-13

    Microcephalin (MCPH1) is the first gene identified among at least six loci that contribute to the autosomal recessive disease, primary microcephaly. MCPH1, like NFBD1/MDC1, 53BP1, and BRCA1, encodes a protein with twin carboxyl-terminal BRCT domains (PTCB). Here, we report that Mcph1 forms ionizing radiation-induced foci. Down-regulation of Mcph1, like other PTCBs, by siRNA, impairs ionizing radiation-induced intra-S-phase and G(2)/M checkpoints. Inhibition of the expression of Mcph1 decreases both protein and transcript levels of endogenous Brca1 but not exogenous Brca1. Mcph1 inhibition also decreases both endogenous and heterologous Chk1 transcripts and protein. We conclude that Mcph1 is involved in DNA damage-induced cellular responses, and we propose that regulation of Brca1 and/or Chk1 by Mcph1 may contribute to these cellular responses.

  12. Screening of BRCA1 sequence variants within exon 11 by heteroduplex analysis

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2013-03-01

    Full Text Available Germ-line mutations of either BRCA1 or BRCA2 represents the major hereditary risk to breast and ovariancancer. Screening for mutations in these genes is now standard practice in molecular diagnosis, opening the way tooncogenetic counselling and follow-up. Because mutations in both BRCA1 and BRCA2 are distributed throughout theloci, accepted clinical protocols involve screening their entire coding regions. Systematic Sanger sequencing is time andmoney consuming. Therefore, a lot of pre-screening techniques evolved over time in order to identify anomalousamplicons prior to sequencing. Because BRCA mutations are always heterozygous, heteroduplex analysis proved to be asuitable pre-screening step. We previously implemented mismatch specific endonuclease heteroduplex analysis forBRCA1 exon7. Here we show the utility of the same method for mutations and SNPs found in BRCA1 exon 11

  13. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M;

    2012-01-01

    Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number...... of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

  14. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Science.gov (United States)

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  15. BRCA1, microRNAs and cancer predisposition : challenging the dogma

    OpenAIRE

    Almeida, Maria Inês; Reis,R.M.; Calin, George A

    2011-01-01

    The importance of SNPs in conveying susceptibility to different kinds of cancer. The study by Pelletier et al. (2011) is particularly vital because it describes new genetic markers in BRCA1 3’UTR noncoding regions that can improve our determination of breast cancer susceptibility. Inclusion of these SNPs in BRCA1 haplotypes that are associated with breast cancer risk may guide future studies of functional miRNA interactions and their cellular consequences. This has the...

  16. BRCA1 and BRCA2 Germline Mutations Screening in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2010-01-01

    Full Text Available Background: Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer.

  17. Characterization of RACK7 as a Novel Factor Involved in BRCA1 Mutation Mediated Breast Cancer

    Science.gov (United States)

    2012-10-01

    control for the restriction digestion. Fig. 2. Library screening and cloning of the gene(s) involved in BRCA-1 mediated DNA damage...hypersensitivity. A. A diagram of the library screening procedure. B. Isolation of the gene candidates that confer the resistance to DNA damage hypersensitivity...in HCC1937 cells. Fig 3. Effect of BRCA1, Noc-4, PKCBP and H3.3 on protection from irradiation hypersensitivity. A. . A diagram of the library

  18. The Role of BRCA1 Domains and Motifs in Tumor Suppression

    Science.gov (United States)

    2010-08-01

    poorly characterized but conserved domains in BRCA1 directly participate in its tumor suppression function. To test this hypothesis we choose a global ...after ionizing radiation than HCC1937 e xpressing lacZ, delta 12/13, C61G or M1775 R mutants. This suggests that the RING, coiled-coil and BRCT...conserved domains in BRCA1 dire ctly participate in its tumor suppression fun ction. To te st this hypothesis we choose a global ap proach

  19. Microglandular adenosis of the breast in a BRCA1 mutation carrier: radiological features

    Energy Technology Data Exchange (ETDEWEB)

    Sabate, J.M.; Gomez, A.; Torrubia, S. [Department of Diagnostic Radiology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Matias-Guiu, X. [Department of Pathology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Alonso, C.; Pericay, C. [Department of Oncology, Hospital de Sant Pau, Universitat Autonoma de Barcelona, Sant Antoni M. Claret, 167, 08025 Barcelona (Spain); Diaz, O. [Department of Genetics, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain)

    2002-06-01

    Microglandular adenosis is a very uncommon benign proliferative disorder of the breast that may mimic tubular carcinoma radiologically and pathologically. We describe the radiological features of this rare condition in a patient with BRCA 1 mutation. To our knowledge, this is the first case of microglandular adenosis reported in the radiology literature. The relationship between microglandular adenosis and malignancy and the association between BRCA 1 and proliferative benign disorders are also discussed. (orig.)

  20. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Spurdle, A.B.; Marquart, L.; McGuffog, L.; Healey, S.; Sinilnikova, O.; Wan, F.; Chen, X.; Beesley, J.; Singer, C.F.; Dressler, A.C.; Gschwantler-Kaulich, D.; Blum, J.L.; Tung, N.; Weitzel, J.; Lynch, H.; Garber, J.; Easton, D.F.; Peock, S.; Cook, M.; Oliver, C.T.; Frost, D.; Conroy, D.; Evans, D.G.; Lalloo, F.; Eeles, R.; Izatt, L.; Davidson, R.; Chu, C.; Eccles, D.; Selkirk, C.G.; Daly, M.; Isaacs, C.; Stoppa-Lyonnet, D.; Sinilnikova, O.M.; Buecher, B.; Belotti, M.; Mazoyer, S.; Barjhoux, L.; Verny-Pierre, C.; Lasset, C.; Dreyfus, H.; Pujol, P.; Collonge-Rame, M.A.; Rookus, M.A.; Verhoef, S.; Kriege, M.; Hoogerbrugge, N.; Ausems, M.G.; Os, T.A. van; Wijnen, J.; Devilee, P.; Meijers-Heijboer, H.E.; Blok, M.J.; Heikkinen, T.; Nevanlinna, H.; Jakubowska, A.; Lubinski, J.; Huzarski, T.; Byrski, T.; Durocher, F.; Couch, F.J.; Lindor, N.M.; Wang, X.; Thomassen, M.; Domchek, S.; Nathanson, K.; Caligo, M.; Jernstrom, H.; Liljegren, A.; Ehrencrona, H.; Karlsson, P.; Ganz, P.A.; Olopade, O.I.; Tomlinson, G.; Neuhausen, S.; Antoniou, A.C.; Chenevix-Trench, G.; Rebbeck, T.R.

    2011-01-01

    BACKGROUND: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. METHODS: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutat

  1. Unsolved mystery: the role of BRCA1 in DNA end-joining.

    Science.gov (United States)

    Saha, Janapriya; Davis, Anthony J

    2016-08-01

    Heritable mutations in the tumor suppressor gene BRCA1 increase a woman's lifetime risk of developing breast and ovarian cancer. BRCA1's tumor suppressor function is directly linked to its myriad of functions in the cellular response to DNA double-strand breaks (DSBs). BRCA1 interacts with an extensive array of DNA damage responsive proteins and plays important roles in DSB repair, mediated by the homologous recombination pathway, and in the activation of cell cycle checkpoints. However, the role of BRCA1 in the other two DSB repair pathways, classical non-homologous end-joining (C-NHEJ) and alternative NHEJ (A-NHEJ), remains unclear. In this review, we will discuss the current literature on BRCA1's potential role(s) in modulating both C-NHEJ and A-NHEJ. We also present a model showing that BRCA1 contributes to genomic maintenance by promoting precise DNA repair across all cell cycle phases via the direct modulation of DNA end-joining.

  2. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

    Science.gov (United States)

    Chang, Suhwan; Wang, Rui-Hong; Akagi, Keiko; Kim, Kyung-Ae; Martin, Betty K; Cavallone, Luca; Haines, Diana C; Basik, Mark; Mai, Phuong; Poggi, Elizabeth; Isaacs, Claudine; Looi, Lai M; Mun, Kein S; Greene, Mark H; Byers, Stephen W; Teo, Soo H; Deng, Chu-Xia; Sharan, Shyam K

    2012-01-01

    BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors. PMID:21946536

  3. Ovarian Cancer and BRCA1/2 Testing: Opportunities to improve clinical care and disease prevention

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    Katherine eKarakasis

    2016-05-01

    Full Text Available Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High grade serous ovarian cancer (HGSOC is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer, those at risk of developing cancer, but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many which are now being found to have BRCA1/2 involvement.

  4. BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

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    Harriet E Feilotter

    Full Text Available The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

  5. BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland.

    Science.gov (United States)

    Perkowska, Magdalena; BroZek, Izabela; Wysocka, Barbara; Haraldsson, Karin; Sandberg, Therese; Johansson, Ulla; Sellberg, Gunilla; Borg, Ake; Limon, Janusz

    2003-05-01

    Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.

  6. 下调PPP2R5C表达对K562细胞TP53相关通路基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    沈琦[1,2; 张新友[1; 李扬秋[2,3

    2016-01-01

    目的:利用基因芯片技术研究RNA干扰下调PPP2R5C对K562细胞中TP53通路相关基因表达的影响。方法:Affymetrix U133 plus 2.0基因表达谱芯片检测核转染PPP2R5C-siRNA991和SC对照组的K562细胞,应用Genespring GX 11.0软件分析差异基因相关信号通路变化情况。结果:基因芯片分析TP53信号通路紧密相关的22个基因,发现全部基因发生了差异表达,其中上调基因有8个,下调基因有14个。明显上调的基因有EP300、CCND1、BRCA2和USP7,而明显下调的基因则有MDM4、ESR1、ATM、CDK2、CDKN1A、TP53和CDKN2A。结论:下调K562细胞PPP2R5C基因时,在一定程度上选择性调节与细胞增殖密切相关的TP53信号通路相关基因的表达,从而抑制K562细胞增殖,促进了K562细胞凋亡。

  7. Alterations in TP53, cyclin D2, c-Myc, p21WAF1/CIP1 and p27KIP1 expression associated with progression in B-CLL

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    Antosz Halina

    2010-04-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL originates from B lymphocytes that may differ in the activationlevel, maturation state or cellular subgroups in peripheral blood. Tumour progression in CLL B cells seems to result in gradualaccumulation of the clone of resting B lymphocytes in the early phases (G0/G1 of the cell cycle. The G1 phase isimpaired in B-CLL. We investigated the gene expression of five key cell cycle regulators: TP 53, c-Myc, cyclin D2,p21WAF1/CIP1 and p27KIP1, which primarily regulate the G1 phase of the cell cycle, or S-phase entry and ultimately controlthe proliferation and cell growth as well as their role in B-CLL progression. The study was conducted in peripheral bloodCLL lymphocytes of 40 previously untreated patients. Statistical analysis of correlations of TP53, cyclin D2, c-Myc,p21WAF1/CIP1 and p27KIP1 expressions in B-CLL patients with different Rai stages demonstrated that the progression of diseasewas accompanied by increases in p53, cyclin D2 and c-Myc mRNA expression. The expression of p27KIP1 was nearlystatistically significant whereas that of p21 WAF1/CIP1 showed no such correlation. Moreover, high expression levels of TP53and c-Myc genes were found to be closely associated with more aggressive forms of the disease requiring earlier therapy.

  8. 大肠高、中分化腺癌临床特点、遗传不稳定性、TP53与KRAS基因突变的差异比较%Comparison on Clinicopathological Features, Genetic Instability, TP53 and KRAS Gene Mutations between Well and Moderately Differentiated Colorectal Adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    赵岩; 郑志超; 挂地吉弘; 冲 英次; 张涛; 张剑军; 赵宜良; 前原喜彦

    2010-01-01

    目的:近年来大肠中分化腺癌检出比例有所增高.本研究旨在探讨大肠中分化腺癌临床病理学及分子遗传学特征.方法:回顾过去30年1073例大肠癌的病理分型,比较其中328例高、中分化腺癌临床病理学特点.激光细胞学扫描技术,双荧光高分辨率微卫星不稳定性技术评价129例大肠癌遗传不稳定性特点,TP53、KRAS基因突变采用直接测序法检测.结果:由1979年始每10年为1组,至2008年计3组.中分化腺癌所占比例分别为37%、38%及55%.其中的328例大肠癌高、中分化腺癌病理学研究表明,中分化者较高分化者病期晚、浸润深、淋巴结转移率高、静脉侵袭阳性率高.对74例高分化腺癌与55例中分化腺癌的分子遗传学研究表明,高、中分化腺癌的DNA倍体与微卫星不稳定性情况无显著性差异,TP53与KRAS基因突变频率也无显著差异.但TP53的移码突变仅在高分化腺癌中检出(4例,P<0.05).KRAS的颊换突变在高分化癌中检出5例(23%),在中分化癌中检出12例(57%),差异有显著性意义(P<0.05).结论:高、中分化腺癌在临床病理学特征方面存在明显差异.大肠中分化腺癌较高分化腺癌生物学行为差,发现时病期较晚,治疗随访中需要引起足够重视.两种病理学类型的肿瘤遗传不稳定性急基因突变频率等背景相似,但基因突变谱的差别提示两种腺癌的发生背景的不同.

  9. BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses.

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    Huchun Li

    Full Text Available BACKGROUND: BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-beta is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-beta activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report an important role of BRCA1 in modulating TGF-beta signaling during oxidative stress responses. Wild-type (WT BRCA1, but not mutated BRCA1 failed to activate TGF-beta mediated transactivation of the TGF-beta responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-beta1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298-436aa of BRCA1 and Smad3 domain of 207-426aa. In addition, H(2O(2 increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-beta1 induced Smad3 and Smad4 interaction was increased in the presence of H(2O(2 in cells expressing WT-BRCA1, while the TGF-beta1 induced interaction between Smad3 and Smad4 was decreased upon H(2O(2 treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1. Further, loss of BRCA1 resulted in H(2O(2 induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-beta and in significant decrease in Smad3 and Smad4 transcriptional

  10. A Novel Frequent BRCA1 Allele in Chinese Patients with Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHOU Dongxian; XIONG Wen; XU Hongxan; SHAO Chaopeng

    2006-01-01

    The whole length of exon 11 of BRCA1 was sequenced (total 3427 bp) in 59 patients and 10 healthy female blood donors. To allow a rapid determination of the different BRCA1 alleles, a sequence-specific primer PCR method (PCR-SSP) was established and was applied to 57 additional female donors. Finally, the full-length coding region of BRCA1 was analyzed through reversed-transcriptase PCR (RT-PCR) and cDNA sequencing (total 5554 bp) in one donor with wild-type allele and 2 patients with one or two mutated alleles. By genomic DNA sequencing, 5 homozygous polymorphisms were observed in 18 patients: 2201C>T, 2430T>C, 2731C>T, 3232A>G and 3667A>G. All of them were previously observed in Caucasians, Malay and Chinese, but for the first time the mutations were found in one allele (GenBank AY304547). Twenty-six patients and 4donors were heterozygous at these 5 nucleotide positions. The remaining 15 patients and 6 donors showed a sequence identical with the standard BRCA1 gene. Combined the PCR-SSP results and in a summary, 6 of 67 (9.0 %) healthy individuals were homozygous for the mutated allele, whereas 18 of 59 (30.5 %) breast cancer patients were homozygous. A Chi-square test showed a significant correlation between homozygous mutated BRCA1 allele and breast cancer. The cDNA sequencing showed that 2 additional mutations, 4427T>C in exon 13 and 4956A>G in exon 16, were found. A new BRCA1 allele, which is BRCA1-2201T/2430C/2731T/3232G/3667G/4427C/4956G (GenBank AY751490), was found in Chinese. And the homozygote of this mutated allele may implicate a disease-association in Chinese.

  11. BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases

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    Nancy Uhrhammer, Amina Abdelouahab, Laurence Lafarge, Viviane Feillel, Ahmed Ben Dib, Yves-Jean Bignon

    2008-01-01

    Full Text Available Breast cancer rates and median age of onset differ between Western Europe and North Africa. In Western populations, 5 to 10 % of breast cancer cases can be attributed to major genetic factors such as BRCA1 and BRCA2, while this attribution is not yet well defined among Africans. To help determine the contribution of BRCA1 mutations to breast cancer in a North African population, we analysed genomic DNA from breast cancer cases ascertained in Algiers. Both familial cases (at least three breast cancers in the same familial branch, or two with one bilateral or diagnosed before age 40 and sporadic cases less than 38 years of age were studied. Complete sequencing plus quantitative analysis of the BRCA1 gene was performed. 9.8 % (5/51 of early-onset sporadic and 36.4 % (4/11 of familial cases were found to be associated with BRCA1 mutations. This is in contrast 10.3 % of French HBOC families exhibiting a BRCA1 mutation. One mutation, c.798_799delTT, was observed in two Algerian families and in two families from Tunisia, suggesting a North African founder allele. Algerian non-BRCA1 tumors were of significantly higher grade than French non-BRCA tumors, and the age at diagnosis for Algerian familial cases was much younger than that for French non-BRCA familial cases. In conclusion, we observed a much higher frequency of BRCA1 mutations among young breast cancer patients than observed in Europe, suggesting biological differences and that the inclusion criterea for analysis in Western Europe may not be applicable for the Northern African population.

  12. BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

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    Ainur R. Akilzhanova

    2013-05-01

    Full Text Available Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05; higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation.