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Sample records for gen cdkn2a p16

  1. EZH2 expression in gliomas: Correlation with CDKN2A gene deletion/ p16 loss and MIB-1 proliferation index.

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    Purkait, Suvendu; Sharma, Vikas; Jha, Prerana; Sharma, Mehar Chand; Suri, Vaishali; Suri, Ashish; Sharma, B S; Sarkar, Chitra

    2015-10-01

    Enhancer of zeste homolog 2 (EZH2) mediated down-regulation of CDKN2A/p16 has been observed in cell lines as well as in a few carcinomas. However, there is no study correlating EZH2 expression with CDKN2A/p16 status in gliomas. Hence, the present study was conducted to evaluate EZH2 expression in astrocytic and oligodendroglial tumors and correlate with CDKN2A/p16 status as well as MIB-1 labeling index (LI). Gliomas of all grades (n = 118) were studied using immunohistochemistry to assess EZH2, p16 and MIB-1 LI and fluorescence in situ hybrization to evaluate CDKN2A gene status. EZH2 expression and CDKN2A homozygous deletion (HD) were both significantly more frequent in high-grade gliomas (HGG). Further, strong EZH2 expression (LI ≥ 25%) was significantly more common in HGGs without CDKN2A HD (48.7%; 19/39) as compared to cases with deletion (15.8%; 3/19). Loss of p16 expression was noted in 100% and 51.3% of CDKN2A deleted and non-deleted tumors, respectively. Notably, 80% (16/20) of the CDKN2A non-deleted HGGs with p16 loss had strong EZH2 expression, in contrast to only 15.8% (3/19) in the deleted group. Loss of p16 expression significantly correlated with MIB-1 LI, irrespective of EZH2 status. Thus, this study shows that EZH2 expression correlates with tumor grade in both astrocytic and oligodendroglial tumors and hence can be used as a diagnostic marker to differentiate between low and HGGs. Further, this is the first report demonstrating an inverse correlation of strong EZH2 expression with CDKN2A HD in HGGs. Loss of p16 protein expression is mostly attributable to CDKN2A HD and correlates significantly with MIB-1 LI. Notably, our study for the first time suggests a possible epigenetic mechanism of p16 loss in CDKN2A non-deleted HGGs mediated by strong EZH2 expression. A hypothetical model for control of proliferative activity in low versus HGGs is therefore proposed. © 2015 Japanese Society of Neuropathology.

  2. Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma.

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    Mohseny, Alexander B; Tieken, Chris; van der Velden, Pieter A; Szuhai, Karoly; de Andrea, Carlos; Hogendoorn, Pancras C W; Cleton-Jansen, Anne-Marie

    2010-12-01

    Conventional osteosarcoma is characterized by rapid growth, high local aggressiveness, and metastasizing potential. Patients developing lung metastases experience poor prognosis despite extensive chemotherapy regimens and surgical interventions. Previously we identified a subgroup of osteosarcoma patients with loss of CDKN2A/p16 protein expression in the primary tumor biopsies which was significantly predictive of a very poor prognosis. Here we aimed to identify the underlying mechanism(s) of this protein loss in relation to osteosarcoma behavior. The CDKN2A locus was analyzed in osteosarcoma cases with total loss of CDKN2A/p16 expression and in cases with high protein expression using melting curve analysis-methylation assay (MCA-Meth), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and mutation analysis. All cases with complete CDKN2A/p16 protein loss showed homozygous deletions at the CDKN2A locus. In none of the cases hyper methylation of the promoter region was seen which was confirmed by sequencing this region. Taken together we show that large or smaller deletions of the CDKN2A locus are evident in patient samples and underlie the CDKN2A/p16 protein expression loss while promoter methylation does not appear to be a mechanism of this expression loss. Genomic loss of CDKN2A instead of promoter methylation might be a plausible explanation for the rapid proliferation and high aggressiveness of osteosarcoma by simultaneous impairment CDKN2A/p14(ARF) function. © 2010 Wiley-Liss, Inc.

  3. Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

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    Lim, Annette M; Do, Hongdo; Young, Richard J; Wong, Stephen Q; Angel, Christopher; Collins, Marnie; Takano, Elena A; Corry, June; Wiesenfeld, David; Kleid, Stephen; Sigston, Elizabeth; Lyons, Bernard; Fox, Stephen B; Rischin, Danny; Dobrovic, Alexander; Solomon, Benjamin

    2014-08-15

    CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome. © 2014 UICC.

  4. CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

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    Stenvinkel, Peter; Luttropp, Karin; McGuinness, Dagmara; Witasp, Anna; Rashid Qureshi, Abdul; Wernerson, Annika; Nordfors, Louise; Schalling, Martin; Ripsweden, Jonaz; Wennberg, Lars; Söderberg, Magnus; Bárány, Peter; Olauson, Hannes; Shiels, Paul G

    2017-01-01

    Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence. PMID:28192277

  5. Loss of p16 expression and copy number changes of CDKN2A in a spectrum of spitzoid melanocytic lesions.

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    Harms, Paul W; Hocker, Thomas L; Zhao, Lili; Chan, May P; Andea, Aleodor A; Wang, Min; Harms, Kelly L; Wang, Michael L; Carskadon, Shannon; Palanisamy, Nallasivam; Fullen, Douglas R

    2016-12-01

    Spitzoid melanocytic lesions, including Spitz nevi (benign), spitzoid melanoma (malignant), and borderline atypical Spitz tumors (ASTs), frequently present challenges for accurate diagnosis and prognosis. Evaluation for loss of the tumor suppressor p16, encoded by CDKN2A gene on chromosome 9p21.3, has been proposed to be useful for evaluation of spitzoid melanocytic lesions. However, reports on the utility of p16 immunohistochemistry for spitzoid lesions have been conflicting, and few studies have directly compared p16 immunohistochemistry with fluorescence in situ hybridization (FISH) for CDKN2A genomic status. We analyzed a spectrum of benign (n=24), borderline (n=27), and malignant (n=19) spitzoid lesions for p16 protein expression by immunohistochemistry and CDKN2A copy number by FISH. Immunohistochemistry was evaluated by 2 scoring methods: H score and 2-tiered score (positive or negative for p16 loss). By immunohistochemistry, loss of p16 expression was not observed in Spitz nevi (0/24) but was seen in ASTs (7/27; 26%) and spitzoid melanomas (3/19; 16%). By H score, p16 expression was significantly higher in Spitz nevi relative to ASTs or spitzoid melanomas. Similarly, copy number aberrations of CDKN2A by FISH were absent in Spitz nevi but were found in 2 (9.5%) of 21 ASTs and 4 (33%) of 12 spitzoid melanomas. Our findings from this large cohort suggest that p16 aberrations are highly specific for borderline and malignant spitzoid neoplasms relative to Spitz nevi. Similar to ASTs, p16 loss in spitzoid melanomas may occur in the presence or absence of genomic CDKN2A loss.

  6. Promoter methylation status of hMLH1,MGMT,and CDKN2A/p16 in colorectal adenomas

    Institute of Scientific and Technical Information of China (English)

    Vasiliki; Psofaki; Chryssoula; Kalogera; Nikolaos; Tzambouras; Dimitrios; Stephanou; Epameinondas; Tsianos; Konstantin; Seferiadis; Georgios; Kolios

    2010-01-01

    AIM:To investigate aberrant DNA methylation of CpG islands and subsequent low-or high-level DNA microsatellite instability(MSI)which is assumed to drive colon carcinogenesis. METHODS:DNA of healthy individuals,adenoma(tu-bular or villous/tubulovillous)patients,and colorectal carcinoma patients who underwent colonoscopy was used for assessing the prevalence of aberrant DNA methylation of human DNA mismatch repair gene mutator L homologue 1(hMLH1),Cyclin-dependent kinase inhibitor 2A(CDKN2A/p16),and O-6-methy...

  7. Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma.

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    Wu, Di; Hiroshima, Kenzo; Yusa, Toshikazu; Ozaki, Daisuke; Koh, Eitetsu; Sekine, Yasuo; Matsumoto, Shinji; Nabeshima, Kazuki; Sato, Ayuko; Tsujimura, Tohru; Yamakawa, Hisami; Tada, Yuji; Shimada, Hideaki; Tagawa, Masatoshi

    2017-02-01

    Malignant mesothelioma is a highly aggressive neoplasm, and the histologic subtype is one of the most reliable prognostic factors. Some biphasic mesotheliomas are difficult to distinguish from epithelioid mesotheliomas with atypical fibrous stroma. The aim of this study was to analyze p16/CDKN2A deletions in mesotheliomas by fluorescence in situ hybridization (FISH) and BAP1 immunohistochemistry to evaluate their potential role in the diagnosis of biphasic mesothelioma. We collected 38 cases of pleural mesotheliomas. The results of this study clearly distinguished 29 cases of biphasic mesothelioma from 9 cases of epithelioid mesothelioma. The proportion of biphasic mesotheliomas with homozygous deletions of p16/CDKN2A in total was 96.6% (28/29). Homozygous deletion of p16/CDKN2A was observed in 18 (94.7%) of 19 biphasic mesotheliomas with 100% concordance of the p16/CDKN2A deletion status between the epithelioid and sarcomatoid components in each case. Homozygous deletion of the p16/CDKN2A was observed in 7 (77.8%) of 9 epithelioid mesotheliomas but not in fibrous stroma. BAP1 loss was observed in 5 (38.5%) of 13 biphasic mesotheliomas and in both epithelioid and sarcomatoid components. BAP1 loss was observed in 5 (62.5%) of 8 epithelioid mesotheliomas but not in fibrous stroma. Homozygous deletion of p16/CDKN2A is common in biphasic mesotheliomas, and the analysis of only one component of mesothelioma is sufficient to show that the tumor is malignant. However, compared with histology alone, FISH analysis of the p16/CDKN2A status and BAP1 immunohistochemistry in the spindled mesothelium provide a more objective means to differentiate between biphasic mesothelioma and epithelioid mesothelioma with atypical stromal cells.

  8. BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.

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    M McGregor, Stephanie; McElherne, James; Minor, Agata; Keller-Ramey, Jennifer; Dunning, Ryan; Husain, Aliya N; Vigneswaran, Wickii; Fitzpatrick, Carrie; Krausz, Thomas

    2017-02-01

    BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.

  9. Correlation between indoleamine 2,3 dioxygenase mRNA and CDKN2A/p16 mRNA: a combined strategy to cervical cancer diagnosis.

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    Saffi Junior, Mario Cezar; Duarte, Ivone da Silva; Brito, Rodrigo Barbosa de Oliveira; Prado, Giovana Garcia; Makabe, Sergio; Dellê, Humberto; Camacho, Cleber P

    2016-11-01

    Cervical cancer (CC) is one of the most common cancers among women worldwide. The relation of the human papillomavirus (HPV) with CC and its precursor lesions was first suspected for over 40 years. The indoleamine 2,3 dioxygenase (IDO) is an immune modulator enzyme responsible for the immune system tissue protection mechanism, which may be the key to the tumoural persistence. HPV oncoprotein E7 promotes the increase in cyclin-dependent kinase inhibitor p16 (CDKN2A/p16). The isolated and combined analysis of CDKN2A/p16 mRNA to CC diagnosis was done with promising results. The aim of this study is to evaluate the correlation between IDO mRNA and CDKN2A/p16 mRNA. We will explore the potential of both as diagnostic tools. RNA was extracted from tissue samples. cDNA was generated with High Capacity RNA-to-cDNA kit. The real-time PCR results were analysed using nonlinear curve estimation, ROC curve, Chi-squared test, the proportion of variance explained and Galen and Gambino formulas. From 270 patients attended, colposcopy examination was performed in 110 and the biopsy in 75 patients. We found a positive correlation in patients older than 28 years old with low-risk lesions, but the correlation is lost in high-risk lesions. Although cytology, IDO mRNA and CDKN2A/p16 mRNA could not differentiate the risk groups, IDO combined with CDKN2A/p16 mRNA results could (p = 0.028). The best diagnostic result was achieved by IDO coupled with CDKN2A/p16 mRNA, which may considerably increase the sensitivity of screening for CC.

  10. Inverse association of p16 INK4a and p14 ARF methylation of the CDKN2a locus in different Gleason scores of prostate cancer.

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    Verdoodt, B; Sommerer, F; Palisaar, R-J; Noldus, J; Vogt, M; Nambiar, S; Tannapfel, A; Mirmohammadsadegh, A; Neid, M

    2011-12-01

    Promoter hypermethylation is an important epigenetic mechanism in the regulation of several key modulators of prostate carcinoma progression. Recent studies suggest that the polycomb-group (PcG) protein BMI1 may have an impact on epigenetic regulation of several targets, including the CDKN2a locus. In this study, we investigated the association of BMI1 expression, promoter methylation of CDKN2a (p16(INK4a) and p14(ARF)) and TMS1 with pathological variables (Gleason score, TNM stage, perineural invasion) in prostate cancer (PCa). Methylation of p16(INK4a) and p14(ARF) revealed an inverse association with Gleason score 7b and Gleason score 6. No significant association could be demonstrated for BMI1 -overexpression and promoter methylation of p16(INK4a), p14(ARF) and TMS1 as well as pT category. Our data suggest that the CDKN2a locus is a switch in PCa with methylation of p16(INK4a) being a marker for more aggressive tumours of Gleason score 7b, but no association with BMI overexpression was observed.

  11. Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells.

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    Tolg, Cornelia; Sabha, Nesrin; Cortese, Rene; Panchal, Trupti; Ahsan, Alya; Soliman, Ashraf; Aitken, Karen J; Petronis, Arturas; Bägli, Darius J

    2011-06-01

    Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH-negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P=0.002 UPEC vs non-inoculated and 250-fold P=0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P=0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P=0.007 UPEC vs non-inoculated and 3.3-fold P=0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P=0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8-fold P=0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence.

  12. Lack of evidence for mutations or deletions in the CDKN2A/p16 and CDKN2B/p15 genes of Brazilian neuroblastoma patients

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    Bassi C.L.

    2004-01-01

    Full Text Available Neuroblastoma, the most common extracranial tumor in childhood, has a wide spectrum of clinical and biological features. The loss of heterozygosity within the 9p21 region has been reported as a prognostic factor. Two tumor suppressor genes located in this region, the CDKN2B/p15 and CDKN2A/p16 (cyclin-dependent kinase inhibitors 2B and 2A, respectively genes, play a critical role in cell cycle progression and are considered to be targets for tumor inactivation. We analyzed CDKN2B/p15 and CDKN2A/p16 gene alterations in 11 patients, who ranged in age from 4 months to 13 years (male/female ratio was 1.2:1. The most frequent stage of the tumor was stage IV (50%, followed by stages II and III (20% and stage I (10%. The samples were submitted to the multiplex PCR technique for homozygous deletion analysis and to single-strand conformation polymorphism and nucleotide sequencing for mutation analysis. All exons of both genes were analyzed, but no deletion was detected. One sample exhibited shift mobility specific for exon 2 in the CDKN2B/p15 gene, not confirmed by DNA sequencing. Homozygous deletions and mutations are not involved in the inactivation mechanism of the CDKN2B/p15 and CDKN2A/p16 genes in neuroblastoma; however, these two abnormalities do not exclude other inactivation pathways. Recent evidence has shown that the expression of these genes is altered in this disease. Therefore, other mechanisms of inactivation, such as methylation of promoter region and unproperly function of proteins, may be considered in order to estimate the real contribution of these genes to neuroblastoma genesis or disease progression.

  13. CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma.

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    Sibin, M K; Bhat, Dhananjaya I; Narasingarao, K V L; Lavanya, Ch; Chetan, G K

    2015-09-01

    Human high-grade glioma is heterogeneous in nature based on pathological and genetic profiling. Various tumour suppressor gene alterations are considered as prognostic markers in high-grade glioma. Gene expression of CDKN2A (p16) is used in various cancers as a prognostic biomarker along with methylation and deletion status of this gene. Expression levels of p16 mRNA were not studied as a biomarker in gliomas before. In this study, we have performed mRNA quantification analysis on 48 high-grade glioma tissues and checked for a possible prognostic role. The decreased expression of p16 mRNA in majority of the tumour tissues (57.1 %) was observed when compared to control tissues (P = 0.02). mRNA expression level was correlated with clinical variables also. p16 deletion status and BMI1 mRNA expression were also considered for comparison. p16 mRNA was negatively correlated with the BMI1 mRNA (P = p16 deletion. p16 mRNA expression, midline shift in MRI and tumour type were able to predict patient survival in overall survival (OS) and progression-free survival (PFS). p16 mRNA could independently predict prognosis of OS (P = 0.0146) and PFS (P = 0.0305) in multivariate analysis. We have shown that p16 mRNA expression can act as an independent prognostic biomarker in high-grade glioma.

  14. Evaluation of feline oral squamous cell carcinomas for p16CDKN2A protein immunoreactivity and the presence of papillomaviral DNA.

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    Munday, John S; Knight, Cameron G; French, Adrienne F

    2011-04-01

    Oral squamous cell carcinomas (OSCCs) develop commonly in cats. While the cause of the feline neoplasms is unknown, a quarter of human OSCCs are caused by papillomavirus (PV) infection. As PV DNA has been previously detected in a feline OSCC, it was hypothesised that PV infection could be a significant cause of feline OSCCs. Human OSCCs that are caused by PVs contain increased p16(CDKN2A) protein (p16), which can be detected using immunohistochemistry. In cats, increased p16 immunoreactivity has been reported within PV-associated skin lesions. This study evaluated p16 immunoreactivity within 30 feline OSCCs. Additionally, PCR was used to amplify PV DNA from the OSCCs. Increased p16 immunoreactivity was present within 2 OSCCs. However, as PV DNA was not amplified from any OSCC in this study, it cannot be confirmed that the increased p16 was caused by PV infection. Therefore, these results do not support the hypothesis that PVs are a significant cause of OSCCs in cats. Loss of p16 expression is considered an important process in the development of human non-PV-induced OSCCs. In contrast, loss of p16 immunoreactivity was only present in 2 feline OSCCs. This suggests that human and feline OSCCs develop due to different molecular mechanisms.

  15. CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small cell lung cancer

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    Tam, Kit W.; Zhang, Wei; Soh, Junichi; Stastny, Victor; Chen, Min; Sun, Han; Thu, Kelsie; Rios, Jonathan J.; Yang, Chenchen; Marconett, Crystal N.; Selamat, Suhaida A.; Laird-Offringa, Ite A; Taguchi, Ayumu; Hanash, Samir; Shames, David; Ma, Xiaotu; Zhang, Michael Q; Lam, Wan L.; Gazdar, Adi

    2013-01-01

    Introduction CDKN2A(p16) inactivation is common in lung cancer and occurs via homozygous deletions (HD), methylation of promoter region, or point mutations. While p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. Methods We determined all three p16 inactivation mechanisms using multiple methodologies for genomic status, methylation, RNA and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary NSCLC. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. Results p16 inactivation was the major mechanism of RB pathway perturbation in NSCLC, with HD being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. Conclusions Our results confirm that all of the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status. PMID:24077454

  16. CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer.

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    Tam, Kit W; Zhang, Wei; Soh, Junichi; Stastny, Victor; Chen, Min; Sun, Han; Thu, Kelsie; Rios, Jonathan J; Yang, Chenchen; Marconett, Crystal N; Selamat, Suhaida A; Laird-Offringa, Ite A; Taguchi, Ayumu; Hanash, Samir; Shames, David; Ma, Xiaotu; Zhang, Michael Q; Lam, Wan L; Gazdar, Adi

    2013-11-01

    CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.

  17. Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population.

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    Thakur, Nisha; Hussain, Showket; Nasare, Vilas; Das, Bhudev C; Basir, Seemi Farhat; Bharadwaj, Mausumi

    2012-01-01

    The potent tumor suppressors P16 and RB1 are the key regulators of cell cycle machinery in eukaryotes. Polymorphisms in these genes play an important role in the outcome of various diseases including cancer. In the present study, we evaluated the association of p16 and RB1 polymorphisms with cervical cancer susceptibility in Indian population. We screened 150 histologically confirmed cervical cancer cases along with equal number of healthy controls with normal cervical cytology. PCR-RFLP method was employed for genotyping of SNPs in p16 C540G (rs11515), C580T (rs3088440) in the 3'-UTR of exon 3 and RB1 A153104G (rs4151580) located in the intron 18 and confirmed by direct sequencing. Both patients and controls were screened for HPV infection. In this case-control study 84.67% (127/150) of cases were found to be positive for HPV DNA sequence. Women carrying p16 C540G carrier genotypes 540 (CG/GG) may have protective effect for the development of cervical cancer (P=0.0001, OR=0.31, 95% CI=0.17-0.56). And SNP at C580T of p16 gene was found to be negatively associated with the risk of cervical cancer (P=0.0004, OR=0.04, 95% CI=0.002-0.63). p16 (540C/580T) has emerged as a major risk haplotype (P=0.033, OR=1.47, 95% CI=1.05-2.07) whereas p16 (540G/580T) as a chief protective haplotype (P=0.014, OR=0.39, 95% CI=0.18-0.83) for the development of cervical cancer among Indian women. Contrary to this, SNP at A153104G of RB1 gene showed statistically significant association (P=0.035, OR=1.69, 95% CI=1.06-2.68) with increased susceptibility for the development of cervical cancer. Our results suggest that single nucleotide polymorphisms in p16, RB1 genes may affect the susceptibility to cervical cancer collectively.

  18. Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis.

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    Wu, Di; Hiroshima, Kenzo; Matsumoto, Shinji; Nabeshima, Kazuki; Yusa, Toshikazu; Ozaki, Daisuke; Fujino, Michio; Yamakawa, Hisami; Nakatani, Yukio; Tada, Yuji; Shimada, Hideaki; Tagawa, Masatoshi

    2013-01-01

    The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.

  19. Increased p16CDKN2A protein within feline cutaneous viral plaques, bowenoid in situ carcinomas, and a subset of invasive squamous cell carcinomas.

    Science.gov (United States)

    Munday, J S; French, A F; Peters-Kennedy, J; Orbell, G M B; Gwynne, K

    2011-03-01

    Cutaneous viral plaques and bowenoid in situ carcinomas (BISCs) in cats are thought to be caused by papillomavirus (PV) infection. There is evidence that PVs may also cause some feline invasive squamous cell carcinomas (ISCCs). Human oncogenic PVs degrade retinoblastoma (RB) protein, impairing cell cycle control. Loss of RB function also increases p16(CDKN2A) protein (p16), and increased p16 immunoreactivity within a human oral ISCC indicates that the neoplasm was caused by PV infection. In the present study, p16 immunoreactivity was evaluated in 14 feline viral plaques, 14 BISCs, 7 non-solar-induced ISCCs, 11 solar-induced ISCCs, and 14 trichoblastomas. Increased p16 was present within all viral plaques, BISCs, and non-solar-induced ISCCs. In contrast, little p16 immunoreactivity was visible in the solar-induced ISCCs or trichoblastomas. PV DNA was consistently amplified from viral plaques, BISCs, and non-solar-induced ISCCs. However, just 5 solar-induced ISCCs and 1 trichoblastoma contained PV DNA. Given that both increased p16 immunoreactivity and PV DNA were present within viral plaques, BISCs, and non-solar-induced ISCCs, all 3 may be caused by PV infection. This suggests that feline non-solar-induced ISCCs may develop as a result of neoplastic progression from viral plaques and BISCs. Whether PVs promote this progression is unknown; however, evidence from this study suggests the PV that is associated with viral plaques and BISCs is able to disrupt the p16-RB pathway and therefore could have oncogenic potential. Immunohistochemical detection of p16 appears to be a useful technique to investigate the role of PVs in feline skin disease.

  20. Papillomaviral DNA and increased p16CDKN2A protein are frequently present within feline cutaneous squamous cell carcinomas in ultraviolet-protected skin.

    Science.gov (United States)

    Munday, John S; Gibson, Isobel; French, Adrienne F

    2011-08-01

    Squamous cell carcinomas (SCCs) are common feline skin tumours. While exposure to ultraviolet (UV) light causes some SCCs, a subset develop in UV-protected skin. In cats, papillomaviruses (PVs) cause viral plaques and Bowenoid in situ carcinomas (BISCs). As both may progress to SCC, it was hypothesized that SCCs in UV-protected skin may represent neoplastic transformation of a PV-induced lesion. To investigate this hypothesis, PCR was used to amplify PV DNA from 25 UV-protected and 45 UV-exposed SCCs. Oncogenic human PVs cause neoplasia by mechanisms that also increase p16(CDKN2A) protein (p16). As increased p16 is present in feline viral plaques and BISCs, immunohistochemistry was used to detect p16 within the SCCs. Papillomaviral DNA was amplified from 76% of UV-protected SCCs, but only 42% of UV-exposed SCCs. Increased p16 was present in 84% of UV-protected SCCs, but only 40% of UV-exposed SCCs. The more frequent detection of PV DNA and increased p16 within UV-protected SCCs supports the hypothesis that some develop from a PV-induced plaque or BISC. Felis domesticus PV-2 is thought to cause viral plaques and BISCs. This PV was detected most frequently within the UV-protected SCCs, supporting development from a PV-induced lesion. Increased p16 and PV DNA were less frequent within UV-exposed SCCs, presumably because these developed from actinic keratosis rather than a PV-induced lesion. The results support the hypothesis that some feline cutaneous SCCs are caused by PV infection and suggest that PVs may cause neoplasia by mechanisms that also increase p16.

  1. A neurogenic tumor containing a low-grade malignant peripheral nerve sheath tumor (MPNST) component with loss of p16 expression and homozygous deletion of CDKN2A/p16: a case report showing progression from a neurofibroma to a high-grade MPNST.

    Science.gov (United States)

    Tajima, Shogo; Koda, Kenji

    2015-01-01

    Development of malignant peripheral nerve sheath tumors (MPNSTs) is a stepwise process that involves the alteration of many cell cycle regulators and the double inactivation of the NF1 gene. Inactivation of the TP53 gene and deletion of the CDKN2A/p16 gene are known to play an important role in the process. Herein, we present a 19-year-old man with a familial history of neurofibromatosis type 1, in whom the tumor arose from the intercostal nerve and showed 3 components: a neurofibroma, a low-grade MPNST, and a high-grade MPNST. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene were observed in both the low-grade and the high-grade MPNST. In contrast to low-grade MPNSTs, high-grade MPNSTs generally tend to lose expression of p16 and harbor homozygous deletion of the CDKN2A/p16 gene. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene in low-grade MPNST in our case might be related to its progression to high-grade MPNST. To the best of our knowledge, this is the first study correlating the p16 expression status and CDKN2A/p16 gene alteration in low-grade MPNSTs.

  2. Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone.

    Science.gov (United States)

    Conceição, André Luis Giacometti; Babeto, Erica; Candido, Natalia Maria; Franco, Fernanda Craveiro; de Campos Zuccari, Débora Aparecida Pires; Bonilha, Jane Lopes; Cordeiro, José Antônio; Calmon, Marilia Freitas; Rahal, Paula

    2015-01-01

    Though benign, giant cell tumor of bone (GCTB) can become aggressive and can exhibit a high mitotic rate, necrosis and rarely vascular invasion and metastasis. GCTB has unique histologic characteristics, a high rate of multinucleated cells, a variable and unpredictable growth potential and uncertain biological behavior. In this study, we sought to identify genes differentially expressed in GCTB, thus building a molecular profile of this tumor. We performed quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry and analyses of methylation to identify genes that are putatively associated with GCTB. The expression of the ADAM23 and CDKN2A genes was decreased in GCTB samples compared to normal bone tissue, measured by qPCR. Additionally, a high hypermethylation frequency of the promoter regions of ADAM23 and CDKN2A in GCTB was observed. The expression of the MAP2K3, MMP14, TIMP2 and VIM genes was significantly higher in GCTB than in normal bone tissue, a fact that was confirmed by qPCR and immunohistochemistry. The set of genes identified here furthers our understanding of the molecular basis of GCTB.

  3. CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer

    National Research Council Canada - National Science Library

    Tam, Kit W; Zhang, Wei; Soh, Junichi; Stastny, Victor; Chen, Min; Sun, Han; Thu, Kelsie; Rios, Jonathan J; Yang, Chenchen; Marconett, Crystal N; Selamat, Suhaida A; Laird-Offringa, Ite A; Taguchi, Ayumu; Hanash, Samir; Shames, David; Ma, Xiaotu; Zhang, Michael Q; Lam, Wan L; Gazdar, Adi

    2013-01-01

    .... Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still...

  4. Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16(Ink4a)) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats.

    Science.gov (United States)

    Tsuchiya, Takuma; Wang, Liyun; Yafune, Atsunori; Kimura, Masayuki; Ohishi, Takumi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-09-28

    Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16(Ink4a) following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P(+) liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P(+) foci, checkpoint proteins at G(1)/S (p21(Cip1), p27(Kip1) and p16(Ink4a)) and G(2)/M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P(+) foci was either increased or decreased with proteins related to G(2)-M phase or DNA damage (topoisomerase IIα, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16(Ink4a) typically downregulated in GST-P(+) foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G(1)/S and G(2)/M proteins, which allows for clonal selection of GST-P(+) foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P(+) foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16(Ink4a)-downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism. Copyright © 2012

  5. Estudo genético do gene p16 pela técnica de PCR-SSCP e expressão de proteína p16 em melanomas de mucosa oral e melanomas cutâneos Genetic analysis of p16 gene by PCR-SSCP technique and protein p16 expression in oral mucosa and skin melanomas

    Directory of Open Access Journals (Sweden)

    Ricardo Hsieh

    2006-10-01

    Full Text Available FUNDAMENTOS: A deleção e mutação do gene CDKN2a que codifica um inibidor específico da ciclina dependente de quinase 4, a proteína p16, têm sido implicadas na tumorigênese do melanoma cutâneo. Entretanto, pouco se conhece sobre essas alterações genéticas em melanomas de mucosa oral. OBJETIVOS: Verificar a presença de alterações no gene p16 e sua expressão protéica em melanomas esporádicos orais e cutâneos. MATERIAL E MÉTODOS: Avaliaram-se 36 espécimes de melanoma primário (sete orais e 29 cutâneos. Analisaram-se três exons do gene p16, pela técnica da reação em cadeia da polimerase/polimorfismo conformacional de fita simples do DNA.Verificou-se a expressão tecidual de proteína p16 por técnica imuno-histoquímica. Relacionaram-se os resultados com a espessura dos melanomas cutâneos. RESULTADOS: Cinco dos sete melanomas orais e 17 dos 29 melanomas cutâneos apresentaram indício de alteração no gene p16. Alterações do exon 2 foram as mais freqüentes, sendo 19 casos nos produtos obtidos com o mesmo iniciador. Observou-se expressão tecidual de p16 em apenas um melanoma oral, em 10/13 (76,9% casos de melanoma cutâneo de espessura até 1mm e em sete de oito (87,5% casos de espessura superior a 1mm. CONCLUSÃO: A freqüência de indícios de alteração na análise genética de p16 nos melanomas de mucosa oral foi de 71,42% e de 58,6% nos cutâneos. É possível sugerir a participação de alterações do gene p16 na patogenia do melanoma esporádico de mucosa oral. Não houve relação da sugestão de alteração genética do gene p16 e de sua expressão tecidual com a espessura dos melanomas cutâneos de diferentes subtipos histológicos.BACKGROUND: Deletion and mutation of gene CDKN2a, which encodes a specific inhibitor of cyclin-dependent kinase 4 (CDK4, the protein p16, has been regarded as related to cutaneous melanoma tumorigenesis. However, little is known about those alterations in oral mucosa melanomas

  6. Detection of Homozygous Deletions and Mutations in the CDKN2A Gene in Hydatidiform Moles

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Shuying Wu; Ying Gu; Yan Zhu; Xiaowei Zhang

    2008-01-01

    OBJECTIVE To investigate homozygous deletions and mutations in the CDKN2A gene (p16INK4a and p14ARF gene) in hydatidiform moles.METHODS A total of 38 hydatidiform mole samples and 30 villi samples were examined for homozygous deletions in the CDKN2A gene by PCR and for mutations by DHPLC.RESULTS I) Among 38 hydatidiform mole samples,homozygous deletions in the p16INK4a exon 1 were identified in 5 cases (13.2%), while no homozygous deletions were found in the p16INK4a exon 1 of 30 early-pregnancy samples. The rates of those deletions in hydatidiform compared to early-pregnancy villi samples was statistically significant (P = 0.036). Ii) No homozygous deletions in the p14ARF exon 1 or p16INK4a exon 2 were found in any of the hydatidiform moles or early-preganancy samples, iii)In all hydatidiform moles and early-pregnancy villi samples, no mutations were detected by DHPLC.CONCLUSION We suggest there may be a close correlation between homozygous deletions in the CDKN2A gene and occurrence of hydatidiform moles variation in the CDKN2A gene is mainly caused by homozygous deletions, while mutations may be not a major cause.

  7. Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma

    DEFF Research Database (Denmark)

    Møller, Michael Boe; Ino, Y; Gerdes, A M

    1999-01-01

    The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases...... of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were...... hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases...

  8. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.

    Science.gov (United States)

    Lund, Anders H; Turner, Geoffrey; Trubetskoy, Alla; Verhoeven, Els; Wientjens, Ellen; Hulsman, Danielle; Russell, Robert; DePinho, Ronald A; Lenz, Jack; van Lohuizen, Maarten

    2002-09-01

    We have used large-scale insertional mutagenesis to identify functional landmarks relevant to cancer in the recently completed mouse genome sequence. We infected Cdkn2a(-/-) mice with Moloney murine leukemia virus (MoMuLV) to screen for loci that can participate in tumorigenesis in collaboration with loss of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF. Insertional mutagenesis by the latent retrovirus was synergistic with loss of Cdkn2a expression, as indicated by a marked acceleration in the development of both myeloid and lymphoid tumors. We isolated 747 unique sequences flanking retroviral integration sites and mapped them against the mouse genome sequence databases from Celera and Ensembl. In addition to 17 insertions targeting gene loci known to be cancer-related, we identified a total of 37 new common insertion sites (CISs), of which 8 encode components of signaling pathways that are involved in cancer. The effectiveness of large-scale insertional mutagenesis in a sensitized genetic background is demonstrated by the preference for activation of MAP kinase signaling, collaborating with Cdkn2a loss in generating the lymphoid and myeloid tumors. Collectively, our results show that large-scale retroviral insertional mutagenesis in genetically predisposed mice is useful both as a system for identifying genes underlying cancer and as a genetic framework for the assignment of such genes to specific oncogenic pathways.

  9. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas

    NARCIS (Netherlands)

    Harinck, Femme; Kluijt, Irma; van der Stoep, Nienke; Oldenburg, Rogier A.; Wagner, Anja; Aalfs, Cora M.; Sijmons, Rolf H.; Poley, Jan-Werner; Kuipers, Ernst J.; Fockens, Paul; van Os, Theo A. M.; Bruno, Marco J.

    2012-01-01

    Background CDKN2A-mutation carriers run a high risk of developing melanomas and have an increased risk of developing pancreatic cancer (PC). Familial PC (FPC) patients with a personal history or family history of melanomas are therefore offered CDKN2A-mutation analysis. In contrast, CDKN2A testing i

  10. The association between methylated CDKN2A and cervical carcinogenesis, and its diagnostic value in cervical cancer: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Li J

    2016-08-01

    specificity, sensitivity, area under the receiver operating characteristic curve, and diagnostic odds ratio were 0.99 (95% CI: 0.97–0.99, 0.36 (95% CI: 0.28–0.45, 0.93 (95% CI: 0.91–0.95, and 43 (95% CI: 19–98, respectively.Conclusion: Our findings indicate that abnormal CDKN2A methylation may be strongly correlated with the pathogenesis of cervical cancer. Our results also demonstrate that CDKN2A methylation might serve as an early detector of cervical cancer. These findings require further confirmation. Keywords: p16, methylation, cervical cancer carcinogenesis

  11. Role of p53 and CDKN2A Inactivation in Human Squamous Cell Carcinomas

    Directory of Open Access Journals (Sweden)

    Alessia Pacifico

    2007-01-01

    Several studies have shown that human SCCs harbour unique mutations in the p53 gene as well as inactivation of the CDKN2A gene. While mutations in the p53 gene are induced by UV radiation and represent tumor initiating events, the majority of alterations detected in the CDKN2A gene do not appear to be UV-dependent. In conclusion, in addition to p53 mutations, silencing of the CDKN2A gene might play a significant role in SCC development.

  12. CDKN2A and MC1R variants found in Cypriot patients diagnosed with cutaneous melanoma

    Indian Academy of Sciences (India)

    GEORGIA KOULERMOU; CHRISTOS SHAMMAS; ANDREAS VASSILIOU; TASSOS C. KYRIAKIDES; CONSTANTINA COSTI; VASSOS NEOCLEOUS; LEONIDAS A. PHYLACTOU; MARIA PANTELIDOU

    2017-03-01

    The prevalence of genetic variants associated to cutaneous melanoma (CM) has never been determined within Cypriot melanomas. This study evaluates the frequency of variants in cyclin-dependent kinase inhibitor 2A (CDKN2A) andmelanocortin-1 receptor (MC1R) in 32 patients diagnosed with CM. Other characteristics and risk factors were also assessed. CDKN2A p.Ala148Thr was detected in three of 32 patients, while the control group revealed no variationswithin CDKN2A. MC1R screening in 32 patients revealed the following variations: p.Val60Leu in 11 patients, p.Arg142His in four patients, p.Thr314Thr in one patient, p.Arg160Trp in one patient, p.Val92Met/p.Thr314Thr in one patient andp.Val92Met/p.Arg142His/p.Thr314Thr in one patient. The control group revealed only p.Val60Leu (in 10 of 45 individuals), which is frequently found in general populations. Two unrelated patients carried CDKN2A p.Ala148Thr in combination with MC1R p.Arg142His, suggesting digenic inheritance that may provide evidence of different gene variants acting synergistically to contribute for CM development. This study confirms the presence of CDKN2A and MC1R variants among Cypriot melanomas and supports existing evidence of a role for these variants in susceptibility to melanoma.

  13. Normal repair of ultraviolet radiation-induced DNA damage in familial melanoma without CDKN2A or CDK4 gene mutation.

    Science.gov (United States)

    Shannon, J A; Matias, C; Luxford, C; Kefford, R F; Mann, G J

    1999-04-01

    Excessive sun exposure and family history are strong risk factors for the development of cutaneous melanoma. Inherited susceptibility to this type of skin cancer could therefore result from constitutively impaired capacity to repair ultraviolet (UV)-induced DNA lesions. While a proportion of familial melanoma kindreds exhibit germline mutations in the cell cycle regulatory gene CDKN2A (p16INK4a) or its protein target, cyclin-dependent kinase 4 (CDK4), the biochemical basis of most familial melanoma is unknown. We have examined lymphoblastoid cell lines from melanoma-affected and unaffected individuals from large hereditary melanoma kindreds which are not attributable to CDKN2A or CDK4 gene mutation. These lines were tested for sensitivity of clonogenic growth to UV radiation and for their ability to repair transfected UV-damaged plasmid templates (host cell reactivation). Two of seven affected-unaffected pairs differed in colony survival after exposure to UVB radiation; however, no significant differences were observed in the host-cell reactivation assays. These results indicate that melanoma susceptibility genes other than CDKN2A and CDK4 do not impair net capacity to repair UV-induced DNA damage.

  14. CDKN2A-mutation i en familie med arveligt malignt melanom

    DEFF Research Database (Denmark)

    Djursby, Malene; Wadt, Karin; Lorentzen, Henrik;

    2014-01-01

    Malignant melanoma (MM) is a frequent form of cancer with increasing incidence. 6-10% of patients with MM report a family history of MM, and in most populations 2% of unselected cases of MM carry a CDKN2A mutation. tvWe present a family with 24 cases of MM in nine persons from several generations......, caused by a previously undescribed germ-line intronic mutation in CDKN2A. Through genetic counselling and genetic testing high-risk persons in the family are located and offered regular screening for MM.......Malignant melanoma (MM) is a frequent form of cancer with increasing incidence. 6-10% of patients with MM report a family history of MM, and in most populations 2% of unselected cases of MM carry a CDKN2A mutation. tvWe present a family with 24 cases of MM in nine persons from several generations...

  15. Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation

    DEFF Research Database (Denmark)

    Nielsen, G P; Stemmer-Rachamimov, A O; Ino, Y

    1999-01-01

    Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We...

  16. The CDKN2A G500 allele is more frequent in GBM patients with no defined telomere maintenance mechanism tumors and is associated with poorer survival.

    Directory of Open Access Journals (Sweden)

    Janice A Royds

    Full Text Available Prognostic markers for glioblastoma multiforme (GBM are important for patient management. Recent advances have identified prognostic markers for GBMs that use telomerase or the alternative lengthening of telomeres (ALT mechanism for telomere maintenance. Approximately 40% of GBMs have no defined telomere maintenance mechanism (NDTMM, with a mixed survival for affected individuals. This study examined genetic variants in the cyclin-dependent kinase inhibitor 2A (CDKN2A gene that encodes the p16(INK4a and p14(ARF tumor suppressors, and the isocitrate dehydrogenase 1 (IDH1 gene as potential markers of survival for 40 individuals with NDTMM GBMs (telomerase negative and ALT negative by standard assays, 50 individuals with telomerase, and 17 individuals with ALT positive tumors. The analysis of CDKN2A showed NDTMM GBMs had an increased minor allele frequency for the C500G (rs11515 polymorphism compared to those with telomerase and ALT positive GBMs (p = 0.002. Patients with the G500 allele had reduced survival that was independent of age, extent of surgery, and treatment. In the NDTMM group G500 allele carriers had increased loss of CDKN2A gene dosage compared to C500 homozygotes. An analysis of IDH1 mutations showed the R132H mutation was associated with ALT positive tumors, and was largely absent in NDTMM and telomerase positive tumors. In the ALT positive tumors cohort, IDH1 mutations were associated with a younger age for the affected individual. In conclusion, the G500 CDKN2A allele was associated with NDTMM GBMs from older individuals with poorer survival. Mutations in IDH1 were not associated with NDTMM GBMs, and instead were a marker for ALT positive tumors in younger individuals.

  17. Promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A genes in cervical carcinoma.

    Science.gov (United States)

    Banzai, Chiaki; Nishino, Koji; Quan, Jinhua; Yoshihara, Kosuke; Sekine, Masayuki; Yahata, Tetsuro; Tanaka, Kenichi

    2014-02-01

    Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of human cancer. This study explored the relationship between promoter methylation and inactivation of the DAPK1, FHIT, MGMT, and CDKN2A genes in cervical cancer. The promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A was investigated by using a methylation-specific polymerase chain reaction in 53 specimens of cervical cancer (42 squamous cell carcinoma, 11 adenocarcinoma), 22 specimens of intraepithelial neoplasia tissues, and 24 control normal cervical tissue specimens. The correlation of promoter methylation with the clinicopathological features of cervical cancer was analyzed. The expressions of DAPK1, FHIT, MGMT, and CDKN2A were detected by measuring relative mRNA levels. The promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A in cervical cancer vs. intraepithelial neoplasia vs. normal cervical tissue was 75.5 vs. 31.8 vs. 4.2 % (p promoter region significantly decreased the expression of only DAPK1 (p = 0.03). The methylation rate of the DAPK1 gene promoter was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasia and normal cervical tissues. Promoter methylation may therefore lead to the inactivation of the DAPK1 gene, and may be related to the progression of cervical oncogenesis.

  18. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study.

    Science.gov (United States)

    Jardin, Fabrice; Jais, Jean-Philippe; Molina, Thierry-Jo; Parmentier, Françoise; Picquenot, Jean-Michel; Ruminy, Philippe; Tilly, Hervé; Bastard, Christian; Salles, Gilles-André; Feugier, Pierre; Thieblemont, Catherine; Gisselbrecht, Christian; de Reynies, Aurelien; Coiffier, Bertrand; Haioun, Corinne; Leroy, Karen

    2010-08-19

    Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

  19. Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein

    NARCIS (Netherlands)

    Ceha, H.M.; Nasser, I.; Medema, R.H.; Slebos, R.J.C.

    1998-01-01

    Cyclin-dependent kinase 4 (CDK4) is a key molecule in the regulation of cell cycle progression at the G1-S phase restriction point. Its activity is specifically regulated by p16 (also known as p16/CDKN2A, p16INK4a, andMTS1), a tumor suppressor frequently altered in human cancers. A specific mutation

  20. p15(Ink4b) is a critical tumour suppressor in the absence of p16(Ink4a)

    NARCIS (Netherlands)

    Krimpenfort, Paul; IJpenberg, Annemieke; Song, Ji-Ying; van der Valk, Martin; Nawijn, Martijn; Zevenhoven, John; Berns, Anton

    2007-01-01

    The CDKN2b-CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15(INK4b) encoded by CDKN2b, p16(INK4a) encoded by CDKN2a and p14(ARF) (p19(Arf) in mice) encoded by an alternative reading frame of CDKN

  1. The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer

    Science.gov (United States)

    Shearin, Abigail L.; Hedan, Benoit; Cadieu, Edouard; Erich, Suzanne A.; Schmidt, Emmett V.; Faden, Daniel L.; Cullen, John; Abadie, Jerome; Kwon, Erika M.; Gröne, Andrea; Devauchelle, Patrick; Rimbault, Maud; Karyadi, Danielle M.; Lynch, Mary; Galibert, Francis; Breen, Matthew; Rutteman, Gerard R.; André, Catherine; Parker, Heidi G.; Ostrander, Elaine A.

    2012-01-01

    Background Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD). Methods Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Impact Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region. PMID:22623710

  2. CDKN2A (INK4A-ARF) mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma.

    NARCIS (Netherlands)

    Blokx, W.A.M.; Lesterhuis, W.J.; Andriessen, M.P.M.; Verdijk, M.A.J.; Punt, C.J.A.; Ligtenberg, M.J.L.

    2007-01-01

    The histologic differential diagnosis between a second primary cutaneous melanoma and cutaneous melanoma metastasis in a patient with a previous history of melanoma can be very difficult. This case report describes the first application of CDKN2A mutation analysis for discriminating a cutaneous

  3. The Regulatory Mechanisms of Tumor Suppressor P16INK4A and Relevance to Cancer†

    OpenAIRE

    Li, Junan; Poi, Ming Jye; Tsai, Ming-Daw

    2011-01-01

    P16INK4A (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly due to the prevalence of genetic inactivation of the p16INK4A (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that elevated expression (up-regulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the r...

  4. Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation

    Science.gov (United States)

    Wei, Lei; Liu, Biao; Hu, Qiang; Miles, Kiersten Marie; Conroy, Jeffrey M.; Glenn, Sean T.; Costantini, Manuela; Magi-Galluzzi, Cristina; Signoretti, Sabina; Choueiri, Toni; Gallucci, Michele; Sentinelli, Steno; Fazio, Vito M.; Poeta, Maria Luana; Liu, Song; Morrison, Carl; Pili, Roberto

    2016-01-01

    The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 −7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53, and ZNF521. SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies. PMID:27144525

  5. Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone

    OpenAIRE

    Conceição, André Luis Giacometti; Babeto, Erica [UNESP; Candido, Natalia Maria [UNESP; Franco, Fernanda Craveiro [UNESP; Zuccari, Débora Aparecida Pires de Campos; Bonilha, Jane Lopes; Cordeiro,José Antônio; Calmon, Marilia de Freitas [UNESP; Rahal, Paula

    2015-01-01

    Though benign, giant cell tumor of bone (GCTB) can become aggressive and can exhibit a high mitotic rate, necrosis and rarely vascular invasion and metastasis. GCTB has unique histologic characteristics, a high rate of multinucleated cells, a variable and unpredictable growth potential and uncertain biological behavior. In this study, we sought to identify genes differentially expressed in GCTB, thus building a molecular profile of this tumor. We performed quantitative real-time polymerase ch...

  6. p16 — EDRN Public Portal

    Science.gov (United States)

    The CDKN2A locus generates several transcript variants which differ in their first exons. Two distinct transcripts are produced from different promoters: p16 (INK4A) and p14 (ARF). At least three alternatively spliced variants encoding distinct proteins have been reported, two of which (p16 and p14) encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, MDM1, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.

  7. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

    DEFF Research Database (Denmark)

    Xu, Heng; Zhang, Hui; Yang, Wenjian;

    2015-01-01

    There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant...... of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation...

  8. Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF.

    Science.gov (United States)

    Mangas, C; Potrony, M; Mainetti, C; Bianchi, E; Carrozza Merlani, P; Mancarella Eberhardt, A; Maspoli-Postizzi, E; Marazza, G; Marcollo-Pini, A; Pelloni, F; Sessa, C; Simona, B; Puig-Butillé, J A; Badenas, C; Puig, S

    2016-11-01

    Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate-to-high CM incidence. We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives. Healthy blood donors (n = 146) were included as a control group. From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty-six were melanoma-prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2·76, 95% confidence interval 0·83-9·20). At least one MC1R melanoma-associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0·7%). Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population. © 2016 British Association of Dermatologists.

  9. Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria.

    Directory of Open Access Journals (Sweden)

    Marc Gingell-Littlejohn

    Full Text Available CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post-transplant serum creatinine when compared to "Gold Standard" clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008. Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future.

  10. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.

    Science.gov (United States)

    Mavrakis, Konstantinos J; McDonald, E Robert; Schlabach, Michael R; Billy, Eric; Hoffman, Gregory R; deWeck, Antoine; Ruddy, David A; Venkatesan, Kavitha; Yu, Jianjun; McAllister, Gregg; Stump, Mark; deBeaumont, Rosalie; Ho, Samuel; Yue, Yingzi; Liu, Yue; Yan-Neale, Yan; Yang, Guizhi; Lin, Fallon; Yin, Hong; Gao, Hui; Kipp, D Randal; Zhao, Songping; McNamara, Joshua T; Sprague, Elizabeth R; Zheng, Bing; Lin, Ying; Cho, Young Shin; Gu, Justin; Crawford, Kenneth; Ciccone, David; Vitari, Alberto C; Lai, Albert; Capka, Vladimir; Hurov, Kristen; Porter, Jeffery A; Tallarico, John; Mickanin, Craig; Lees, Emma; Pagliarini, Raymond; Keen, Nicholas; Schmelzle, Tobias; Hofmann, Francesco; Stegmeier, Frank; Sellers, William R

    2016-03-11

    5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.

  11. The Regulatory Mechanisms of Tumor Suppressor P16INK4A and Relevance to Cancer†

    Science.gov (United States)

    Li, Junan; Poi, Ming Jye; Tsai, Ming-Daw

    2011-01-01

    P16INK4A (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly due to the prevalence of genetic inactivation of the p16INK4A (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that elevated expression (up-regulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications in the structure-function relationship of P16 and in human cancers. PMID:21619050

  12. Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes

    DEFF Research Database (Denmark)

    Magnusson, S.; Borg, A.; Kristoffersson, U.

    2008-01-01

    The contribution of hereditary factors for development of childhood tumors is limited to some few known syndromes associated with predominance of tumors in childhood. Occurrence of childhood tumors in hereditary cancer syndromes such as BRCA1/2 associated breast and ovarian cancer, DNA-mismatch r......-mismatch repair (MMR) genes associated hereditary non polyposis colorectal cancer and CDKN2A associated familial malignant melanoma are very little studied. Herein we report the prevalence of childhood tumors (diagnosed......The contribution of hereditary factors for development of childhood tumors is limited to some few known syndromes associated with predominance of tumors in childhood. Occurrence of childhood tumors in hereditary cancer syndromes such as BRCA1/2 associated breast and ovarian cancer, DNA...

  13. Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; A case-control study Medical Genetics

    NARCIS (Netherlands)

    T.P. Potjer (Thomas P.); N. van der Stoep (Nienke); J.J. Houwing-Duistermaat (Jeanine); I.C.A.W. Konings (Ingrid C.A.W.); C.M. Aalfs (Cora); P.C. van den Akker (Peter); M.G.E.M. Ausems (Margreet); C.J. Dommering (Charlotte); L. van der Kolk (Lizet); M.C. Maiburg (Merel C.); L. Spruijt (Liesbeth); A. Wagner (Anja); H. Vasen (Hans); F.J. Hes (Frederik)

    2015-01-01

    textabstractBackground: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer.

  14. Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; a case-control study

    NARCIS (Netherlands)

    T.P. Potjer (Thomas P.); N. van der Stoep (Nienke); J.J. Houwing-Duistermaat (Jeanine); I.C.A.W. Konings (Ingrid C.A.W.); C.M. Aalfs (Cora); P.C. van den Akker (Peter); M.G.E.M. Ausems (Margreet); C.J. Dommering (Charlotte); L. van der Kolk (Lizet); M.C. Maiburg (Merel C.); L. Spruijt (Liesbeth); A. Wagner (Anja); H. Vasen (Hans); F.J. Hes (Frederik)

    2015-01-01

    textabstractBackground: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer.

  15. Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.

    Directory of Open Access Journals (Sweden)

    Laura S Burke

    Full Text Available INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04. The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002. One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002 after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

  16. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B

    DEFF Research Database (Denmark)

    Hribal, M L; Presta, I; Procopio, T

    2011-01-01

    The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry....

  17. Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer

    Science.gov (United States)

    Puig-Butille, Joan Anton; Escámez, María José; Garcia-Garcia, Francisco; Tell-Marti, Gemma; Fabra, Àngels; Martínez-Santamaría, Lucía; Badenas, Celia; Aguilera, Paula; Pevida, Marta; Dopazo, Joaquín; del Río, Marcela; Puig, Susana

    2014-01-01

    Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. PMID:24742402

  18. Comparison study of MS-HRM and pyrosequencing techniques for quantification of APC and CDKN2A gene methylation.

    Directory of Open Access Journals (Sweden)

    Francesca Migheli

    Full Text Available There is increasing interest in the development of cost-effective techniques for the quantification of DNA methylation biomarkers. We analyzed 90 samples of surgically resected colorectal cancer tissues for APC and CDKN2A promoter methylation using methylation sensitive-high resolution melting (MS-HRM and pyrosequencing. MS-HRM is a less expensive technique compared with pyrosequencing but is usually more limited because it gives a range of methylation estimates rather than a single value. Here, we developed a method for deriving single estimates, rather than a range, of methylation using MS-HRM and compared the values obtained in this way with those obtained using the gold standard quantitative method of pyrosequencing. We derived an interpolation curve using standards of known methylated/unmethylated ratio (0%, 12.5%, 25%, 50%, 75%, and 100% of methylation to obtain the best estimate of the extent of methylation for each of our samples. We observed similar profiles of methylation and a high correlation coefficient between the two techniques. Overall, our new approach allows MS-HRM to be used as a quantitative assay which provides results which are comparable with those obtained by pyrosequencing.

  19. Comparison Study of MS-HRM and Pyrosequencing Techniques for Quantification of APC and CDKN2A Gene Methylation

    Science.gov (United States)

    Migheli, Francesca; Stoccoro, Andrea; Coppedè, Fabio; Wan Omar, Wan Adnan; Failli, Alessandra; Consolini, Rita; Seccia, Massimo; Spisni, Roberto; Miccoli, Paolo; Mathers, John C.; Migliore, Lucia

    2013-01-01

    There is increasing interest in the development of cost-effective techniques for the quantification of DNA methylation biomarkers. We analyzed 90 samples of surgically resected colorectal cancer tissues for APC and CDKN2A promoter methylation using methylation sensitive-high resolution melting (MS-HRM) and pyrosequencing. MS-HRM is a less expensive technique compared with pyrosequencing but is usually more limited because it gives a range of methylation estimates rather than a single value. Here, we developed a method for deriving single estimates, rather than a range, of methylation using MS-HRM and compared the values obtained in this way with those obtained using the gold standard quantitative method of pyrosequencing. We derived an interpolation curve using standards of known methylated/unmethylated ratio (0%, 12.5%, 25%, 50%, 75%, and 100% of methylation) to obtain the best estimate of the extent of methylation for each of our samples. We observed similar profiles of methylation and a high correlation coefficient between the two techniques. Overall, our new approach allows MS-HRM to be used as a quantitative assay which provides results which are comparable with those obtained by pyrosequencing. PMID:23326336

  20. Up and downregulation of p16(Ink4a) expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer.

    Science.gov (United States)

    Kriegl, Lydia; Neumann, Jens; Vieth, Michael; Greten, Florian R; Reu, Simone; Jung, Andreas; Kirchner, Thomas

    2011-07-01

    P16(Ink4a) is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16(Ink4a) in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16(Ink4a) is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16(Ink4a) expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16(Ink4a) expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16(Ink4a) expression and Ki67 expression were mutually exclusive, indicating that p16(Ink4a) acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16(Ink4a) expression appears to be a useful indicator of induction of senescence. Loss of p16(Ink4a) expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.

  1. ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation.

    Science.gov (United States)

    Kobayashi, Takashi; Wang, Jingqiang; Al-Ahmadie, Hikmat; Abate-Shen, Cory

    2013-08-01

    The cell-cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14(ARF) and p16, which have complementary functions as regulators of p53 and pRB tumor suppressor pathways, respectively. The unusual organization of INK4A-ARF has long led to speculation of a need for coordinated regulation of p14(ARF) and p16. We now show that p14(ARF) (ARF) regulates the stability of p16 protein in human cancer cell lines, as well as in mouse embryonic fibroblasts (MEFs). In particular, ARF promotes rapid degradation of p16 protein, which is mediated by the proteasome and, more specifically, by interaction of ARF with one of its subunits, REGγ. Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knockdown of REGγ or by pharmacologic blockade of its nuclear export. Thus, our findings have uncovered a novel crosstalk of 2 key tumor suppressors mediated by a REGγ-dependent mechanism. The ability of ARF to control p16 stability may influence cell-cycle function. The ability of ARF to control p16 stability may influence cell cycle function. Visual Overview: http://mcr.aacrjournals.org/content/current. ©2013 AACR.

  2. Practical issues in the application of p16 immunohistochemistry in diagnostic pathology.

    Science.gov (United States)

    Mahajan, Aparna

    2016-05-01

    The p16 tumor suppressor gene (CDKN2A) is a member of the INK4 class of cell cycle inhibitors and is located on chromosome 9p21. The p16 protein binds to cyclin-dependent kinases 4 and 6 and maintains the retinoblastoma gene product in its hypophosphorylated state, which in turn binds to E2F transcription factor and prevents cell cycle progression. Expression of p16 protein is increased in aging cells. Immunohistochemistry for p16ink4a is most widely used as a surrogate maker for high-risk human papilloma virus infection in formalin-fixed, paraffin-embedded tissues. The most widely researched, accepted, and practiced use of p16 immunostain is in the lower anogenital tract. In addition, p16 immunostain is widely used for oropharyngeal squamous cell carcinoma. Its applications have also been extended to gynecologic tumors, which are unrelated to human papillomavirus. This article aims to review the literature on the diagnostic utility of p16 immunohistochemistry and highlight the practical issues in the application and interpretation of this stain.

  3. 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.

  4. CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A.

    Science.gov (United States)

    Tu, Q; Hao, J; Zhou, X; Yan, L; Dai, H; Sun, B; Yang, D; An, S; Lv, L; Jiao, B; Chen, C; Lai, R; Shi, P; Zhao, X

    2017-09-11

    Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRAS(G12D) expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRAS(G12D) overexpression in these cells activated transforming growth factor-β signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery.Oncogene advance online publication, 11 September 2017; doi:10.1038/onc.2017.316.

  5. Transcriptomic Analysis of the Claudin Interactome in Malignant Pleural Mesothelioma: Evaluation of the Effect of Disease Phenotype, Asbestos Exposure, and CDKN2A Deletion Status

    Science.gov (United States)

    Rouka, Erasmia; Vavougios, Georgios D.; Solenov, Evgeniy I.; Gourgoulianis, Konstantinos I.; Hatzoglou, Chrissi; Zarogiannis, Sotirios G.

    2017-01-01

    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor primarily associated with asbestos exposure. Early detection of MPM is restricted by the long latency period until clinical presentation, the ineffectiveness of imaging techniques in early stage detection and the lack of non-invasive biomarkers with high sensitivity and specificity. In this study we used transcriptome data mining in order to determine which CLAUDIN (CLDN) genes are differentially expressed in MPM as compared to controls. Using the same approach we identified the interactome of the differentially expressed CLDN genes and assessed their expression profile. Subsequently, we evaluated the effect of tumor histology, asbestos exposure, CDKN2A deletion status, and gender on the gene expression level of the claudin interactome. We found that 5 out of 15 studied CLDNs (4, 5, 8, 10, 15) and 4 out of 27 available interactors (S100B, SHBG, CDH5, CXCL8) were differentially expressed in MPM specimens vs. healthy tissues. The genes encoding the CLDN-15 and S100B proteins present differences in their expression profile between the three histological subtypes of MPM. Moreover, CLDN-15 is significantly under-expressed in the cohort of patients with previous history of asbestos exposure. CLDN-15 was also found significantly underexpressed in patients lacking the CDKN2A gene. These results warrant the detailed in vitro investigation of the role of CDLN-15 in the pathobiology of MPM. PMID:28377727

  6. Deletion status of p16 in effusion smear preparation correlates with that of underlying malignant pleural mesothelioma tissue.

    Science.gov (United States)

    Hida, Tomoyuki; Matsumoto, Shinji; Hamasaki, Makoto; Kawahara, Kunimitsu; Tsujimura, Tohru; Hiroshima, Kenzo; Kamei, Toshiaki; Taguchi, Kenichi; Iwasaki, Akinori; Oda, Yoshinao; Honda, Hiroshi; Nabeshima, Kazuki

    2015-11-01

    Differentiating malignant pleural mesothelioma (MPM) cells morphologically from reactive mesothelial hyperplasia cells is problematic. Homozygous deletion (HD) of p16 (CDKN2A), detected by FISH, is a good marker of malignancy and is useful to differentiate between these cells. However, the correlation between the p16 status of effusion smears and that of the underlying MPM tissues has not been investigated. We used p16-specific FISH to investigate 20 cases of MPM from which both effusion cytologic smears and histologic specimens were available. In five cases, histologic specimens included both an invasive component and surface mesothelial proliferation. In 14 cases (70%), MPM cells in both tissue sections and effusion smears were p16 HD-positive. Conversely, MPM cells in the remaining six tumors (30%) were p16 HD-negative in both tissue sections and effusion smears. For all five MPM cases with surface mesothelial proliferations and invasive components, the effusion smears, surface mesothelial proliferations, and invasive MPM components all displayed p16 deletion. Moreover, the extent to which p16 was deleted in smears highly correlated with the extent of p16 deletion in tissues. The p16 deletion percentages were also similar among smears, tissue surface proliferations, and invasive components. In cases with clinical and radiologic evidence of a diffuse pleural tumor, detection of p16 deletion in cytologic smear samples may permit MPM diagnosis without additional tissue examination. However, the absence of p16 deletion in cytologic smear samples does not preclude MPM.

  7. Genome-Wide Overexpression Screen Identifies Genes Able to Bypass p16-Mediated Senescence in Melanoma.

    Science.gov (United States)

    Lee, Won Jae; Škalamera, Dubravka; Dahmer-Heath, Mareike; Shakhbazov, Konstanin; Ranall, Max V; Fox, Carly; Lambie, Duncan; Stevenson, Alexander J; Yaswen, Paul; Gonda, Thomas J; Gabrielli, Brian

    2017-03-01

    Malignant melanomas often arise from nevi, which result from initial oncogene-induced hyperproliferation of melanocytes that are maintained in a CDKN2A/p16-mediated senescent state. Thus, genes that can bypass this senescence barrier are likely to contribute to melanoma development. We have performed a gain-of-function screen of 17,030 lentivirally expressed human open reading frames (ORFs) in a melanoma cell line containing an inducible p16 construct to identify such genes. Genes known to bypass p16-induced senescence arrest, including the human papilloma virus 18 E7 gene ( HPV18E7), and genes such as the p16-binding CDK6 with expected functions, as well as panel of novel genes, were identified, including high-mobility group box (HMGB) proteins. A number of these were further validated in two other models of p16-induced senescence. Tissue immunohistochemistry demonstrated higher levels of CDK6 in primary melanomas compared with normal skin and nevi. Reduction of CDK6 levels drove melanoma cells expressing functional p16 into senescence, demonstrating its contribution to bypass senescence.

  8. Doxycycline-Regulated p16(MTS1) Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16.

    Science.gov (United States)

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state.

  9. Doxycycline-Regulated p16MTS1 Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16

    Science.gov (United States)

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state.

  10. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort.

    Directory of Open Access Journals (Sweden)

    Jie Wen

    Full Text Available BACKGROUND: Recent genome-wide association studies (GWASs have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort. METHODOLOGY/PRINCIPAL FINDINGS: Selected type 2 diabetes-associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (PCDKN2A/B rs10811661, OR: 1.26 (1.12-1.43 P = 1.8*10(-4; CDKAL1 rs10946398, OR: 1.23 (1.09-1.39; P = 7.1*10(-4, and TCF7L2 rs7903146, OR: 1.61 (1.19-2.18 P = 2.3 * 10(-3. Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002, postprandial plasma glucose (P = 0.002, and fasting C-peptide levels (P = 0.006 in the diabetic patients, and with BMI in controls (P = 0.033. CONCLUSIONS/SIGNIFICANCE: We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities.

  11. RB1CC1 activates the p16 promoter through the interaction with hSNF5.

    Science.gov (United States)

    Ochi, Yasuko; Chano, Tokuhiro; Ikebuchi, Kaichiro; Inoue, Hirokazu; Isono, Takahiro; Arai, Akihito; Tameno, Hitosuke; Shimada, Taketoshi; Hisa, Yasuo; Okabe, Hidetoshi

    2011-10-01

    RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) is involved in dephosphorylation and increase of retinoblastoma tumor suppressor protein (RB1), but the RB1CC1 molecular mechanism in the dephosphorylation of RB1 is not fully understood. We determined that RB1CC1 activates the expression of p16 (also called INK4a/CDKN2a) through the activation of its promoter, using chromatin immunoprecipitation (ChIP) and p16 promoter-luciferase reporter assays. In addition, RB1CC1 essentially requires binding with hSNF5 (also known as BAF47/INI1, a chromatin-remodeling factor) to activate the p16 promoter, in order to enhance the RB1 pathway and acts as a tumor suppressor. Evaluation of the RB1CC1 mechanism of action is expected to provide useful information for clinical practice and future therapeutic strategies in human cancers.

  12. p16 (INK4a) has clinicopathological and prognostic impact on oropharynx and larynx squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Silva, S.D. [Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital A.C. Camargo, São Paulo, SP (Brazil); Department of Oncology, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec (Canada); Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, McGill University, Montreal, Quebec (Canada); Nonogaki, S. [Departamento de Anatomia Patológica, Hospital A.C. Camargo, São Paulo, SP (Brazil); Soares, F.A. [Departamento de Anatomia Patológica, Hospital A.C. Camargo, São Paulo, SP (Brazil); Departamento de Estomatologia, Faculdade de Odontologia, Universidade de São Paulo, São Paulo, SP (Brazil); Kowalski, L.P. [Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital A.C. Camargo, São Paulo, SP (Brazil)

    2012-09-07

    CDKN2A encodes proteins such as p16 (INK4a), which negatively regulate the cell-cycle. Molecular genetic studies have revealed that deletions in CDKN2A occur frequently in cancer. Although p16 (INK4a) may be involved in tumor progression, the clinical impact and prognostic implications in head and neck squamous cell carcinoma (HNSCC) are controversial. The objective of this study was to evaluate the frequency of the immunohistochemical expression of p16 (INK4a) in 40 oropharynx and 35 larynx from HNSCC patients treated in a single institution and followed-up at least for 10 years in order to explore potential associations with clinicopathological outcomes and prognostic implications. Forty cases (53.3%) were positive for p16 (INK4a) and this expression was more intense in non-smoking patients (P = 0.050), whose tumors showed negative vascular embolization (P = 0.018), negative lymphatic permeation (P = 0.002), and clear surgical margins (P = 0.050). Importantly, on the basis of negative p16 (INK4a) expression, it was possible to predict a probability of lower survival (P = 0.055) as well as tumors presenting lymph node metastasis (P = 0.050) and capsular rupture (P = 0.0010). Furthermore, increased risk of recurrence was observed in tumors presenting capsular rupture (P = 0.0083). Taken together, the alteration in p16 (INK4a) appears to be a common event in patients with oropharynx and larynx squamous cell carcinoma and the negative expression of this protein correlated with poor prognosis.

  13. p16 (INK4a has clinicopathological and prognostic impact on oropharynx and larynx squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    S.D. Silva

    2012-12-01

    Full Text Available CDKN2A encodes proteins such as p16 (INK4a, which negatively regulate the cell-cycle. Molecular genetic studies have revealed that deletions in CDKN2A occur frequently in cancer. Although p16 (INK4a may be involved in tumor progression, the clinical impact and prognostic implications in head and neck squamous cell carcinoma (HNSCC are controversial. The objective of this study was to evaluate the frequency of the immunohistochemical expression of p16 (INK4a in 40 oropharynx and 35 larynx from HNSCC patients treated in a single institution and followed-up at least for 10 years in order to explore potential associations with clinicopathological outcomes and prognostic implications. Forty cases (53.3% were positive for p16 (INK4a and this expression was more intense in non-smoking patients (P = 0.050, whose tumors showed negative vascular embolization (P = 0.018, negative lymphatic permeation (P = 0.002, and clear surgical margins (P = 0.050. Importantly, on the basis of negative p16 (INK4a expression, it was possible to predict a probability of lower survival (P = 0.055 as well as tumors presenting lymph node metastasis (P = 0.050 and capsular rupture (P = 0.0010. Furthermore, increased risk of recurrence was observed in tumors presenting capsular rupture (P = 0.0083. Taken together, the alteration in p16 (INK4a appears to be a common event in patients with oropharynx and larynx squamous cell carcinoma and the negative expression of this protein correlated with poor prognosis.

  14. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects

    DEFF Research Database (Denmark)

    Grarup, Niels; Rose, Chrisian S; Andersson, Ehm A

    2007-01-01

    In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed...

  15. Inactivation of CDKN2A gene in larynx cancer patients and its clinical significance.%CDKN2A基因失活对喉癌的影响及其临床意义

    Institute of Scientific and Technical Information of China (English)

    曹婧; 王亚辉; 刘红; 司迎; 张雅美; 关庆捷

    2011-01-01

    Objective To study the inactivation of cyclindependent kinase inhibitor 2A ( CDKN 2A) gene and to analyze its clinical significance in larynx cancer. Methods The rejected tissues of larynx cancer surgery and non - tumor larynx tissue were collected from 68 patients. The expression of CDKN2A was assayed by the semiquantitative counter reverse transcription polymerase chain rcaction ( RT - PCR). The protein expresssion of CDKN2A was determined by Western blot analysis. The relationship between CDKN2A expression and the occurrence and development of larynx cancer was analyzed. Results ( 1 ) The CDKN2A mRNA expression in laryngeal carcinoma was significantly less than that in non -tumor laryngeal tissues (P<0.05). (2)The expression of CDKN2A protein in laryngeal carcinoma was significantly lower than that in non - tumor laryngeal tissues ( the low expression rates were 80.9% and 47.1%, respectively,and the lower expression rates were 52.9% and 22.1%, respectively ,P <0. 05). The expression was not related to pathological types. (3)Western blot analysis showed that the CDKN2A protein expression in laryngeal carcinoma was significantly lower than that in non - minor laryngeal tissues ( t = 3.246, P < O. 05). Conclusion The CDKN2A gene mutation and inactivation of its encoded protein are related to the development of laryngeal cancer significantly.%目的 研究细胞周期依赖性激酶抑制基因(CDKN2A)失活对喉癌的影响及其临床意义.方法 应用半定量反转录聚合酶链反应(RT-PCR)和免疫印迹分析法检测喉癌手术切除组织68例,非肿瘤喉部组织68例,观察CDKN2A基因失活与喉癌发生发展的关系.结果 (1)喉癌组织CDKN2A mRNA表达明显少于非肿瘤喉组织(P<0.05);(2)喉癌组织中CDKN2A蛋白的表达明显低于非肿瘤喉组织,差异有统计学意义(两者的低表达率为80.9%、47.1%,过低表达率为52.9%、22.1%,P<0.05),并与病理分型无关;(3)Western blot电泳结果半定量

  16. HAT-P-16b

    DEFF Research Database (Denmark)

    Buchhave, Lars A.; Bakos, G. A.; Hartman, J. D.

    2010-01-01

    .04 M , radius of 1.24 ± 0.05 R , effective temperature 6158 ± 80 K, and metallicity [Fe/H] = +0.17 ± 0.08. The planetary companion has a mass of 4.193 ± 0.094 M J and radius of 1.289 ± 0.066 R J, yielding a mean density of 2.42 ± 0.35 g cm–3. Comparing these observed characteristics with recent...... theoretical models, we find that HAT-P-16b is consistent with a 1 Gyr H/He-dominated gas giant planet. HAT-P-16b resides in a sparsely populated region of the mass-radius diagram and has a non-zero eccentricity of e = 0.036 with a significance of 10s....

  17. Molecular Analysis of a Multistep Lung Cancer Model Induced by Chronic Inflammation Reveals Epigenetic Regulation of p16 and Activation of the DNA Damage Response Pathway12

    Science.gov (United States)

    Blanco, David; Vicent, Silvestre; Fraga, Mario F; Fernandez-Garcia, Ignacio; Freire, Javier; Lujambio, Amaia; Esteller, Manel; Ortiz-de-Solorzano, Carlos; Pio, Ruben; Lecanda, Fernando; Montuenga, Luis M

    2007-01-01

    The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: γ-H2AX, p16, p53, and TERT. Lung cancer-related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer. PMID:17971904

  18. The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a

    Directory of Open Access Journals (Sweden)

    Mann Graham J

    2009-01-01

    Full Text Available Abstract Background CDKN2A/p16INK4a is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16INK4a inhibits pRb phosphorylation and induces cell cycle arrest, which is considered its main tumour suppressor function. Nevertheless, additional activities may contribute to the tumour suppressor role of p16INK4a and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16INK4a binding partners. Results We now report that p16INK4a interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16INK4a and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16INK4a expression and BRG1 silencing. We found evidence that BRG1 is not required for p16INK4a-induced cell cycle inhibition and propose that the p16INK4a-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16INK4a binding partner as an important tumour suppressor in melanoma. Conclusion This data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16INK4a with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.

  19. Student Success: Statewide P-16 Systems.

    Science.gov (United States)

    Blanco, Cheryl; Crowe, Ed; Lingenfelter, Paul E.; Longanecker, David A.; L'Orange, Hans P.; Rainwater, Terese; Somerville, Janis; Venezia, Andrea; Voorhees, Richard A.; Yi, Yun

    The P-16 initiative of the State Higher Education Executive Officers (SHEEO), which produced the essays in this collection, began in 2000. This initiative has included case studies of P-16 activities in five states and full-day discussions of P-16 issues involving educators and policymakers. These essays articulate what state educational systems…

  20. Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife

    DEFF Research Database (Denmark)

    Sørensen, Christiane Elisabeth; Tritsaris, Katerina; Reibel, Jesper

    2016-01-01

    BACKGROUND: The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21. Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different...... mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age. OBJECTIVE: The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral......RT-PCR for the expression level of p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs. RESULTS: p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a in LSGs was higher...

  1. Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife

    DEFF Research Database (Denmark)

    Sørensen, Christiane Elisabeth; Tritsaris, Katerina; Reibel, Jesper

    2016-01-01

    BACKGROUND: The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21. Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different...... mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age. OBJECTIVE: The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral......RT-PCR for the expression level of p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs. RESULTS: p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a in LSGs was higher...

  2. Immunohistochemical expression of p16 in lipoblastomas.

    Science.gov (United States)

    Cappellesso, Rocco; d'Amore, Emanuele S G; Dall'Igna, Patrizia; Guzzardo, Vincenza; Vassarotto, Elisa; Rugge, Massimo; Alaggio, Rita

    2016-01-01

    Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well-differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry. In this study, we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16. Moreover, p16 immunostaining was performed in 16 liposarcomas (11 WDL and 5 ML), 16 lipomas, and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children. Overall, p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas (10 WDL and 2 ML), with a sensitivity of 75%, a specificity of 90%, a positive predictive value of 80%, and a negative predictive value of 87%. All lipomas were p16 negative, whereas 5 liponecroses were positive. Accounting altogether the benign lesions versus liposarcomas, p16 showed a sensitivity of 75%, a specificity of 87%, a positive predictive value of 60%, and a negative predictive value of 93%. Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts, such as in adolescence or late recurrence. However, such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive.

  3. Induction of p16(INK4a) is the major barrier to proliferation when Epstein-Barr virus (EBV) transforms primary B cells into lymphoblastoid cell lines.

    Science.gov (United States)

    Skalska, Lenka; White, Robert E; Parker, Gillian A; Turro, Ernest; Sinclair, Alison J; Paschos, Kostas; Allday, Martin J

    2013-02-01

    To explore the role of p16(INK4a) as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16(INK4a) and p14(ARF). Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT), we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs) lacking active p16(INK4a) protein but expressing a functional 14(ARF)-fusion protein (p14/p16). The INK4a locus is epigenetically repressed by EBNA3C--in cooperation with EBNA3A--despite the absence of functional p16(INK4a). Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16(INK4a) and growth arrest, EBNA3C inactivation in the p16(INK4a)-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16(INK4a)-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16(INK4a) expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16(INK4a)-null, functional EBNA3C is dispensable for the outgrowth of LCLs.

  4. Induction of p16(INK4a is the major barrier to proliferation when Epstein-Barr virus (EBV transforms primary B cells into lymphoblastoid cell lines.

    Directory of Open Access Journals (Sweden)

    Lenka Skalska

    2013-02-01

    Full Text Available To explore the role of p16(INK4a as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16(INK4a and p14(ARF. Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT, we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs lacking active p16(INK4a protein but expressing a functional 14(ARF-fusion protein (p14/p16. The INK4a locus is epigenetically repressed by EBNA3C--in cooperation with EBNA3A--despite the absence of functional p16(INK4a. Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16(INK4a and growth arrest, EBNA3C inactivation in the p16(INK4a-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16(INK4a-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16(INK4a expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16(INK4a-null, functional EBNA3C is dispensable for the outgrowth of LCLs.

  5. Interferon-γ activates expression of p15 and p16 regardless of 9p21.3 coronary artery disease risk genotype.

    Science.gov (United States)

    Almontashiri, Naif A M; Fan, Meng; Cheng, Brian L M; Chen, Hsiao-Huei; Roberts, Robert; Stewart, Alexandre F R

    2013-01-15

    Because post-transcriptional mechanisms modulate levels of p16 (encoded by CDKN2A) and p15 (encoded by CDKN2B), we tested whether interferon-γ regulates the expression of these proteins and the effect of the 9p21 genotype. The mechanism whereby the common variant at chromosome 9p21.3 confers risk for coronary artery disease (CAD) remains uncertain. A recent report proposed that 9p21.3 confers differential activation of adjacent genes in response to interferon-γ, and reported that mRNA levels of CDKN2B are reduced in response to interferon-γ. Human umbilical vein endothelial cells (HUVECs), aortic smooth muscle cells, HeLa cells, HEK293 cells, and 16 human lymphoblastoid cell lines, all genotyped for the 9p21.3 locus, were treated with interferon-γ and analyzed by immunoblot. In all cells tested--except HUVECs where expression was not modulated by interferon-γ--regardless of 9p21.3 genotype, interferon-γ increased the expression of p16 and p15. Northern blot analysis confirmed that interferon-γ has little effect on mRNA levels of CDKN2A and CDKN2B. The 9p21.3 risk genotype does not affect the activation of cyclin-dependent kinase inhibitors p15 and p16 by interferon-γ. Thus, another mechanism is likely to account for the CAD risk associated with this locus. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  6. Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms

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    Lia E. De Faveri

    2015-10-01

    Full Text Available Urothelial carcinoma (UC causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non–muscle-invasive bladder cancer (NMIBC. Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1 in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription.

  7. Atorvastatin treatment modulates p16 promoter methylation to regulate p16 expression.

    Science.gov (United States)

    Zhu, Boqian; Gong, Yaoyao; Yan, Gaoliang; Wang, Dong; Wang, Qingjie; Qiao, Yong; Hou, Jiantong; Liu, Bo; Tang, Chengchun

    2017-06-01

    Intimal hyperplasia, the key event of arterial restenosis, is a result of cell proliferation and cell migration. Atorvastatin exerts an inhibitory effect on cell proliferation and migration, but the mechanism remains largely unknown. p16, as a well-known tumor suppressor, was also reported to suppress cell growth and migration, but with an unclear mechanism. In this study, we demonstrated that atorvastatin represses cell proliferation and migration in vascular smooth muscle cells (VSMCs) and that this process is mediated by p16. Furthermore, we found that DNA methylation in the p16 promoter was reduced and p16 expression was restored in VSMCs treated with 5-aza-2'-deoxycytidine or atorvastatin. However, the effect was absent when DNA methyltransferase 1 (DNMT1) was knocked down with RNA interference. These observations demonstrated that atorvastatin regulates p16 expression via DNMT1-induced DNA methylation in the p16 promoter. In addition, we found that the mitogen-activated protein kinase (MAPK) pathway was involved in the regulation of p16 by DNMT1, and MAPK inhibitors partially released the effects of atorvastatin on p16 and DNMT1. Finally, we illustrated that atorvastatin inhibits neointima formation and modulates p16 expression in balloon catheter-injured rat carotid artery. Taken together, we demonstrated that atorvastatin inhibits neointima formation through inducing p16 expression by affecting DNA methylation in the p16 promoter region. © 2017 Federation of European Biochemical Societies.

  8. Senescence and p16 gene%衰老与P16基因

    Institute of Scientific and Technical Information of China (English)

    余升红

    2006-01-01

    p16基因被认为是肿瘤抑制基因,它的缺失与许多肿瘤有关,但近年来的研究表明p16还与细胞衰老有着紧密联系,p16的过量表达会诱导细胞发生成熟前衰老,是一个名副其实的衰老基因,这也是p16抑制肿瘤发生的机制,p16诱导衰老的分子机理是因为p16充当细胞周期素依赖性激酶抑制子,使细胞周期停滞而发生衰老,本文就近年来这一领域的进展作一综述.

  9. PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Cheng Hu

    Full Text Available BACKGROUND: Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism. METHODS/PRINCIPAL FINDINGS: Twenty-one single nucleotide polymorphisms (SNPs from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12. But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090. The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006. CONCLUSIONS/SIGNIFICANCE: The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes

  10. Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG.

    Science.gov (United States)

    Cordero, Francisco J; Huang, Zhiqing; Grenier, Carole; He, Xingyao; Hu, Guo; McLendon, Roger E; Murphy, Susan K; Hashizume, Rintaro; Becher, Oren J

    2017-09-01

    Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3.3K27M remain largely unknown. Here, it is demonstrated that H3.3K27M cooperates with PDGF-B in vivo, enhancing gliomagenesis and reducing survival of p53 wild-type (WT) and knockout murine models of DIPG. H3.3K27M expression drives increased proliferation of tumor-derived murine neurospheres, suggesting that cell-cycle deregulation contributes to increased malignancy in mutant tumors. RNA sequencing on tumor tissue from H3.3K27M-expressing mice indicated global upregulation of PRC2 target genes, and a subset of newly repressed genes enriched in regulators of development and cell proliferation. Strikingly, H3.3K27M induced targeted repression of the p16/ink4a (CDKN2A) locus, a critical regulator of the G0-G1 to S-phase transition. Increased levels of H3K27me3 were observed at the p16 promoter; however, pharmacologic reduction of methylation at this promoter did not rescue p16 expression. Although DNA methylation is also present at this promoter, it is not K27M dependent. Intriguingly, inhibition of DNA methylation restores p16 levels and is cytotoxic against murine tumor cells. Importantly, these data reveal that H3.3K27M-mediated p16 repression is an important mechanism underlying the proliferation of H3.3K27M tumor cells, as in vivo cdkn2a knockout eliminates the survival difference between H3.3K27M and H3.3WT tumor-bearing mice.Implications: This study shows that H3.3K27M mutation and PDGF signaling act in concert to

  11. Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife.

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    Christiane Elisabeth Sørensen

    Full Text Available The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a locus on chromosome 9q21. Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age.The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG tissue, and to analyze whether its expression level in LSGs is a peripheral correlate of cognitive decline in late midlife.The present study was a part of a study of causes and predictors of cognitive decline in middle-aged men in a Danish birth cohort. It is based on data from 181 male participants from the Danish Metropolit birth cohort, born in 1953, who were examined for age-associated alterations in cognition, dental health, and morphological and autonomic innervation characteristics of the LSGs. The participants were allocated to two groups based on the relative change in cognitive performance from young adulthood to late midlife. LSG biopsies were analyzed by qRT-PCR for the expression level of p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs.p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a in LSGs was higher in the group of participants with decline in cognitive performance. A logistic regression analysis revealed that the relative p16 expression was predictive of the participant's group assignment. A negative correlation was found between relative p16ink4a expression and the participant's standardized regression residuals from early adulthood to late midlife cognitive performance scores.p16ink4a expression in human LSGs may constitute a potential peripheral correlate of cognitive decline. Human labial

  12. Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife

    Science.gov (United States)

    Sørensen, Christiane Elisabeth; Tritsaris, Katerina; Reibel, Jesper; Lauritzen, Martin; Mortensen, Erik Lykke; Osler, Merete; Pedersen, Anne Marie Lynge

    2016-01-01

    Background The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21. Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age. Objective The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral correlate of cognitive decline in late midlife. Methods The present study was a part of a study of causes and predictors of cognitive decline in middle-aged men in a Danish birth cohort. It is based on data from 181 male participants from the Danish Metropolit birth cohort, born in 1953, who were examined for age-associated alterations in cognition, dental health, and morphological and autonomic innervation characteristics of the LSGs. The participants were allocated to two groups based on the relative change in cognitive performance from young adulthood to late midlife. LSG biopsies were analyzed by qRT-PCR for the expression level of p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs. Results p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a in LSGs was higher in the group of participants with decline in cognitive performance. A logistic regression analysis revealed that the relative p16 expression was predictive of the participant’s group assignment. A negative correlation was found between relative p16ink4a expression and the participant’s standardized regression residuals from early adulthood to late midlife cognitive performance scores. Conclusions p16ink4a expression in human LSGs may constitute a potential peripheral

  13. 9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor-Dependent Transforming Growth Factor β Regulation of p16 Expression in Human Aortic Smooth Muscle Cells.

    Science.gov (United States)

    Almontashiri, Naif A M; Antoine, Darlène; Zhou, Xun; Vilmundarson, Ragnar O; Zhang, Sean X; Hao, Kennedy N; Chen, Hsiao-Huei; Stewart, Alexandre F R

    2015-11-24

    The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect. A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor β, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor β-induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs. Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor β induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk. © 2015 American Heart Association, Inc.

  14. Stromal p16 expression is significantly increased in endometrial carcinoma.

    Science.gov (United States)

    Yoon, Gun; Koh, Chang Won; Yoon, Nara; Kim, Ji-Ye; Kim, Hyun-Soo

    2017-01-17

    p16 is a negative regulator of cell proliferation and is considered a tumor suppressor protein. Alterations in p16 protein expression are associated with tumor development and progression. However, the p16 expression status in the peritumoral stroma has not been investigated in the endometrium. Therefore, we evaluated stromal p16 expression in different types of endometrial lesions using immunohistochemistry. Differences in the p16 expression status according to the degree of malignancy and histological type were analyzed. This study included 62, 26, and 36 cases of benign, precancerous, and malignant endometrial lesions, respectively. Most benign lesions showed negative or weak expression, whereas precancerous lesions showed a variable degree of staining proportion and intensity. Atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) and serous endometrial intraepithelial carcinoma (SEIC) had significantly higher stromal p16 expression levels than benign lesions. Endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma showed significantly elevated stromal p16 expression levels compared with benign and precancerous lesions. In addition, there were significant differences in stromal p16 expression between AH/EIN and SEIC and between EC and SC. In contrast, differences in stromal p16 expression among nonpathological endometrium, atrophic endometrium, endometrial polyp, and hyperplasia without atypia were not statistically significant. Our observations suggest that stromal p16 expression is involved in the development and progression of endometrial carcinoma, and raise the possibility that p16 overexpression in the peritumoral stroma is associated with aggressive oncogenic behavior of endometrial SC.

  15. COX-2、CDKN2A在慢性乙型肝炎、肝硬化肝组织中的表达及意义%The study of the expression of CoX-2 and CDKN2A in chronic hepatitis B and liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    高保华; 刘冰; 郑建云; 吴方雄; 汪雯; 李雷; 牛春燕

    2011-01-01

    Objective To investigate the expression of cyclooxygenase-2(COX-2) and CDKN2A in chronic hepatitis B and liver cirrhosis tissues and the relationship between the expression and the liver injury.Methods There were 46 patients with chronic hepatitis B and 17cases with liver cirrhosis were confirmed through the immunology of liver biopsy; There were 10 normal liver tissues from benign tumors of the liver specimens.Liver inflammation and fibrosis was determined by Pathology.The expression of COX-2 and CDKN2A was determined by immunohisto-chemistry, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot.Results (1) The expression level of the first and second exon of CDKN2A mRNA and the semiquantitative analysis of CDKN2A protein in the normal liver、hepatitis B and cirrhosis were significant (F=28.75, 24.86, 26.43, P=0.036, 0.041, 0.038).(2) The protein level’s expression of COX-2,CDKN2A in normal liver, hepatitis B, cirrhosis was significantly different (x2=13.48, 15.73, P= 0.042, 0.021);The protein level’s expression of COX-2, CDKN2A in liver inflammation with different levels was significantly different (x2=22.45, 23.67, P=0.038, 0.027); The protein level’s expression of COX-2, CDKN2A in Liver fibrosis with different degrees was significantly different (x2=24.16, 22.53, P=0.024, 0.037).Conclusion The expression of COX-2 and CDKN2A was related to the development of process of hepatitis and cirrhosis.The COX-2 and CDKN2A may be used as a good indicator of HBV-related liver disease progress.%目的 了解慢性乙型肝炎(CHB)、肝硬化肝组织中COX-2、CDKN2A的表达及其与肝脏损伤程度的关系.方法 经免疫学及肝穿刺病理学证实为CHB患者46例、乙型肝炎肝硬化17例;正常肝组织10例(来自肝脏良性肿瘤手术切除的标本).应用病理学判断肝组织的炎症及纤维化程度.采用免疫组化方法、半定量逆转录聚合酶链反应(RT-PCR)和

  16. Transcriptional Regulation of the p16 Tumor Suppressor Gene.

    Science.gov (United States)

    Kotake, Yojiro; Naemura, Madoka; Murasaki, Chihiro; Inoue, Yasutoshi; Okamoto, Haruna

    2015-08-01

    The p16 tumor suppressor gene encodes a specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 and is found altered in a wide range of human cancers. p16 plays a pivotal role in tumor suppressor networks through inducing cellular senescence that acts as a barrier to cellular transformation by oncogenic signals. p16 protein is relatively stable and its expression is primary regulated by transcriptional control. Polycomb group (PcG) proteins associate with the p16 locus in a long non-coding RNA, ANRIL-dependent manner, leading to repression of p16 transcription. YB1, a transcription factor, also represses the p16 transcription through direct association with its promoter region. Conversely, the transcription factors Ets1/2 and histone H3K4 methyltransferase MLL1 directly bind to the p16 locus and mediate p16 induction during replicative and premature senescence. In the present review, we discuss the molecular mechanisms by which these factors regulate p16 transcription.

  17. p16 gene methylation in colorectal cancer patients with long-term follow-up Metilación de p16 en pacientes intervenidos de cáncer colorrectal tras un largo periodo de seguimiento

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    Silvia Veganzones-de-Castro

    2012-03-01

    Full Text Available Introduction: p16 gene plays an important role in the cell cycle regulation and is considered an important tumor suppressor gene. Several mechanisms of gene inactivation have been described; in this study we have focused on p16 gene promoter methylation. In colorectal cancer p16 gene methylation is a frequent event. Methods: 326 patients with sporadic colorectal cancer were included. DNA was extracted from tumor tissue samples obtained during the surgical procedure. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. Frequency of p16 methylation was analyzed and compared with other clinicopathological variables. Results: p16 gene methylation was detected in 24,8% of patients. Methylation was associated with differentiation grade and with tumor location: methylation was frequent in poorly differentiated tumors and had low frequency in distal colon. The p16 promoter methylation discriminated a subgroup of patients with better prognosis in poorly differentiated tumors. Conclusions: p16 methylation was a frequent event in our population and was able to induce differences in the overall survival of patients with poorly differentiated tumors.Introducción: el gen p16 está implicado en la regulación del ciclo celular y se considera un importante gen supresor de tumores. Objetivos: se han descrito diferentes mecanismos de inactivación génica, en este estudio nos hemos centrado en la metilación del promotor del gen p16. En el cáncer colorrectal la metilación de p16 es una alteración frecuente. Material y métodos: se incluyeron 326 pacientes con cáncer colorrectal esporádico. El ADN se extrajo de muestras tumorales obtenidas durante la cirugía. La metilación del promotor se analizó mediante un proceso de modificación con bisulfito y posterior PCR cuantitativa especifica para metilación. Se analizó la frecuencia de la metilación de p16 y se comparó con las variables

  18. The utility of p16 immunostaining in fine needle aspiration in p16-positive head and neck squamous cell carcinoma.

    Science.gov (United States)

    Xu, Bin; Ghossein, Ronald; Lane, Jason; Lin, Oscar; Katabi, Nora

    2016-08-01

    Many patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma present initially with cervical nodal metastasis. Fine needle aspiration (FNA) of the nodal disease might be the only diagnostic material available for p16 immunohistochemistry (IHC) and HPV testing. The current study aims to evaluate p16 IHC in FNA and establish guidelines for its interpretation. The percentage and intensity of p16 IHC staining were examined in 60 matched FNA and surgical cases. Cytomorphologic features were included in the analysis. p16 IHC staining was correlated with the results seen in the surgical specimens and with HPV in situ hybridization (ISH). Analysis of different thresholds demonstrated that the threshold of 10% p16 tumor cell positivity had the best overall concordance rate with surgical p16 IHC (κ = 0.650) and with FNA HPV-ISH (κ = 0.714). Applying the recommended p16 positivity threshold for surgical specimens (70%) on FNA materials resulted in low sensitivity (39%) and low negative predictive value (26%). In comparison with p16 IHC in surgical specimens, 6/46 FNA cases (13%) were falsely negative for p16. All 6 cases were associated with necrotic background, two (33%) lacked large tumor clusters, and one (17%) had low cellularity. The recommended threshold for p16 IHC on surgical specimens should not be used in cytology materials. The cutoff value for p16 immunostain in FNA specimens showing best results in our series is 10%. When p16 IHC is negative in FNA specimens, a repeat stain on a surgical specimen is recommended to avoid a false-negative diagnosis.

  19. Cellular senescence and tumor suppressor gene p16.

    Science.gov (United States)

    Rayess, Hani; Wang, Marilene B; Srivatsan, Eri S

    2012-04-15

    Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16-mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16. Copyright © 2011 UICC.

  20. Relationship between inactivation of p16 gene and gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Guo-Hai Zhao; Tie-Chen Li; Liang-Hui Shi; Ya-Bin Xia; Lin-Ming Lu; Wen-Bin Huang; Hui-Lan Sun; Yi-Sheng Zhang

    2003-01-01

    AIM: To investigate the relationship between inactivation of p16 gene and gastric carcinoma, and the mechanism of inactivation of p16 gene in gastric carcinogenesis.METHODS: 40 fresh tumor tissue specimens were taken from primary gastric cancer patients. Expression of P16protein was detected by immunohistochemical method.Deletion and point mutation of p16 gene were analyzed by polymerase chain reaction (PCR) and DNA sequencing,respectively.RESULTS: The frequency of loss of P16 protein expression in the gastric cancer tissue, adjacent nontumor tissue, and distal normal tissue was 77.5 %(31/40), 55.0 %(22/40),and 17.5 % (7/40), respectively (P<0.005). Homozygous deletion of exon 1 and exon 3 was observed in two and three cases, respectively, giving an overall frequency of homozygous deletion of 12.5 %. All five cases had diffuse type gastric carcinoma. No p16 gene point mutation was detected.CONCLUSION: These findings suggest a close correlation between inactivation of p16 gene and gastric carcinoma.Further investigations are needed to testify the mechanism of inactivation of p16 gene in gastric carcinogenesis.

  1. Estudio del gen IKZF1 y de microdeleciones intragénicas en la leucemia linfoblástica aguda

    OpenAIRE

    Gómez Seguí, Inés

    2015-01-01

    La leucemia Linfoblástica Aguda (LLA) es una neoplasia caracterizada por una gran diversidad de alteraciones genéticas. En los últimos años, se ha descrito la ocurrencia de pequeñas deleciones focales en genes de relevancia para la célula linfoide. En concreto, las que afectan a IKZF1 parecen tener valor pronóstico en la edad pediátrica. OBJETIVOS: Estudiar la presencia de microdeleciones en los genes CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1, la región pseudoautosómica del cromosoma X/Y...

  2. P16基因治疗与肿瘤

    Institute of Scientific and Technical Information of China (English)

    孙石磊; 沈忠英

    2001-01-01

    P16基因是多肿瘤抑制基因,抑制细胞从G1期向S期转换。其失活机制为缺失、突变及基因的异常甲基化。多数恶性肿瘤中普遍存在P16基因的不同程度失活和P16蛋白的表达低下。P16基因的异常不仅参与多种肿瘤的发生,还关系着肿瘤的进展及复发。对于多种恶性肿瘤,P16基因治疗具有优势且有了一定的效果。

  3. Expression and methylation pattern of p16 in neuroblastoma tumorigenesis.

    Science.gov (United States)

    Aktas, Safiye; Celebiler, Aydan Cavusoglu; Zadeoğlulari, Zeynep; Diniz, Gulden; Kargi, Aydanur; Olgun, Nur

    2010-03-01

    Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.

  4. Diabetes susceptibility in Mayas: Evidence for the involvement of polymorphisms in HHEX, HNF4α, KCNJ11, PPARγ, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes.

    Science.gov (United States)

    Lara-Riegos, J C; Ortiz-López, M G; Peña-Espinoza, B I; Montúfar-Robles, I; Peña-Rico, M A; Sánchez-Pozos, K; Granados-Silvestre, M A; Menjivar, M

    2015-07-01

    Association of type 2 diabetes (T2D) with common variants in HHEX, HNF4α, KCNJ11, PPARγ, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes have been reported, mainly in populations of European and Asian ancestry and to a lesser extent in Latin Americans. Thus, we aimed to investigate the contribution of rs1111875 (HHEX), rs1800961 (HNF4α), rs5219 (KCNJ11), rs1801282 (PPARγ), rs10811661 (CDKN2A/2B), rs13266634 (SLC30A8), rs12779790 (CDC123/CAMK1D), rs7903146 (TCF7L2), rs9282541 (ABCA1) and rs13342692 (SLC16A11) polymorphisms in the genetic background of Maya population to associate their susceptibility to develop T2D. This is one of the first studies designed specifically to investigate the inherited component of T2D in the indigenous population of Mexico. SNPs were genotyped by allelic discrimination method in 575 unrelated Maya individuals. Two SNPs rs10811661 and rs928254 were significantly associated with T2D after adjusting for BMI; rs10811661 in a recessive and rs9282541 in a dominant model. Additionally, we found phenotypical alterations associated with genetic variants: HDL to rs9282541 and insulin to rs13342692. In conclusion, these findings support an association of genetic polymorphisms to develop T2D in Maya population.

  5. EXPRESSION OF p16 AND p53 IN GASTRIC CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Objective:To investigate the clinical significance of p53 and p16 expression in gastric carcinoma with special reference to the prognosis.Methods:One hundred and fifty-two patients with gastric carcinoma undergoing operation in our hospital between 1991 and 1998 were evaluated for expression of p53 and p16 in formalin-fixed and paraffin-embedded tumor tissue utilizing Avidin-Biotin immunohistochemistry techniques. Statistical correlations with stage, histological type, differentiation degree, location, size, and overall survival were done. The Cox proportional hazard model was also performed to evaluate which factors had an independent prognostic value.Results:In 152 cases of resected gastric cancer, 110 (72.4%) were p16 positive and 49 (32.2%) showed p53 overexpression. Differences were observed in the frequency of p16 positivity with respect to age, gender and tumor size. The frequency of p53 positivity cells in well-differentiated tumors was significantly higher than that in poorly differentiated tumors (41.9% vs. 25.6%; P= 0.034). In a multivariate analysis, tumor TNM stage, perioperation chemotherapy and the expression of p16 were independent prognostic factors in gastric cancer.Conclusions:The results of the current study suggest that expression of p16 may be a useful prognostic factor for patients with gastric carcinoma, but the expression of p53 as detected by immunohistochemistry were of no value in predicting the prognosis of patients with gastric carcinoma independently.

  6. p16 is Consistently Expressed in Endometrial Tubal Metaplasia

    Directory of Open Access Journals (Sweden)

    N. Horree

    2007-01-01

    Full Text Available Background: Cell cycle proteins and HIF-1α with downstream factors are often abberrantly expressed in (preneoplastic tissue. Methods: Paraffin-embedded specimens of inactive endometrium with TM (n=15, ovarian inclusion cysts (n=6, cervix with TM (tubal metaplasia (n=3, Fallopian tubes (n=7, cycling endometrium (n=9 and a ciliated cell tumor of the ovary were stained for p16 and LhS28. 39 Endometrioid endometrial carcinomas and 5 serous endometrial carcinomas were stained for p16. Additionally, inactive endometrium (n=15 was immunohistochemically stained for p21, p27, p53, cyclin A, cyclin D1, cyclin E, HIF-1α, CAIX, Glut-1 and MIB-1. Results: A mosaic pattern of expression of p16 was seen throughout in all cases of endometrial TM (15/15, in 2/6 of the ovarian inclusion cysts with TM, in all (3/3 cervical TM and focal in 5/7 of Fallopian tube cases. Mosaic expression was also seen in a ciliated cell tumor of the ovary and in 18/39 of endometrioid endometrial carcinomas, and diffuse p16 expression was seen in 5/5 serous carcinomas. In comparison with normal endometrium, TM areas in the endometrium showed significantly increased expression of HIF-1α, cyclin E, p21 and cyclin A, and decreased expression of p27. Membranous expression of CAIX and Glut-1 was only seen in TM areas, pointing to functional HIF-1α. Conclusion: As p16 is consistently expressed in TM, less and only patchy expressed in the normal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1α, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion.

  7. Translocation t(8;14)(q24;q11) with concurrent PTEN alterations and deletions of STIL/TAL1 and CDKN2A/B in a pediatric case of acute T-lymphoblastic leukemia: A genetic profile associated with adverse prognosis.

    Science.gov (United States)

    Skalska-Sadowska, Jolanta; Dawidowska, Małgorzata; Szarzyńska-Zawadzka, Bronisława; Jarmuż-Szymczak, Małgorzata; Czerwińska-Rybak, Joanna; Machowska, Ludomiła; Derwich, Katarzyna

    2017-04-01

    We report a pediatric case of acute T-lymphoblastic leukemia (T-ALL) with NOTCH1(wt) , FBXW7(wt) , STIL/TAL1, and PTEN (exons 2, 3, 4, 5) monoallelic deletions, biallelic CDKN2A/B deletion, and a minor t(8;14)(q24;q11)-positive subclone. Undetectable by a flow cytometric minimal residual disease assay, the t(8;14)(q24;q11) subclone expanded as detected by fluorescence in situ hybridization from 5% at diagnosis to 26% before consolidation and 100% at relapse bearing a monoallelic deletion (exons 2, 3) with a new frameshift mutation of PTEN and the same set of remaining molecular alterations. This case documents an unfavorable prognostic potential of a co-occurrence of this set of molecular genetic events and addresses risk stratification in T-ALL.

  8. p16 promoter methylation in Pb2+ -exposed individuals.

    Science.gov (United States)

    Kovatsi, Leda; Leda, Kovatsi; Georgiou, Elisavet; Elisavet, Georgiou; Ioannou, Antrea; Antrea, Ioannou; Haitoglou, Costas; Costas, Haitoglou; Tzimagiorgis, George; George, Tzimagiorgis; Tsoukali, Helen; Helen, Tsoukali; Kouidou, Sofia; Sofia, Kouidou

    2010-02-01

    One of the principle symptoms of lead poisoning is the development of neurological disorders. Neuronal response is closely related to DNA methylation changes. Aim. In this study, we estimated p16 methylation in nine individuals exposed to lead using methylation-specific polymerase chain reaction followed by analysis of the methylated cytosine content of the product by thermal denaturation. We found that, based on lead blood concentration, lead-exposed individuals were divided into two groups. Among highly exposed individuals (blood Pb(2+) concentration = 51-100 microg/dL), we observed complete CpG methylation, whereas for low Pb(2+) concentrations (blood Pb(2+) concentration = 6-11 microg/dL), we observed partial methylation. Our results show that among lead-overexposed individuals, p16 methylation is frequent and extensive, and suggest that DNA methylation could be involved in the mechanism by which lead induces neurotoxicity.

  9. P16 overexpression in BRAF-mutated gastrointestinal stromal tumors.

    Science.gov (United States)

    Shi, Shan-Shan; Wang, Xuan; Xia, Qiu-Yuan; Rao, Qiu; Shen, Qin; Ye, Sheng-Bin; Li, Rui; Shi, Qun-Li; Lu, Zhen-Feng; Ma, Heng-Hui; Zhou, Xiao-Jun

    2017-02-01

    The aims of this study were to analyze the histopathology, immunophenotype, molecular features, and prognosis in cases of BRAF-mutated gastrointestinal stromal tumors (GISTs) and to examine the p16 expression in these tumors, and further discuss its effects on tumor formation and progression. In all, 283 GIST cases (201 KIT mutants, 12 PDGFRA mutants and 70 wild-type) from the 2010 to 2014 surgical pathology files of the Department of Pathology at Nanjing Jinling Hospital were analyzed for mutations in BRAF exon 15. Patient follow-up and clinical data were collected if available in the medical records. To determine the clinicopathological features and potential molecular mechanism, the authors examined 10 BRAF-mutated GIST cases for KIT, DOG1, SMA, desmin, S-100, Ki-67 and p16 expression. The authors identified 10 cases (3.5%) of BRAF (V600E) mutations in a series of 283 primary GISTs, without KIT (exons 9, 11, 13, 17) or PDGFRA (exons 12, 18) gene mutations. All 10 cases exhibited spindle-cell features, and the morphology and immunophenotype of these cases were no different from those in cases of KIT-mutated GISTs. The clinical results indicated that BRAF-mutated GISTs tended to occur more frequently in females (7/10), older individuals (mean age, 54.9 years) and the stomach (7/10), and that these tumors were low risk and exhibited low recurrence and mortality rates. Two different forms of p16 were identified, which presented with simultaneously strong and diffuse nuclear and cytoplasmic expression patterns. GISTs with the BRAF V600E mutation are relatively benign tumors with a distinctive molecular mechanism. The expression of the nuclear and cytoplasmic forms of p16 represent two independent mechanisms, and both seemed to control proliferation in response to oncogenic stimuli, protecting the cell from malignant transformation in BRAF-mutated GISTs.

  10. 中药复方药物血清对CDKN2A和RPS3a基因在人卵巢癌细胞株SKOV3中表达的影响%Impacts of Chinese Herbal Compound Drug Serum on the Expressions of CDKN2A and RPS3a in Human Ovarian Cancer Cell Lines(SKOV3)

    Institute of Scientific and Technical Information of China (English)

    王熙月; 韩凤娟; 汤欣; 吴效科; 侯丽辉

    2011-01-01

    目的 研究CDKN2A(细胞周期依赖性激酶抑制基因)和RPS3a基因(核糖体蛋白质S3a)在中药复方理冲生髓饮诱导人卵巢癌细胞株人卵巢浆液性乳头状囊腺癌(SKOV3)细胞凋亡中的作用.方法 将20只Wistar大鼠随机分为理冲生髓饮组和生理盐水组,灌胃给药,采血制备含药血清.提取生理盐水组及理冲生髓饮组肿瘤细胞mRNA,制备DNA探针并分别用Cy3和Cy5两种荧光染料标记,与人细胞凋亡寡核苷酸微阵列芯片进行杂交,经扫描、分析,得出药物作用后表达有差异的基因.结果 共筛选出显著差异表达基因66个,其中20个基因表达水平上调,46个基因表达水平下调.结论 理冲生髓饮可能通过上调CDKN2A基因和下调RPS3a基因,达到诱导卵巢癌细胞凋亡的目的.诱导细胞周期停滞,阻碍肿瘤细胞蛋白质合成,影响细胞正常代谢等,可能是其诱导细胞凋亡的作用机制.%Objective To study the effects of CDKN2A( cyclin - dependent kinase inhibitor gene )and RPS3a(ribosomal protein S3a)on apoptosis in human ovarian serious cyctadenocarcinoma( SKOV3 )induced by Chinese herbal compound formula,lichong shengsui yin. Methods 20 Wistar rats were randomized into a lichong shengsui yin group and a physiological saline group. The medication was done with gastric infusion. Blood was collected to prepare medicine - contained serum. mRNA of cancer cells in physiological saline group and lichong shengsui yin group were extracted. DNA prohe pin was prepared and two fluorescent dyes, Cy3 and Cy5 were used for laheling separately. The hybridization was done with human apoptosis oligonucleotide microarray chip. Through scanning and analyzing,the genes with expression differences after medicinal action were obtained. Results 66 genes with significant differences were screened totally. Of them,the expressions of 20 genes were up - regulated and those of 46 genes were down - regulated. Conclusion Lichong shengsui yin works on

  11. The tRNA methyltransferase NSun2 stabilizes p16INK4 mRNA by methylating the 3′-untranslated region of p16

    OpenAIRE

    Zhang, Xiaotian; Liu, Zhenyun; Yi, Jie; Tang, Hao; Xing, Junyue; Yu, Minqwei; Tong, Tanjun; Shang, Yongfeng; Gorospe, Myriam; Wang, Wengong

    2012-01-01

    The impact of methylation of the 3′-untranslated region (UTR) of a messenger RNA (mRNA) remains largely unknown. Here we show that NSun2, a transfer RNA methyltransferase, inhibits the turnover of p16INK4 mRNA. Knockdown of NSun2 reduces p16 expression by shortening the half-life of the p16 mRNA, while overexpression of NSun2 stabilizes the p16 mRNA. In vitro methylation assays show that NSun2 methylates the p16 3′UTR at A988. Knockdown of NSun2 reduces the stability of the EGFP-p16 chimeric ...

  12. The tRNA methyltransferase NSun2 stabilizes p16INK4 mRNA by methylating the 3′-untranslated region of p16

    Science.gov (United States)

    Zhang, Xiaotian; Liu, Zhenyun; Yi, Jie; Tang, Hao; Xing, Junyue; Yu, Minqwei; Tong, Tanjun; Shang, Yongfeng; Gorospe, Myriam; Wang, Wengong

    2012-01-01

    The impact of methylation of the 3′-untranslated region (UTR) of a messenger RNA (mRNA) remains largely unknown. Here we show that NSun2, a transfer RNA methyltransferase, inhibits the turnover of p16INK4 mRNA. Knockdown of NSun2 reduces p16 expression by shortening the half-life of the p16 mRNA, while overexpression of NSun2 stabilizes the p16 mRNA. In vitro methylation assays show that NSun2 methylates the p16 3′UTR at A988. Knockdown of NSun2 reduces the stability of the EGFP-p16 chimeric reporter transcripts bearing wild-type p16 3′UTR, but not p16 3′UTR with a mutant methylation site. Methylation by NSun2 prevents the association of p16 3′UTR with HuR, AUF1 and Ago2/RISC, and prevents the recruitment of EGFP-p16 3′UTR chimeric transcripts to processing bodies. In response to oxidative stress, NSun2 is essential for elevating p16 expression levels. We conclude that NSun2-mediated methylation of the p16 3′UTR is a novel mechanism to stabilize p16 mRNA. PMID:22395603

  13. The tRNA methyltransferase NSun2 stabilizes p16INK⁴ mRNA by methylating the 3'-untranslated region of p16.

    Science.gov (United States)

    Zhang, Xiaotian; Liu, Zhenyun; Yi, Jie; Tang, Hao; Xing, Junyue; Yu, Minqwei; Tong, Tanjun; Shang, Yongfeng; Gorospe, Myriam; Wang, Wengong

    2012-03-06

    The impact of methylation of the 3'-untranslated region (UTR) of a messenger RNA (mRNA) remains largely unknown. Here we show that NSun2, a transfer RNA methyltransferase, inhibits the turnover of p16(INK4) mRNA. Knockdown of NSun2 reduces p16 expression by shortening the half-life of the p16 mRNA, while overexpression of NSun2 stabilizes the p16 mRNA. In vitro methylation assays show that NSun2 methylates the p16 3'UTR at A988. Knockdown of NSun2 reduces the stability of the EGFP-p16 chimeric reporter transcripts bearing wild-type p16 3'UTR, but not p16 3'UTR with a mutant methylation site. Methylation by NSun2 prevents the association of p16 3'UTR with HuR, AUF1 and Ago2/RISC, and prevents the recruitment of EGFP-p16 3'UTR chimeric transcripts to processing bodies. In response to oxidative stress, NSun2 is essential for elevating p16 expression levels. We conclude that NSun2-mediated methylation of the p16 3'UTR is a novel mechanism to stabilize p16 mRNA.

  14. Mutations of the p16 gene in gliomas.

    Science.gov (United States)

    Kyritsis, A P; Zhang, B; Zhang, W; Xiao, M; Takeshima, H; Bondy, M L; Cunningham, J E; Levin, V A; Bruner, J

    1996-01-04

    In the present study we investigated the frequency of p16 gene exon 2 mutations in 35 malignant gliomas, using either direct sequencing of the PCR products or cloning into the pCRII vector and sequencing of the cloned PCR products. No mutations were detected during direct sequencing of the PCR products. However, after sequencing of individual clones, we found multiple mutations in 5 tumors involving codons 73(GCC to ACC, Ala to Thr), 76 (GCC to GTC, Ala to Val), 85(GCT to ACT, Ala to Thr), 98(CAC to TAC, His to Tyr), 102 (GCG to GTG, Ala to Val), 106 (GTG to ATG, Val to Met), 107 (CGC to TGC, Arg to Cys), 127 (GCA to GTA, Ala to Val), 128 (CGG to TGG, Arg to Trp) and 136 (GGC to GAC, Gly to Asp). Mutations were found only in glioblastomas and were either C to T or G to A transitions. Each mutation was detected in a small percentage of tumor cells (1.3-22%) using individual colony sequencing and southern hybridization with mutant oligonucleotides, consistent with the heterogenous cell population of glioblastomas. The presence of p16 gene mutations only in glioblastomas suggests that they are late events in glioma development.

  15. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in Esophageal Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Memar Bahram

    2010-04-01

    Full Text Available Abstract Background Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis. We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average. Methods Cancerous tissues and the adjacent normal tissue obtained from 50 ESCC patients were assessed with Methylation-Specific-PCR to examine the methylation status of p16. The expression of p16, p53 and MDM2 proteins was detected by immunohistochemical staining. Results Abnormal expression of p16 and p53, but not MDM2, was significantly higher in the tumoral tissue. p53 was concomitantly accumulated in ESCC tumor along with MDM2 overexpression and p16 negative expression. Aberrant methylation of the p16INK4a gene was detected in 31/50 (62% of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P p16INK4a aberrant methylation was significantly associated with decreased p16 protein expression (P = 0.033, as well as the overexpression of p53 (P = 0.020. Conclusions p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development. It is associated with p53 protein overexpression and may influence the accumulation of abnormally expressed proteins in p53-MDM2 and p16-Rb pathways, suggesting a possible cross-talk of the involved pathways in ESCC development.

  16. 肺癌p16基因缺失与P16蛋白失活的关系研究%Study of CDKN2/P16 Gene Deficit State in Lung Cancers

    Institute of Scientific and Technical Information of China (English)

    苏长青; 叶玉坤; 单祥年

    1999-01-01

    @@ 抑癌基因p16是细胞增殖周期P16-CDK4-Cyclin D1-Rb调节环路的重要组件之一,P16蛋白的丢失,必将引起细胞周期的失控,导致肿瘤的发生[1,2].采用免疫组化和多重PCR技术,对肺癌组织P16蛋白的表达和p16基因的缺失进行了研究,探讨该基因的变化与肺癌发生发展的关系.

  17. GEN 480 uop / uophelp

    OpenAIRE

    2015-01-01

    GEN 480 Week 1 Individual Assignment Ethics Awareness Inventory GEN 480 Week 1 DQ 1 GEN 480 Week 1 DQ 2 GEN 480 Week 1 DQ 3 GEN 480 Week 1 DQ 4 GEM 480 Week 1 Summary GEN 480 Week 2 Individual Assignment Ethics Awareness Inventory Analysis GEN 480 Week 2 Individual Assignment Professional Workplace Dilemma Paper GEN 480 Week 2 Learning Team Assignment Skills Assessment Paper and Matrix GEN 480 Week 2 DQ 1 GEN 480 Week 2 DQ 2 GEN 480 Week 2 DQ 3 ...

  18. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Taghavi, Noushin; Biramijamal, Firouzeh; Sotoudeh, Masoud; Khademi, Hooman; Malekzadeh, Reza; Moaven, Omeed; Memar, Bahram; A'rabi, Azadeh; Abbaszadegan, Mohammad Reza

    2010-04-13

    Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis. We assessed the aberrant methylation of the p16 gene and its impact on p16INK4a protein expression and correlations with p53 and MDM2 protein expressions in patients with ESCC in the Golestan province of northeastern Iran in which ESCC has the highest incidence of cancer, well above the world average. Cancerous tissues and the adjacent normal tissue obtained from 50 ESCC patients were assessed with Methylation-Specific-PCR to examine the methylation status of p16. The expression of p16, p53 and MDM2 proteins was detected by immunohistochemical staining. Abnormal expression of p16 and p53, but not MDM2, was significantly higher in the tumoral tissue. p53 was concomitantly accumulated in ESCC tumor along with MDM2 overexpression and p16 negative expression. Aberrant methylation of the p16INK4a gene was detected in 31/50 (62%) of esophageal tumor samples, while two of the adjacent normal mucosa were methylated (P p16 protein expression (P = 0.033), as well as the overexpression of p53 (P = 0.020). p16 hypermethylation is the principal mechanism of p16 protein underexpression and plays an important role in ESCC development. It is associated with p53 protein overexpression and may influence the accumulation of abnormally expressed proteins in p53-MDM2 and p16-Rb pathways, suggesting a possible cross-talk of the involved pathways in ESCC development.

  19. High CpG island methylation of p16 gene and loss of p16 protein expression associate with the development and progression of tetralogy of Fallot.

    Science.gov (United States)

    Gao, Si-Ju; Zhang, Gui-Fang; Zhang, Rong-Peng

    2016-12-01

    We examined CpG island methylation in p16 gene and its effect on p16 protein expression in tetralogy of Fallot (ToF) patients to explore its potential implications in the development and progression of ToF. The study subjects consisted of 75 healthy controls and 63 ToF patients recruited at Linyi People's Hospital between January 2012 and June 2014. The 4 mL of peripheral venous blood of each subject was obtained and saved in ethylene diamine tetraacetic acid (EDTA) tubes. Methylation-specific polymerase chain reaction (MSP) was employed to detect CpG island methylation in p16 promoter region andWestern blotting was used to detect p16 expression of all subjects. Real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) was performed to test p16 mRNA expression. The results showed that p16-methylation rates in ToF group were significantly higher than the control group (ToF group, 58.73%; control group, 13.33%; P p16 protein expression was significantly lower in ToF group compared tothe control group (0.76 ± 0.21 versus 2.31 ± 0.35; P p16 gene expression was also markedly decreased in ToF group (1.212 ± 0.152 versus 1.346 ± 0.191, P p16 promoters in ToF patients was negatively correlated with p16 protein and gene expression (both P p16 gene and loss of p16 protein expression associate with the development and progression of ToF, which may have significant therapeutic applications for ToF.

  20. P16基因表达与宫颈癌预后相关性分析%Expression and prognosis significance of P16 in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    陈悦; 张晓薇; 邓志校; 谭伟坚; 黄晓军; 范良生

    2014-01-01

    目的:通过检测 P16基因在宫颈癌中的表达,分析 P16基因与宫颈癌预后的关系,评价 P16基因在宫颈癌预后预测中的价值。方法:采用免疫组织化学SP法检测P16基因在74例宫颈癌患者组织中的表达,并对P16基因表达与宫颈癌预后的关系进行相关性分析。结果:74例宫颈癌病例中,P16基因的表达阳性率为85%(63/74),P16基因阳性表达与宫颈癌预后呈正相关(P=0.041)。 P16基因阳性表达组2年累积生存率为85.2%,P16基因阴性表达组2年累积生存率为100%。 P16基因阳性表达组2年累积生存率低于P16基因阴性表达组(P=0.043),两者比较有统计学意义。 P16基因阳性表达与临床分期、间质浸润及LVSI呈正相关(P<0.05),而与TNM及组织分化无相关性(P>0.05)。结论:P16基因的阳性表达与宫颈癌患者的预后密切相关,可作为预测宫颈癌预后的指标之一。%Objective To access the expression of germ P16 in cervical cancer patients , find out the connection between with the expression in germ of P16 and the prognosis of cervical cancer , and discuss whether P16 can role as an indicator to predict the prognosis. Methods The pathological sections of all 74 cases were tested for the presence of P16 germ , using an immunohistochemistry technique. And the results were analyzed to investigate the value of P16 on the prediction of prognosis of cervical cancer. Results Of all 74 cervical cancer cases, there are 63 cases show positive expression of P16, with the positive expression rate of 85% (63/74). The positive expression of gene P16 is associated with the prognosis of cervical cancer (P = 0.041). The cumulative survival rate for two years of the positive expression set is 85.2%, and the negative set 100%, which is statistically significant (P = 0.043). Positiveexpression of P16 is closely related (P 0.05) with TNM and histological differentiation

  1. P16蛋白在人脑胶质瘤中的表达%Expression of P16 protein in glioma

    Institute of Scientific and Technical Information of China (English)

    李卫国; 李新钢; 孔建新; 郭春

    2001-01-01

    To observe the expression of P16 protein in human gliomas,theanti-P16 polyclonal antibody was applied to detect the expression of P16 protein in glioma cells by immunohistochemical method.The results showed that P16 pr otein was detected in plastic region of tumor cell.The frequency of positive exp ression of P16 protein in astrocytoge nic gliomas and ependymogenic gliomas wa s 42.9% and 100% respectively.The differ ence was significance(P<0.025)in statist ic.The distribution of positive expressi on rate of P16 protein was different in different grade of gliomas.The differ ences were significant(P<0.05).This sugg ested that as the malignant degree o f gl ioma was raising, the expression rate of P16 protein in gliomas was decreasing. The deletions of P16 protein expressi on,e.g.the P16 gene homozygous deleti ons play an important role in malignant transformation of gliomas. The clinical results could be pre dicted by different expression levels of P16%采用免疫组化LSAB法检测P16蛋白在人脑胶质瘤中表达。结果显示:P16蛋白染色强度的分布在各级胶质瘤间存在显著性差异(P<0.025),星形细胞起源的胶质瘤与室管膜细胞起源的胶质瘤P16蛋白阳性率分别为42.9%和100%,二者存在显著性差异(P<0.05);临床分期Ⅰ、Ⅲ期间亦存在显著差异。认为P16蛋白表达随胶质瘤恶性程度升高而降低,检测P16蛋白表达有助于判断胶质瘤的预后,并指导其治疗方案的选择。

  2. Helicobacter pylori upregulates the expression of p16(INK4) in gastric cancer cells.

    Science.gov (United States)

    Wang, Ping; Mei, Juan; Zhang, Ning; Tao, Jing; Tian, Hua; Fu, Guo-Hui

    2011-01-01

    Previous studies have suggested that p16(INK4) protein is over expressed in gastric cancer. However, whether H. pylori infection induces p16(INK4) in human gastric epithelial cells remains to be determined. The aim of this study was to analyze the molecular mechanism of H. pylori-induced p16(INK4) expression. Expression of p16(INK4) mRNA and Sp1 mRNA were assessed by reverse transcription-PCR. Expression of p16(INK4) protein was assessed by Western blot and immunocytochemistry. A luciferase assay was used to monitor activation of the p16(INK4) gene promoter and to explore the binding of transcription factors to this promoter. H. pylori upregulates the expression of p16(INK4) in gastric cancer SGC7901 cells. p16 promoter is highly actived in SGC7901 cells by H. pylori. Sp1 activates the expression of p16(INK4)-Luc and promotes the protein level of p16(INK4). H. pylori upregulates the expression of p16(INK4) in gastric cancer SGC7901 cells via the p16(INK4) promoter, and Sp1 is involved in the activation of p16(INK4) promoter by H. pylori.

  3. Adenovirus with p16 gene exerts antitumor effect on laryngeal carcinoma Hep2 cells.

    Science.gov (United States)

    Yang, Zhengang; Hu, Jingxia; Li, Dajun; Pan, Xinliang

    2016-08-01

    Laryngeal cancer is an uncommon form of cancer. The tumor suppressor P16, known to be mutated or deleted in various types of human tumor, including laryngeal carcinoma, is involved in the formation and development of laryngeal carcinoma. It has been previously reported that the inactivation or loss of P16 is associated with the acquisition of malignant characteristics. The current study hypothesized that restoring wild‑type P16 activity into P16‑null malignant Hep2 cells may exert an antitumor effect. A recombinant adenovirus carrying the P16 gene (Ad‑P16) was used to infect and express high levels of P16 protein in P16‑null Hep2 cells. Cell proliferation and invasion assays and polymerase chain reaction were performed to evaluate the effects of the P16 gene on cell proliferation and the antitumor effect on Hep2 cells. The results demonstrated that the Hep2 cells infected with Ad‑P16 exhibited significantly reduced cell proliferation, invasion and tumor volume compared with untreated or control adenovirus cells. Furthermore, the expression of laryngeal carcinoma‑associated genes, EGFR, survivin and cyclin D1, were measured in Ad‑P16‑infected cells and were significantly reduced compared with control groups. The results of the current study demonstrate that restoring wild‑type P16 activity into P16-null Hep2 cells exerts an antitumor effect.

  4. STUDY OF DELETION OF P16 GENE IN THE PROGRESSION OF BRAIN ASTROCYTOMAS

    Institute of Scientific and Technical Information of China (English)

    Zhai Guang; Yuan Xianhou

    1998-01-01

    Objective:To study the relationship between deletion of P16 gene and occurrence and progression of astrocytomas. Methods: The techniques of polymerase chain reaction (PCR) and immunohistochemistry were used to detect the deletion of exon2 of P16 gene and expression of P16 gene in 52 cases of Brain astrocytoma.Results: The deletion rate of exon2 of P16 gene in the tumors analyzed was 34.6%. Most of them with deletion of exon2 of p16 gene were high grade astrocytomas (grade Ⅲ 42%, grade Ⅳ 50%). 61.5% of the tumors were absent from expression of p16 and the deletion rate of p16 protein increased with the grade of astrocytoma (X2=10.83, P<0.005). Conclusion: Deletion of p16 gene and protein may correlate with the malignant progression of astrocytoma.

  5. Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Po Zhao; Ying-Chuan Hu; Ian C. Talbot

    2003-01-01

    AIM: To describe the correlation between innunostaining patterns of p16 and CDK4 and prognosis in colorectal carcinoma.METHODS: Paraffin sections of 74 cases of colorectal carcinoma were analysed immunohistochemically for expression of p16 and CDK4 proteins.RESULTS: Most carcinomas showed stronger p16 and CDK4immunostaining in the cytoplasm than the adenomas or the adjacent normal mucosa. Strong immunostaining of p16 was a predictor for better prognosis whereas strong cytoplasmic immunostaining of CDK4 was a predictor for poor prognosis.Both p16 and CDK4 immunostainings were correlated with histological grade or Dukes' stage.CONCLUSION: These results support the experimental evidence that interaction of expression of p16 and CDK4may play an important role in the Rb/p16 pathway, and the expression paterns of CDK4 and p16 may be imperative in the development of colorectal carcinoma, thus becoming a new prognostic marker in colorectal cancer.

  6. Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon

    Science.gov (United States)

    Elder age and chronic alcohol consumption are important risk factors for the development of colon cancer. Each factor can alter genomic and gene-specific DNA methylation. This study examined the effects of aging and chronic alcohol consumption on genomic and p16-specific methylation, and p16 express...

  7. CONSTRUCTTION OF RECOMBINED TRANSFER VECTOR CARRYING p16 cDNA%含抑癌基因p16转移载体的构建

    Institute of Scientific and Technical Information of China (English)

    马春红; 孙汶生; 张利宁; 曹英林; 宋静; 刘素侠

    2000-01-01

    目的:为获得高表达有活性的p16蛋白,构建含p16 cDNA的重组转移载体.方法:EcoRI-xhoI双酶切克隆质粒pBLUESCRIPT-p16,低融点琼脂糖回收0.8kb的p16 cDNA片段,插入质粒pSXIVVI+X3,构建含p16的重组载体pX3-p16,并对重组子以菌落原位杂交和酶切电泳两种方法进行鉴定.结果:电泳证实低融点琼脂糖回收的片段为0.8kb.菌落原位杂交筛选8个阳性克隆,酶切电泳证实阳性克隆中p16 cDNA插入方向正确.结论:成功构建了含p16 cDNA的重组转移载体,为p16在昆虫细胞和活体昆虫中的表达奠定了基础.

  8. Research progress of p16 gene detection in lung cancer%肺癌患者p16基因检测的研究进展

    Institute of Scientific and Technical Information of China (English)

    蔡淑娟; 陈建荣

    2011-01-01

    细胞周期与细胞癌变密切相关,抑癌基因p16参与细胞周期调控,p16的改变可导致细胞的失控性生长,所以p16基因可成为肿瘤选择作用的治疗靶点。p16基因检测对肺癌的发病机制研究、早期诊断、预后评估和分子靶向治疗有一定帮助。%The cell cycle is closely related with the cellular canceration. Tumor-suppressor gene p16 is involved in cell cycle regulation. The change of tumor-suppressor gene p16 could cause cells out of growth, p16 gene can become treatment target of trmor. The detection of p16 gene is helpful for the pathogenesis of lung cancer,early diagnosis,prognosis assessment and molecular-targeted therapy.

  9. Aging and chronic alcohol consumption are determinants of p16 gene expression, genomic DNA methylation and p16 promoter methylation in the mouse colon

    Science.gov (United States)

    Elder age and chronic alcohol consumption are important risk factors for the development of colon cancer. Each factor can alter genomic and gene-specific DNA methylation. This study examined the effects of aging and chronic alcohol consumption on genomic and p16-specific methylation, and p16 express...

  10. Construction of recombinant p16 Adenovirus plasmid%重组pAd/CMV/V5-DEST-p16质粒的构建

    Institute of Scientific and Technical Information of China (English)

    姚彬; 胡勇; 熊自忠; 李旭

    2006-01-01

    摘要目的构建并鉴定pAd/CMV/V5-DEST-p16重组腺病毒质粒.方法合成人p16-INK4表达基因,构建pENTR1A-p16质粒.通过LR反应,入口克隆pENTR1A-p16质粒的外源性合成的修饰后的p16 cDNA,取代目的质粒pAd/CMV/V5-DEST中的ccdB基因,形成表达克隆pAd/CMV/V5-DEST-p16,测序证实质粒含有目的基因.结果构建了p16重组腺病毒质粒,为研究p16-INK4的作用创造了条件.结论用通路克隆系统构建重组p16腺病毒质粒稳定、可靠、方便.

  11. Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model.

    Science.gov (United States)

    Duquette, Mark; Sadow, Peter M; Husain, Amjad; Sims, Jennifer N; Antonello, Zeus A; Fischer, Andrew H; Song, Chen; Castellanos-Rizaldos, Elena; Makrigiorgos, G Mike; Kurebayashi, Junichi; Nose, Vania; Van Hummelen, Paul; Bronson, Roderick T; Vinco, Michelle; Giordano, Thomas J; Dias-Santagata, Dora; Pandolfi, Pier Paolo; Nucera, Carmelo

    2015-12-15

    BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for

  12. Expression of P16 and Rb Proteins in Gastric Carcinoma%胃癌中P16、Rb蛋白表达分析

    Institute of Scientific and Technical Information of China (English)

    贺修胜; 陈主初; 何冬梅; 苏琦; 龙志峰

    2002-01-01

    目的研究p16和Rb基因表达产物P16、Rb蛋白与胃癌发生发展的关系及分析胃癌组织中p16、Rb基因表达的相互关系.方法运用链霉菌抗生物素蛋白-过氧化物酶(S-P)免疫组织化学方法检测胃癌、癌前病变及正常胃粘膜组织中P16、RB蛋白的表达.结果 P16、R b蛋白表达阳性率分别为:正常胃粘膜96.25% (77/80)、98.75%(79/80),不典型增生92. 00%(46/50)、80.00%(40/50),胃癌47.54%(58/122)、59.84%(73/122),胃癌组中P16、R b蛋白表达低于正常胃粘膜及不典型增生(P<0.05);胃癌中P16、Rb蛋白的表达的相互关系:P16 、Rb蛋白均为阳性15.56%(14/90),P16、Rb蛋白均为阴性7.78%(7/90),P16蛋白阳性、Rb蛋白阴性33.33%(30/90),P16蛋白阴性、Rb蛋白阳性43.33%(39/90),P16、Rb蛋白表达呈负相关(P<0.05).结论 P16、Rb蛋白表达缺失与胃癌的发生发展有关;胃癌组织中P16蛋白与Rb蛋白表达呈负相关关系.

  13. P16和PCNA在食管癌中的表达及意义%The expression and significance of P16 and PCNA in esophageal cancer

    Institute of Scientific and Technical Information of China (English)

    王蒨; 张桂荣; 周健

    2001-01-01

    Objective To investigate the expression of anti-oncogene P16 and proliferative cell nuclear antigen (PCNA) in esophageal squamous cell cancer and their clinical pathology.Methods The SP immunohistochemistry method was used in the study.Results The positive P16 expression was found in the 68.9% of the total 64 cases of esophageal squamous cell cancer, the average PCNA positive cell proliferation incidence(PCNA-PI) was 53.4%. P16 expression was very low in the poorly differentiated esophageal cancer. In contrast, the average PCNA-PI was low in highly differentiated cancer cells, while being high in the poorly differentiated cells (P<0.05). Low P16 expression was found while there was lymph node metastasis and as the cancer developed, the percentage of P16 positive cell decreased (P<0.01). PCNA-PI was low in the P16 positive group and was high in the P16 negative group (P>0.05).Conclusion Combined examination of the P16 and PCNA is of great significance in determining the malignancy state, therapy method and evaluating the prognosis of the esophageal squamous cell cancer.%目的观察抑癌基因P16、增殖细胞核抗原PCNA在食管鳞状细胞癌中的表达特性及与临床病理联系。方法应用SP免疫组织化学方法。结果在64例食管鳞癌中P16阳性表达率为68.9%,PCNA阳性细胞增殖指数(PCNA-PI)平均值53.4。P16在低分化癌中较高分化癌阳性表达率低,相反,PCNA-PI在高分化癌平均值低,在低分化癌高(P<0.05)。有淋巴结转移的P16阳性表达率低,且随着病期的进展阳性表达率降低(P<0.05)。P16阴性组PCNA-PI高(P>0.05)。结论联合检测P16蛋白和PCNA蛋白对食管鳞癌恶性度评定,治疗的选择,预后估计有重要意义。

  14. 16例妇科肿瘤中P16基因缺失的研究%Deletion of P16 gene in 16 gynaecological tmnors

    Institute of Scientific and Technical Information of China (English)

    赵春艳; 张耀铮; 孙静

    2000-01-01

    目的:研究P16基因缺失与妇科肿瘤发生及恶性变的关系.方法:采用聚合酶链式反应技术(PCR),扩增16例妇科肿瘤组织中的P16基因.结果:16例妇科肿瘤组织中,有12例为恶性肿瘤,其中有4例出现P16基因缺失,缺失率为33.3%;有4例为良性肿瘤.未见P16基因缺失.结论:P16基因缺失可能与妇科肿瘤的发生及恶性变有关.

  15. P16在食管癌变过程中的表达%Expression of p16 in Carcinogenesis of the Esophagus

    Institute of Scientific and Technical Information of China (English)

    刘海明

    2011-01-01

    目的 探讨p16基因在食管癌变过程中的表达.方法 应用免疫组织化学S-P法检测p16基因在17例癌变组和40例非癌变组中的表达.结果 p16在癌变组中的表达降低(P<0.05).结论 p16基因的表达和食管癌的发生有关,p16基因表达的变化可能是食管癌发生中的早期事件.

  16. Significance of p16 Protein Expression in Nephroblastoma%p16蛋白在肾母细胞瘤中的表达

    Institute of Scientific and Technical Information of China (English)

    宋兰云; 王学文; 胡晓丽; 宁培儒

    2003-01-01

    目的:探讨p16蛋白在肾母细胞瘤中的表达及临床意义.方法:应用S-P免疫组织化学方法对42例肾母细胞瘤常规石蜡标本进行p16蛋白检测.结果:42例中p16蛋白表达缺失率为69.05%,p16蛋白阳性表达与病理组织类型、患儿预后显著相关(P<0.01),阳性表达者预后好.结论:p16蛋白表达可作为判断肾母细胞瘤预后的指标.

  17. 卵巢肿瘤p16蛋白的表达及意义%Expression of p16 in Ovarian Tumors and Its Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    张士伟; 袁碧波; 刘容珍; 孙保存

    2000-01-01

    目的:研究p16在卵巢肿瘤中的表达及意义.方法:应用免疫组化ABC法检测133例卵巢肿瘤和12例正常卵巢组织p16的表达.结果:卵巢肿瘤与正常卵巢组织p16表达有显著性差异.正常卵巢没有p16表达的缺失,良性、交界性、恶性组p16表达明显下降(P<0.05).上皮性组晚期、残存癌灶≥2cm者p16表达明显低于早期、残存癌灶〈2cm者(P<0.05);p16表达与组织类型、组织分化、淋巴结转无关(P<0.05).生存分析表明p16尚不能作为卵巢癌的独立预后因素.结论:p16蛋白在卵巢肿瘤中存在不同程度的缺失,与卵巢癌的发生、发展有一定关系.p16能否作为卵巢癌的预后指标尚需进一步研究.

  18. p16 Stimulates CDC42-dependent migration of hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Ya-Wen Chen

    Full Text Available Hepatocellular carcinoma (HCC is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells - ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.

  19. p16 Stimulates CDC42-dependent migration of hepatocellular carcinoma cells.

    Science.gov (United States)

    Chen, Ya-Wen; Chu, Hsiao-Chien; Ze-Shiang Lin; Shiah, Wei-Jyh; Chou, Chen-Pin; Klimstra, David S; Lewis, Brian C

    2013-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells - ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.

  20. GEN 300 Courses/sanptutorial

    OpenAIRE

    2015-01-01

    GEN 300 Ethics in an Academic Environment Assignment POWERPOINT ONLY GEN 300 Team Dynamics Instructions GEN 300 Effects of Technology Essay GEN 300 Research,Summary, and Paraphrase Activity GEN 300 Ethics in an Academic Environment Assignment PAPER ONLY GEN 300 Final Paper on Team Dynamics GEN 300 Student Web Scavenger Hunt GEN 300 Week 1 DQs GEN 300 Week 2 DQs GEN 300 Week 3 DQs GEN 300 Week 4 DQs GEN 300 Week 5 DQ

  1. GEN 105 Courses/sanptutorial

    OpenAIRE

    2015-01-01

    GEN 105 Assignment: Reading and Retention GEN 105 Assignment: Elevator Speech GEN 105 CheckPoint: Technological Tools GEN 105 CheckPoint: Distance Learning I GEN 105 CheckPoint: Distance Learning II GEN 105 CheckPoint: Communicating in Forums GEN 105 Week 2 Discussion Questions GEN 105 Week 4 Discussion Questions GEN 105 Week 6 Discussion Questions GEN 105 Week 8 Discussion Questions GEN 105 Assignment: University Library Article Search GEN 105 Chec...

  2. Prognostic significance of p16 expression in advanced cervical cancer treated with definitive radiotherapy.

    Science.gov (United States)

    Schwarz, Julie K; Lewis, James S; Pfeifer, John; Huettner, Phyllis; Grigsby, Perry

    2012-09-01

    The purpose of this study was to evaluate the prognostic significance of p16 immunohistochemistry (IHC) in patients with advanced cervical cancer treated with radiation therapy. This was a retrospective study of 126 patients with International Federation of Gynecology and Obstetrics Stages Ib1-IVb cervical cancer treated with radiation. Concurrent cisplatin chemotherapy was given to 108 patients. A tissue microarray (TMA) was constructed from the paraffin-embedded diagnostic biopsy specimens. Immunoperoxidase staining was performed on the TMA and a p16 monoclonal antibody was utilized. IHC p16 extent was evaluated and scored in quartiles: 0 = no staining, 1 = 1-25% of cells staining, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. The p16 IHC score was 4 in 115 cases, 3 in 1, 2 in 3 and 0 in 7. There was no relationship between p16 score and tumor histology. Patients with p16-negative tumors were older (mean age at diagnosis 65 vs. 52 years for p16-positive tumors; p = 0.01). The 5-year cause-specific survivals were 33% for p16-negative cases (score = 0) compared with 63% for p16-positive cases (scores 1, 2, 3 or 4; p = 0.07). The 5-year recurrence-free survivals were 34% for those who were p16-negative vs. 57% for those who were p16-positive (p = 0.09). In addition, patients with p16-positive tumors (score > 0) were more likely to be complete metabolic responders as assessed by the 3-month posttherapy 18 [F]-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomograph compared with patients with p16-negative tumors (p = 0.03). p16 expression is predictive of improved survival outcome after chemoradiation therapy for advanced-stage invasive cervical carcinoma. Further testing will be needed to evaluate p16-negative cervical tumors. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Prognostic Significance of p16 Expression in Advanced Cervical Cancer Treated With Definitive Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Schwarz, Julie K., E-mail: jschwarz@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO (United States); Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO (United States); Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (United States); Lewis, James S. [Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (United States); Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO (United States); Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (United States); Pfeifer, John [Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (United States); Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO (United States); Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (United States); Huettner, Phyllis [Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (United States); Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO (United States); Grigsby, Perry [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO (United States); Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO (United States); Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO (United States); Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (United States)

    2012-09-01

    Purpose: The purpose of this study was to evaluate the prognostic significance of p16 immunohistochemistry (IHC) in patients with advanced cervical cancer treated with radiation therapy. Materials and Methods: This was a retrospective study of 126 patients with International Federation of Gynecology and Obstetrics Stages Ib1-IVb cervical cancer treated with radiation. Concurrent cisplatin chemotherapy was given to 108 patients. A tissue microarray (TMA) was constructed from the paraffin-embedded diagnostic biopsy specimens. Immunoperoxidase staining was performed on the TMA and a p16 monoclonal antibody was utilized. IHC p16 extent was evaluated and scored in quartiles: 0 = no staining, 1 = 1-25% of cells staining, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. Results: The p16 IHC score was 4 in 115 cases, 3 in 1, 2 in 3 and 0 in 7. There was no relationship between p16 score and tumor histology. Patients with p16-negative tumors were older (mean age at diagnosis 65 vs. 52 years for p16-positive tumors; p = 0.01). The 5-year cause-specific survivals were 33% for p16-negative cases (score = 0) compared with 63% for p16-positive cases (scores 1, 2, 3 or 4; p = 0.07). The 5-year recurrence-free survivals were 34% for those who were p16-negative vs. 57% for those who were p16-positive (p = 0.09). In addition, patients with p16-positive tumors (score > 0) were more likely to be complete metabolic responders as assessed by the 3-month posttherapy 18 [F]-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomograph compared with patients with p16-negative tumors (p = 0.03). Conclusion: p16 expression is predictive of improved survival outcome after chemoradiation therapy for advanced-stage invasive cervical carcinoma. Further testing will be needed to evaluate p16-negative cervical tumors.

  4. p16基因在乳腺癌中的表达及临床意义%Clinical Significance of p16 Expression in Breast Carcinoma

    Institute of Scientific and Technical Information of China (English)

    宫向前; 寿楠海; 张永生; 王启堂

    2002-01-01

    目的:研究p16基因在乳腺癌中的表达及临床意义.方法:应用免疫组织化学方法(SABC法),检测了92例乳腺癌组织p16基因蛋白的表达.结果:发现p16基因表达阳性率为45.7%(42/92),p16基因表达与腋淋巴结转移无关;但p16阳性者远隔转移率14.3%(6/42)低于p16阴性组34%(17/50,P<0.05).本组p16基因表达与疾病缓解期无关.结论:提示p16基因在乳腺癌病程中起重要作用,对筛选乳腺癌术后高危转移患者,加强随访诊治有一定参考意义.

  5. P16 and retinoblastoma protein expression in endometrial carcinoma and clinical significance.

    Science.gov (United States)

    Koh, V Mue; Shi, Y X; Tang, Q H

    2011-01-01

    To investigate the clinical significance of p16 expression, a product of the cyclin dependent kinase inhibitor CDKN2 (also known as MTS1, multiple tumor suppressor 1) and assess its relationship with retinoblastoma protein expression in the pathogenesis of endometrial cancer. p16 and pRb expression were histochemically evaluated, using p16 and RB polyclonal antibodies on paraffin sections of 27 primary endometrial adenocarcinomas with no therapy prior to surgery, through the streptavidin peroxydase conjugated method. Further analyses were carried out using the polymerase chain reaction for exon 1 gene amplification to investigate the mechanism of abnormal p16 expression. p16 expression was detected in 100% of normal endometriums and in 74.04% of endometrial carcinomas (p p16 expression revealed four homozygous deletions. Additionally, the inverse correlation between RB and p16 expression was confirmed in this study, with 71.42% of tumors demonstrating inverse expression of p16 and RB (p p16 expression decrease is a significant event in endometrial carcinoma pathogenesis, and it is inversely correlated to tumor cell grade. Exon 1 homozygous deletion might be one of the mechanisms of loss of p16 expression. The p16/pRb growth suppressor pathway is targeted in human endometrial carcinoma.

  6. Hypermethylation of the CPG Island of p16 Gene Correlates with Gene Inactivation in Brain Glioma

    Institute of Scientific and Technical Information of China (English)

    JIAOBaohua; GENGShaomei; 等

    2002-01-01

    Objective:To study the correlation between hypermethylation of the CPG island of p16 gene and its inactivation in gliomas.Mehtods:In 50 cases of brain glioma,immunohistochemical method was applied to detect the expression of p16 protein; PCR a-nalysis was performed to identify the deletion of exons 1,2 of p16 gene and hypermethylation of CPG island of exon 1 of p16 gene in brain glioma.Results:Immunohistochemical analysis showed that p16 protein expression was negative in 27 cases(54%) and positive in 23 cases(46%) of 50 cases of brain gliomas.In the group with negative p16 protein expression(n=27 cases),RT-PCR analysis showed that there were 9 cases(33%) with homozygous deletions ofp16 gene and 7 cases(26%) with hypermethylation of CPG island of p16 gene.Conclusion:The transcriptional inhibition of p16 gene may be induced by aberrant hypermethylation of p16 gene 5'-CPG island in some of the cases without the homozygous deletions of p16 gene.Hypermethylation of 5'-CPG island is one of the important mechanisms for p16 gene inactivation.

  7. Effects of p16 gene on biological behavious in hepatocellular carcirnoma cells

    Institute of Scientific and Technical Information of China (English)

    Jian-Zhao Huang; Sui-Sheng Xia; Qi-Fa Ye; Han-Ying Jiang; Zhong-Hua Chen

    2003-01-01

    AIM: To investigate the effects of p16 gene on biologicalbehavious in hepatocellular carcinoma cells.METHODS: HCC cell lines SNU-449 and HepG2.2.15 wereinfected respectively by a replication defective, recombinantretrovirus capable of producing a high level of p16 proteinexpression (pCLXSN-p16). G418 resistant stable P16 proteinexpression cell lines were selected. And the biological behavioursof the p16 gene transfected HCC cells were observed.RESULTS: Initialin vitro experiments in HCC cell line SNU-449 with loss of p16 protein expression demonstrated thepCLXSN-p16 treatment significantly inhibited cell growth.But there was no treatment effect when the pCLXSN-p16was used in another HCC cell line HepG2.2.15 which haspositive p16 protein expression. Subsequent study in a nudemouse model demonstrated that the p16 gene transfectedSNU-449 had a lower succeeding rate in the first timeestablishment of tumors and grew more slowly in the nudemice when compared with non-transfected SNU-449.Moreover, the nude mice inoculated with transfected SNU-449 had a longer surviving time than those inoculated withnon-transfected SNU-449.CONCLUSION: Our results show that the p16INK4a genetransfer can inhibit the proliferation and reduce the invasionability of hepatocellular carcinoma.

  8. P16 METHYLATION OF THE COLORECTAL CANCER AND ASSOCIATION WITH DUKES STAGES

    Institute of Scientific and Technical Information of China (English)

    王志伟; 易静; 仓辉; 邹鸿志; 郁宝铭; 汤雪明

    2001-01-01

    To explore whether methylation of the CpG island in the promoter of the p16 tumor suppressor gene was associated with clinicopathological characteristics of the colorectal cancer patients. Methods: Methylation- specific PCR (MSP) was used to detect p16 methylation of the colorectal cancer patients. Results: In 58 sporadic colorectal cancer, 43.1% of the tumors had detectable p16 methylation. Dukes' stage was associated with p16 methylation status. Dukes C, D patients (75%) were more likely to contain methylated p16 compared with Dukes A, B patients (13.3%). Conclusion: p16 methylation plays a role in the carcinogenesis of a subset of colorectal cancer. P16 methylation might be considered as a prognostic indicator.

  9. High CpG island methylation of p16 gene and loss of p16 protein expression associate with the development and progression of tetralogy of Fallot

    Indian Academy of Sciences (India)

    SI-JU GAO; GUI-FANG ZHANG; RONG-PENG ZHANG

    2016-12-01

    We examined CpG island methylation in p16 gene and its effect on p16 protein expression in tetralogy of Fallot (ToF) patients to explore its potential implications in the development and progression of ToF. The study subjects consisted of 75 healthy controls and 63 ToF patients recruited at Linyi People’s Hospital between January 2012 and June 2014. The 4 mL of peripheral venous blood of each subject was obtained and saved in ethylene diamine tetraacetic acid (EDTA) tubes. Methylation-specific polymerase chain reaction (MSP) was employed to detect CpG island methylation in p16 promoter region andWestern blotting was used to detect p16 expression of all subjects. Real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) was performed to test p16 mRNA expression. The results showed that p16-methylation rates in ToF group were significantly higher than the control group (ToF group, 58.73%; control group, 13.33%; P < 0.001). Remarkably, Western blotting and FQ-PCR results derived from RVOT revealed that p16 protein expression was significantly lower in ToF group compared to the control group (0.76± 0.21 versus 2.31 ± 0.35; P < 0.001), and p16 gene expression was also markedly decreased in ToF group (1.212 ± 0.152 versus 1.346 ± 0.191, P< 0.001). Additionally, our analysis suggested that CpG island methylation in p16 promoters in ToF patients was negatively correlated with p16 protein and gene expression (both P < 0.05). Our study reports that high CpG island methylation of p16 gene and loss of p16 protein expression associate with the development and progression of ToF, which may have significant therapeutic applications for ToF.

  10. Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization

    Directory of Open Access Journals (Sweden)

    Pannone Giuseppe

    2012-02-01

    Full Text Available Abstract Background Recent emerging evidences identify Human Papillomavirus (HPV related Head and Neck squamous cell carcinomas (HN-SCCs as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC; 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR; and 3 viral integration into the host by in situ hybridization method (ISH. This triple method has been applied to HN-SCC originated from oral cavity (OSCC and oropharynx (OPSCC, the two anatomical sites in which high risk (HR HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics. Results All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC but lower specificity level (74% in OSCC and 93% in OPSCC. Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC (κ = 0.38 and a moderate agreement in OSCC (κ = 0.44. Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE samples (100% in OSCC and 78.5% in OPSCC, but reduced the sensitivity (33% in OSCC and 60% in OPSCC. The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach. Conclusions Although HR

  11. GEN 480 UOP Course Tutorial / gen480dotcom

    OpenAIRE

    2015-01-01

    GEN 480 Entire Course For more course tutorials visit www.gen480.com   GEN 480 Week 1 Individual Assignment Ethics Awareness Inventory GEN 480 Week 1 DQ 1 GEN 480 Week 1 DQ 2 GEN 480 Week 1 DQ 3 GEN 480 Week 1 DQ 4 GEN 480 Week 1 Summary GEN 480 Week 2 Individual Assignment Ethics Awareness Inventory Analysis GEN 480 Week 2 Individual Assignment Professional Workplace Dilemma Paper GEN 480 Week 2 Learning Team Assignment Skills Assessment P...

  12. p16INK4A immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia.

    Science.gov (United States)

    Kong, Christina S; Balzer, Bonnie L; Troxell, Megan L; Patterson, Bruce K; Longacre, Teri A

    2007-01-01

    In situ hybridization (ISH) assays for high-risk human papillomavirus (HR-HPV) and immunohistochemical (IHC) assays for surrogate markers such as p16 can be useful in detecting HR-HPV in cervical dysplasia, but the use of these markers in problematic cervical biopsies has not been well-established. We evaluated 3 chromogenic ISH assays (Ventana INFORM HPVII and HPVIII and DakoCytomation GenPoint) in conjunction with p16 IHC and HPV polymerase chain reaction in a study set consisting of 12 low-grade squamous intraepithelial lesions, 16 high-grade squamous intraepithelial lesions, and 30 benign cervix samples. A test set of 28 cases of atypical squamous metaplasia were also evaluated withVentana HPVIII ISH and p16 IHC. In the study set, the sensitivity of the DakoCytomation ISH assay (which detects HPV subtypes 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, and 68) was similar to the Ventana HPVII assay but less than that of the Ventana HPVIII ISH assay (both of which detect HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) and less than p16 IHC (55.6% vs. 53.6 vs. 69.2% vs. 82.1%). All HPV ISH assays exhibited 100% specificity. p16 reactivity consisted of 2 patterns: focal strong and diffuse strong. Because focal strong p16 reactivity was identified in benign squamous epithelium (6.7% cases) and dysplastic epithelium, it was considered an equivocal result and only diffuse strong reactivity was considered to be specific for the presence of HR-HPV. In the squamous intraepithelial lesions study set, the difference in sensitivity between Ventana HPVIII ISH and p16 was not statistically significant. However, in the atypical squamous metaplasia test set cases, p16 reactivity (focal strong and diffuse strong) was significantly more sensitive than Ventana HPVIII ISH in correlating with the presence of human papillomavirus as detected by polymerase chain reaction (83.3% vs. 33.3% P=0.004). Because focal strong p16 reactivity is less specific, cases with this

  13. Deletion Mutation Analysis of p16 Gene in Lung Cancer%肺癌组织中p16基因缺失的初步研究

    Institute of Scientific and Technical Information of China (English)

    王旭光; 王建勋

    2001-01-01

    目的探讨p16基因缺失与肺癌发生的关系.方法采用PCR方法检测48例肺癌组织标本中p16基因缺失的情况,其中包括23例原发性小细胞肺癌(SCLC)和25例原发性非小细胞肺癌(NSCLC).结果在23例SCLC中没发现p16基因缺失,而25例NSCLC中,7例存在p16基因缺失,缺失率达28%.结论结果提示p16基因的变异与原发性非小细胞肺癌的发生及发展相关.

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

    Science.gov (United States)

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

    2002-08-01

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

  15. The Value of P16 Positive Expression in Pancreatic Cancer%胰腺癌中p16蛋白阳性表达的价值

    Institute of Scientific and Technical Information of China (English)

    赫淑倩; 王海斌

    2001-01-01

    Objective To study the expression of p16 in pancreatic cancer and the relationships among the expression,the clinical patheological characteristics and the prognosis.Methods  The expressions of p16 in 40 cases of pancreatic cancer, 12 cases of pancreatic serous adenoma and 16 cases of pancreatitis were detected through the immunohisochemistry S-P method. Results The expressing rate of p16 in the pancreatic cancer was much lower than those in pancreatic serous adenoma and pancreatitis, there was obvious differences of expression in the level of pancreatic cancer and ductal adenocarcinoma differentiation of high, medial and low degrees. Conclusion The expression of p16 is closely related to the level and classification of pancreatic cancer, the gene of p16 can be the index of judging the melignant degree of oncocyte and the prognosis.%目的观察p16蛋白在胰腺癌中的表达,探讨其与胰腺癌临床病理学特征及预后的关系。方法采用免疫组织化学S-P 法检测p16蛋白在40例胰腺癌、12例胰腺浆液性腺瘤、16例胰腺炎中的表达情况。结果 p16蛋白在胰腺癌中表达率明显低于胰腺炎及胰腺浆液性腺瘤,且 p16蛋白在胰腺癌分期及导管腺癌高、中、低分化组间表达有显著差异。结论 p16蛋白的表达与胰腺癌的分级和分期的关系密切, p16基因可作为判定瘤细胞恶性程度及预后的客观指标。

  16. 肝癌中P16与PRb的表达及意义%Expression and significance of P16、PRb in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    黄志勇; 刘漪沦

    2002-01-01

    目的了解P16、PRb在肝癌中的表达及其在肝癌发生、发展中的作用.方法用免疫组化S-P法,对4 6例肝癌及癌旁组织和10例正常肝组织进行对比研究.结果(1)46例肝癌组织中P16及PRb的阳性率分别为45.6%和56.5%,均明显低于相应癌周组织89%、91.3%和正常组织100%的水平(P<0.01);(2)P16与PRb呈负相关;(3)P16与肿癌的病理分级、门静脉癌栓及肿瘤包膜密切相关;PRb仅与前者有关.结论(1)P16、PRb在肝癌中有较高的缺失率,可能与肝癌的发生、发展关系密切;(2)P16与PRb呈负相关,验证了P16与PRb在细胞周期调节中的负反馈学说;(3)P16、PRb与肝癌的大小、病理分级、门静脉癌栓及具有完整包膜等因素有密切关系,可考虑将其作为评价肝癌预后的指标.

  17. GEN 200 Courses/sanptutorial

    OpenAIRE

    2015-01-01

    GEN 200 Week 1 Assignment- Map Out an Important Goal GEN 200 Week 1 DQ 1 GEN 200 Week 1 DQ 2 GEN 200 Week 2 Assignment- Communication and Collaboration Strategy Paper GEN 200 Week 2 DQ 1 GEN 200 Week 2 DQ 2 GEN 200 Week 3 Assignment- Student Web Scavenger Hunt GEN 200 Week 3 DQ 1 GEN 200 Week 3 DQ 2 GEN 200 Week 4 Assignment-Research Strategy Paper GEN 200 Week 4 DQ 1 GEN 200 Week 4 DQ 2 GEN 200 Week 5 DQ 1 GEN 200 Week 5 DQ 2 GEN 200 We...

  18. p16(INK4a translation suppressed by miR-24.

    Directory of Open Access Journals (Sweden)

    Ashish Lal

    Full Text Available BACKGROUND: Expression of the tumor suppressor p16(INK4a increases during aging and replicative senescence. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3'-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites. CONCLUSIONS/SIGNIFICANCE: Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation.

  19. A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway.

    Science.gov (United States)

    Cimino-Mathews, Ashley; Hicks, Jessica L; Sharma, Rajni; Vang, Russell; Illei, Peter B; De Marzo, Angelo; Emens, Leisha A; Argani, Pedram

    2013-11-01

    Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb, and Ki-67 and by in situ hybridization for high-risk human papillomavirus. Cytoplasmic and nuclear p16 were scored by percentage labeling (0%-100%, diffuse >95%) and intensity. Nuclear Rb was scored by percentage labeling (0%-100%, diffuse >75%) and intensity. p16 and Rb labeling were repeated on whole sections of cases with Rb loss on the tissue microarray. Twenty-nine percent (4/14) malignant phyllodes showed diffuse strong p16 labeling with Rb loss in malignant cells (diffuse p16+/Rb-), whereas 21% (3/14) malignant phyllodes showed the reverse pattern of p16 loss with diffuse strong Rb (p16-/diffuse Rb+). Results were consistent between tissue microarrays and whole sections. No borderline phyllodes, benign phyllodes, or fibroadenoma showed diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. No cases contained high-risk human papillomavirus. Average Ki-67 proliferation indices were 15% in malignant phyllodes, 1.7% in borderline phyllodes, 0.5% in benign phyllodes, and 0% in fibroadenoma. Ki-67 was highest in malignant phyllodes with diffuse p16+/Rb- labeling. In summary, 50% malignant phyllodes display evidence of Rb/p16 pathway alterations, likely reflecting p16 or Rb inactivation. These and other mechanisms may contribute to the increased proliferation in malignant phyllodes relative to other fibroepithelial neoplasms.

  20. Meiotic and pedigree segregation analyses in carriers of t(4;8)(p16;p23.1) differing in localization of breakpoint positions at 4p subband 4p16.3 and 4p16.1.

    Science.gov (United States)

    Midro, Alina T; Zollino, Marcella; Wiland, Ewa; Panasiuk, Barbara; Iwanowski, Piotr S; Murdolo, Marina; Śmigiel, Robert; Sąsiadek, Maria; Pilch, Jacek; Kurpisz, Maciej

    2016-02-01

    The purpose of this study was to compare meiotic segregation in sperm cells from two carriers with t(4;8)(p16;p23.1) reciprocal chromosome translocations (RCTs), differing in localization of the breakpoint positions at the 4p subband-namely, 4p16.3 (carrier 1) and 4p16.1 (carrier 2)-and to compare data of the pedigree analyses performed by direct method. Three-color fluorescent in situ hybridization (FISH) on sperm cells and FISH mapping for the evaluation of the breakpoint positions, data from pedigrees, and direct segregation analysis of the pedigrees were performed. Similar proportions of normal/balanced and unbalanced sperm cells were found in both carriers. The most common was an alternate type of segregation (about 52 % and about 48 %, respectively). Unbalanced adjacent I and adjacent II karyotypes were found in similar proportions about 15 %. The direct segregation analysis (following Stengel-Rutkowski) of the pedigree of carriers of t(4;8)(p16.1;p23.1) was performed and results were compared with the data of the pedigree segregation analysis obtained earlier through the indirect method. The probability of live-born progeny with unbalanced karyotype for carriers of t(4;8)(p16.1;p23.1) was moderately high at 18.8 %-comparable to the value obtained using the indirect method for the same carriership, which was 12 %. This was, however, markedly lower than the value of 41.2 % obtained through the pedigree segregation indirect analysis estimated for carriers of t(4;8)(p16.3;p23.1), perhaps due to the unique composition of genes present within the 4p16.1-4p 16.3 region. Revealed differences in pedigree segregation analysis did not correspond to the very similar profile of meiotic segregation patterns presented by carrier 1 and carrier 2. Most probably, such discordances may be due to differences in embryo survival rates arising from different genetic backgrounds.

  1. P16蛋白在肺癌中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    于爱平; 王雪楠; 苏昕

    2001-01-01

    目的探讨P16基因与肺癌发生、发展的关系.方法采用免疫组化技术检测肺癌组织中P16蛋白的存在情况,分析P16基因的失活情况结果32例肺癌组织中P16蛋白表达的缺失率达到40.6%,明显高于正常对照组(P<0.05).结论 P16蛋白的缺失表达与肺癌的发生、发展密切相关,抑癌基因P16的遗传改变是导致肺癌发生、发展的重要生物学因素之一.

  2. The Change and Implication of p16 Protein in CA and Its Cancerization

    Institute of Scientific and Technical Information of China (English)

    苏向阳; 徐广坤; 苏祖兰; 赖维; 陆春

    2001-01-01

    Objective: To investigate the role and clinical significance of p16 protein in Condyloma Acuminatum (CA) and its cancerization.Methods.. The expression of p16 protein was tested in 33 CA samples and 7 cancerized CA samples by immunohistochemical assays.Results: There was abnormal expression of p16 protein in CA and cancerized CA, mainly major protein expression. The p16 protein expresseed in different locations in different cases was as follows: In basal layer cells in normal cuits; in spinous layer, granular layer and stratum corneum layer cells in CA;in keratin pearl peripheral and spinous layer cells in cancerized CA.Conclusion: There was major expression of p16 protein in CA and cancerized CA, and these protein of the two groups might not naturally be the same. Our study indicated that in clinical practice, when major p16 protein expression in CA occurs, it's risk of cancerization shoud be suspected.

  3. Correlation between methylation of the p16 promoter and cervical cancer incidence.

    Science.gov (United States)

    Wang, F-L; Yang, Y; Liu, Z-Y; Qin, Y; Jin, T

    2017-05-01

    To study the methylation of the promoter of the p16 gene in cervical cancer patients and explore the correlation between methylation and the incidence of cervical cancer. We recruited 78 patients with cervical cancer and 48 healthy individuals. The methylation-specific PCR was used to detect the methylation status in the promoter of the p16 gene. The mRNA expression of p16 was studied by quantitative fluorescence PCR. The protein expression of p16 was monitored by Enzyme-linked immunosorbent assay (ELISA) and Western blot. Immunohistochemistry was applied to detect the expression and distribution of p16 in cervical tissues. The methylation sequencing results showed that samples from cervical cancer patients had a methylation rate of 78.52% in the p16 gene promoter region compared with a much lower rate of 9.8% in the control group (9.8%). Quantitative fluorescence PCR indicated that the p16 mRNA expression was significantly reduced in cervical cancer patients compared with controls. ELISA and Western blot results showed that expression of the p16 protein in cancer tissue was 0.81 ± 0.12 µg/l, whereas in the healthy controls it was 3.21 ± 0.24 µg/l. Immunohistochemical results showed that the p16 protein was mainly present in the cytoplasm. The rate of p16 positive cells in the healthy cervical tissue 83.29% was higher than in cervical cancer 10.18%. The methylation of the p16 gene promoter could significantly reduce p16 expression, losing its tumor suppressor activity and promoting the development of cervical cancer.

  4. Potential diagnostic value of P16 expression in premalignant and malignant cervical lesions

    Directory of Open Access Journals (Sweden)

    Narges Izadi-Mood

    2012-01-01

    Full Text Available Background: The goal of this study was to evaluate the results of the expression of p16INK4a in normal uterine cervical epithelium, low-grade cervical intraepithelial neoplasia (CIN, high-grade CIN, squamous cell carcinoma (SCC, and adenocarcinoma of the cervix, in order to help draw a distinction between low risk and high risk patients with cervical lesions. Materials ans Methods : P16INK4a expression was evaluated by immunohistochemistry in 78 paraffin-embedded tissue samples including 39 normal cervical tissues, 11 low-grade CINs, 11 high-grade CINs, 22 cervical SCCs and 8 cervical adenocarcinomas. Two parameters in immunohistochemical p16 expression were evaluated: percentage of p16-positive cells, and reaction intensity. Results: The p16INK4a expression rate was 81.8% in low-grade CINs, 91% in high-grade CINs, 90% in SCCs and 75% in cervical adenocarcinomas. 10% of normal cervical samples expressed p16. Moreover, there was a significant relationship between the histological diagnoses and percentage of positive cells and reaction intensity of p16 (p < 0.005. The intensity of the reaction was the best parameter to evaluate the positivity of p16. Conclusions: Over-expression of the p16INK4a was typical for dysplastic and neoplastic epithelia of the uterine cervix. However, p16INK4a-negative CINs and carcinomas did exist. Although negative p16INK4a expression does not definitely exclude the patient with cervical lesion from the high-risk group, immunohistochemical study for p16INK4a may be used as a supplementary test for an early diagnosis of cervical cancers.

  5. Human papillomavirus DNA and p16 expression in Japanese patients with oropharyngeal squamous cell carcinoma

    OpenAIRE

    Kawakami, Hisato; Okamoto, Isamu; Terao, Kyoichi; Sakai, Kazuko; SUZUKI, MINORU; Ueda, Shinya; Tanaka, Kaoru; Kuwata, Kiyoko; Morita, Yume; Ono, Koji; Nishio, Kazuto; Nishimura, Yasumasa; Doi, Katsumi; Nakagawa, Kazuhiko

    2013-01-01

    Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methyla...

  6. p16 methylation does not affect protein expression in cervical carcinogenesis.

    Science.gov (United States)

    Nehls, Kristina; Vinokurova, Svetlana; Schmidt, Dietmar; Kommoss, Friedrich; Reuschenbach, Miriam; Kisseljov, Fjodor; Einenkel, Jens; von Knebel Doeberitz, Magnus; Wentzensen, Nicolas

    2008-11-01

    Previous studies have reported a frequency range of 19-61% for p16 methylation in cervical cancers. However, p16 is strongly expressed in over 90% of cervical cancers and pre-cancers, due to interactions of HPV oncogenes with p53 and pRb. In order to clarify these controversial findings, we developed a new bisulphite sequencing protocol to determine the methylation status of p16. DNA extracted from 17 cell lines and 94 microdissected clinical samples was subjected to methylation analysis. p16 expression was confirmed in Western blot and immunohistochemistry. Complete methylation of p16 was found in none of the dysplastic lesions, but in 26% of the cervical carcinomas. However, immunohistochemistry showed strong p16 expression in all cancers. These findings indicate that p16 methylation does not implicate loss of p16 expression in HPV-induced tumours. In cervical cancer, methylation of p16 does not seem to be an underlying pathogenic mechanism, but may be a result of increasing genetic and epigenetic instability.

  7. Immunohistochemical study of p53, pRb, p16 in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zo, Jae Ill; Zo, Kyung Ja; Park, Jong Ho; Kim, Mi Hee [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1998-01-01

    To confirm the expression of molecular genetic alterations of p53, pRb, p16 in esophageal cancer and to investigate the expression of p53, pRb, p16 in esophageal cancer according to the pathologic steps of carcinogenesis, immuno-histochemistry was performed in 15 resected esophageal cancer specimens with multiple separated lesions after pathologic mapping. The accumulation of mutant p53 was observed in 60 % of dysplasia and 47 % of invasive cancer, while pRb was not detected in 91 % of dysplasia and 72.7 % of invasive cancer. But p16 was not observed in 0 % in dysplasia and 7 % of invasive cancer. But p16 was not observed in 0 % in dysplasia and 28.6 % in invasive cancer. There was no simultaneous negative pRb and p16 expression. There was no relations between p53 and p16, pRb. As a results, the expression of p53, pRb, p16 was co-related well with molecular genetic changes and inactivation of p53, pRb, p16 was co-related well with molecular genetic changes and inactivation of p53 and pRb was common and early event in esophageal carcinogenesis in Korea, but inactivation of p16 was a infrequent change. (author). 17 refs., 2 tabs., 7 figs

  8. Stromal p16 expression is significantly increased in malignant ovarian neoplasms.

    Science.gov (United States)

    Yoon, Nara; Yoon, Gun; Park, Cheol Keun; Kim, Hyun-Soo

    2016-10-04

    Alterations in p16 protein expression have been reported to be associated with tumor development and progression. However, p16 expression status in the peritumoral stroma has been rarely investigated. We investigated the stromal p16 expression in ovarian neoplasms using immunohistochemistry, and differences in the expression status depending on the degree of malignancy and histological type were analyzed. This study included 24, 21, and 46 cases of benign, borderline, and malignant ovarian lesions, respectively, of which 29, 25, and 32 cases were serous, mucinous, and endometriosis-associated lesions. Most benign lesions showed negative or weak expression, whereas borderline lesions showed focal, moderate expression. Malignant lesions showed markedly elevated stromal p16 expression compared with benign or borderline lesions. There were significant differences in stromal p16 expression between benign and borderline lesions (P p16 expression among the histological types were not significant. Stromal p16 expression in ovarian neoplasms was absent or weak in benign and focal, moderate in borderline lesions, whereas malignant lesions exhibited diffuse, moderate-to-strong p16 immunoreactivity. Our observations suggest that stromal p16 expression is involved in the development of ovarian carcinoma. Further studies are necessary to confirm our preliminary results.

  9. Expression of Anion Exchanger 1 Sequestrates p16 in the Cytoplasm in Gastric, Colonic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Wei-Wei Shen

    2007-10-01

    Full Text Available p16INK4A (p16 binds to cyclin-dependent kinase 4/6, negatively regulates cell growth. Recent studies have led to an understanding of additional biologic functions for p16; however, the detailed mechanisms involved are still elusive. In this article, we show an unexpected expression of anion exchanger 1 (AEi in the cytoplasm in poorly, moderately differentiated gastric, colonic adenocarcinoma cells, in its interaction with p16, thereby sequestrating the protein in the cytoplasm. Genetic alterations of p16, AEi were not detectable. Forced expression of AEi in these cells sequestrated more p16 in the cytoplasm, whereas small interfering RNA-mediated silencing of AEi in the cells induced the release of p16 from the cytoplasm to the nucleus, leading to cell death, growth inhibition of tumor cells. By analyzing tissue samples obtained from patients with gastric, colonic cancers, we found that 83.33% of gastric cancers, 56.52% of colonic cancers coexpressed AEi, p16 in the cytoplasm. We conclude that AEi plays a crucial role in the pathogenesis of gastric, colonic adenocarcinoma, that p16 dysfunction is a novel pathway of carcinogenesis.

  10. p16 upregulation is linked to poor prognosis in ERG negative prostate cancer.

    Science.gov (United States)

    Burdelski, Christoph; Dieckmann, Tatsiana; Heumann, Asmus; Hube-Magg, Claudia; Kluth, Martina; Beyer, Burkhard; Steuber, Thomas; Pompe, Raisa; Graefen, Markus; Simon, Ronald; Minner, Sarah; Tsourlakis, Maria Christina; Koop, Christina; Izbicki, Jakob; Sauter, Guido; Krech, Till; Schlomm, Thorsten; Wilczak, Waldemar; Lebok, Patrick

    2016-09-01

    Altered expression of the p16 tumor suppressor is frequently found in prostate cancer, but its role for tumor development and patient prognosis is disputed. In order to clarify the prognostic role of p16 and to draw conclusions on interactions with key molecular features of prostate cancer, we studied p16 expression in a tissue microarray (TMA) with more than 12,400 prostate cancers and attached clinical, pathological, and molecular data such as ERG status and deletions of 3p13, 5q21, 6q15, and PTEN. p16 immunostaining was absent in non-neoplastic prostate cells but was found in 37 % of 9627 interpretable prostate cancers. Finding p16 expression in 58 % of ERG positive but in only 22 % of ERG negative cancers (p p16 upregulation and tumor phenotype or patient prognosis were strictly limited to the subset of ERG negative cancers. For example, p16 positivity increased from 15 % in Gleason ≤3 + 3 to 38 % in Gleason ≥4 + 4 cancers (p p16 upregulation was strongly linked to deletions of PTEN (p p16 upregulation is a strong prognostic factor in ERG negative cancers. The strict limitation of its prognostic impact to a molecularly defined subgroup challenges the concept of molecular prognosis testing without considering molecular subtypes.

  11. Protein p16 as a marker of dysplastic and neoplastic alterations in cervical epithelial cells

    Directory of Open Access Journals (Sweden)

    Spitkovsky Dimitry

    2004-08-01

    Full Text Available Abstract Background Cervical carcinomas are second most frequent type of women cancer. Success in diagnostics of this disease is due to the use of Pap-test (cytological smear analysis. However Pap-test gives significant portion of both false-positive and false-negative conclusions. Amendments of the diagnostic procedure are desirable. Aetiological role of papillomaviruses in cervical cancer is established while the role of cellular gene alterations in the course of tumor progression is less clear. Several research groups including us have recently named the protein p16INK4a as a possible diagnostic marker of cervical cancer. To evaluate whether the specificity of p16INK4a expression in dysplastic and neoplastic cervical epithelium is sufficient for such application we undertook a broader immunochistochemical registration of this protein with a highly p16INK4a-specific monoclonal antibody. Methods Paraffin-embedded samples of diagnostic biopsies and surgical materials were used. Control group included vaginal smears of healthy women and biopsy samples from patients with cervical ectopia. We examined 197 samples in total. Monoclonal antibody E6H4 (MTM Laboratories, Germany was used. Results In control samples we did not find any p16INK4a-positive cells. Overexpression of p16INK4a was detected in samples of cervical dysplasia (CINs and carcinomas. The portion of p16INK4a-positive samples increased in the row: CIN I – CIN II – CIN III – invasive carcinoma. For all stages the samples were found to be heterogeneous with respect to p16INK4a-expression. Every third of CINs III and one invasive squamous cell carcinoma (out of 21 analyzed were negative. Conclusions Overexpression of the protein p16INK4a is typical for dysplastic and neoplastic epithelium of cervix uteri. However p16INK4a-negative CINs and carcinomas do exist. All stages of CINs and carcinomas analyzed are heterogeneous with respect to p16INK4a expression. So p16INK4a-negativity is

  12. Methylation and mutation analysis of p16 gene in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Yi Ding; Xiao-Ping Le; Qin-Xian Zhang; Peng Du

    2003-01-01

    AIM: To study methylation, frequencies of homozygous deletion and mutation of p16 gene in gastric carcinoma.METHODS: The methylation pattern in exon 1 and exon 2of p16 gene was studied with polymerase chain reaction (PCR), using methylation sensitive restriction endonuclease HpaⅡ and methylation insensitive restriction endonudease MspⅠ. PCR technique was used to detect homozygous deletions of exon 1 and exon 2 of p16 gene and single strand conformation polymorphism (SSCP) technique was used to detect the mutation of the gene.RESULTS: Hypermethylation changes in exon 1 and exon 2 of p16 gene were observed in 25 % and 45 % of 20gastric cancer tissues, respectively, while no methylation abnormality was found in normal tissues. The homozygous deletion frequency of exon 1 and exon 2 of p16 gene in 20gastric cancer tissues was 20 % and 10 %, respectively. No mutation was found in exon 1 of p16 gene, while abnormal single strands were found in 2 (10 %) cases in exon 2 as detected by SSCP.CONCLUSION: The results suggest that hypermethylation and abnormality of p16 gene may play a key role in the progress of gastric cancer. Hypermethylation of exon 2 of p16 gene may have effects on the carcinogenesis of gastric mucosa and may be a later event.

  13. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma

    Directory of Open Access Journals (Sweden)

    Radotra Bishan

    2005-06-01

    Full Text Available Abstract Background Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. Methods We investigated the status of p16 gene by polymerase chain reaction (PCR, nonradioisotopic single strand conformation polymorphism (SSCP, DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC using a monoclonal antibody clone (MS-887-PO. Results Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25. Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25 cases, followed by coding sequence mutations in 16% (4/25 cases and presumably homozygous deletion in 12% (3/25 cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%. Conclusion These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type.

  14. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma

    Science.gov (United States)

    Attri, Jyotika; Srinivasan, Radhika; Majumdar, Siddhartha; Radotra, Bishan Dass; Wig, Jaidev

    2005-01-01

    Background Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. Methods We investigated the status of p16 gene by polymerase chain reaction (PCR), nonradioisotopic single strand conformation polymorphism (SSCP), DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC) using a monoclonal antibody clone (MS-887-PO). Results Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25). Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25) cases, followed by coding sequence mutations in 16% (4/25) cases and presumably homozygous deletion in 12% (3/25) cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%). Conclusion These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type. PMID:15985168

  15. Immunohistochemical comparison of cyclin D1 and P16 in odontogenic keratocyst and unicystic ameloblastoma

    Directory of Open Access Journals (Sweden)

    Seyed Mohammad Razavi

    2013-01-01

    Conclusion: Cyclin D1 did show a higher staining intensity in UAs compared to the keratocysts, although the expression of P16 was similar in the studied groups. The invasive growth of OKC might be related to the state of expression of cyclin D1 and P16 in the epithelium of this cyst.

  16. Validation of signalling pathways: Case study of the p16-mediated pathway.

    Science.gov (United States)

    Akçay, Nimet İlke; Bashirov, Rza; Tüzmen, Şükrü

    2015-04-01

    p16 is recognized as a tumor suppressor gene due to the prevalence of its genetic inactivation in all types of human cancers. Additionally, p16 gene plays a critical role in controlling aging, regulating cellular senescence, detection and maintenance of DNA damage. The molecular mechanism behind these events involves p16-mediated signaling pathway (or p16- Rb pathway), the focus of our study. Understanding functional dependence between dynamic behavior of biological components involved in the p16-mediated pathway and aforesaid molecular-level events might suggest possible implications in the diagnosis, prognosis and treatment of human cancer. In the present work, we employ reverse-engineering approach to construct the most detailed computational model of p16-mediated pathway in higher eukaryotes. We implement experimental data from the literature to validate the model, and under various assumptions predict the dynamic behavior of p16 and other biological components by interpreting the simulation results. The quantitative model of p16-mediated pathway is created in a systematic manner in terms of Petri net technologies.

  17. Hydrogen peroxide induces p16(INK4a) through an AUF1-dependent manner.

    Science.gov (United States)

    Guo, Gai E; Ma, Li Wei; Jiang, Bin; Yi, Jie; Tong, Tan Jun; Wang, Wen Gong

    2010-04-01

    Elevation of p16(INK4a) has been described as an important mechanism for hydrogen peroxide (H2O2)-induced replicative senescence. However, the mechanisms underlying remain unknown. In this study, we demonstrate an important role of RNA-binding protein AUF1-mediated mRNA turnover in H2O2-induced p16(INK4a) expression. The induction of p16 by H2O2 was accompanied with declined cytoplasmic AUF1 level. Accordingly, exposure of cells to H2O2 remarkably reduced the binding of AUF1 to p16 3'UTR and increased the half-life of an EGFP-p16-3'UTR chimeric transcript. In AUF1-silenced cells, the effect of H2O2 on p16 induction was abolished. Furthermore, in cells co-transfected with vectors expressing AUF1s, treatment with H2O2 failed to significantly reduce the expression of AUF1 and subsequently elevate the levels of p16. Moreover, HeLa cells overexpressing AUF1s were resistant to H2O2-induced senescence. Our results indicate that AUF1 is critical for H2O2-induced p16 expression and cellular senescence. Copyright 2010 Wiley-Liss, Inc.

  18. Growth suppression by p16ink4 requires functional retinoblastoma protein

    NARCIS (Netherlands)

    Medema, R.H.; Herrera, R.E.; Lam, F.; Weinberg, R.A.

    1995-01-01

    p16ink4 has been implicated as a tumor suppressor that is lost from a variety of human tumors and human cell lines. p16ink4 specifically binds and inhibits the cyclin-dependent kinases 4 and 6. In vitro, these kinases can phosphorylate the product of the retinoblastoma tumor suppressor gene. Thus, p

  19. Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas

    NARCIS (Netherlands)

    Rietbergen, M.M.; Snijders, P.J.F.; Beekzada, D.; Braakhuis, B.J.M.; Brink, A.; Heideman, D.A.M.; Hesselink, A.T.; Witte, B.I.; Bloemena, E.; Baatenburg-de Jong, R.J.; Leemans, C.R.; Brakenhoff, R.H.

    2014-01-01

    Recent studies have reported that p16 protein overexpression qualifies as a surrogate marker identifying an oncogenic human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC). However, there is still a percentage of OPSCCs that are positive for p16 immunohistochemistry (

  20. Diagnostic utility of p16 immunocytochemistry for Trichomonas in urine cytology

    Directory of Open Access Journals (Sweden)

    Pantanowitz Liron

    2005-06-01

    Full Text Available Abstract We present a case in which p16 immunocytochemistry helped establish the diagnosis of Trichomonas in urine from a male patient. Based on this finding, we recommend p16 immunocytochemistry as a diagnostic tool for unexpected patients or specimen types in which potential trichomonads are identified following routine cytologic evaluation.

  1. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours

    DEFF Research Database (Denmark)

    Grønhøj Larsen, C; Gyldenløve, M; Jensen, D H

    2014-01-01

    A significant proportion of squamous cell carcinomas of the oropharynx (OP-SCC) are related to human papillomavirus (HPV) infection and p16 overexpression. This subgroup proves better prognosis and survival but no evidence exists on the correlation between HPV and p16 overexpression based on diag...

  2. Malignant progress of astrocytomas and expression of P16 protein%星形细胞瘤恶性进展与P16蛋白表达

    Institute of Scientific and Technical Information of China (English)

    邱吉庆; 赵刚; 王长坤; 关毅; 于洪泉

    2001-01-01

    目的 研究细胞周期负性调控蛋白在星形细胞瘤中的表达与肿瘤病理分级的关系,探讨纠正P16蛋白缺乏做为胶质瘤基因治疗策略的可行性。方法 SP免疫组化方法对41例不同级别星形细胞瘤的P16蛋白表达进行观察,评价染色强度和阳性细胞百分数与星形细胞瘤恶性度的关系。结果 随着星形细胞瘤恶性度的增高,P16蛋白表达阴性例数增多,阳性染色细胞呈减少趋势。结论 星形细胞瘤P16蛋白表达水平与其分级呈负相关,P16蛋白表达异常是影响星形细胞瘤发生发展的重要因素。%Objective To research the relationship between the expression of cell cyclic negative control protein and pathologic grade in astrocytomas, to discuss the feasibility of using correct the scarce of P16 protein as genic treatment strategy in glioma. Methods An SP immunohistochemical staining technique was undertaken for detection the expression of P16 protein in 41 cases astrocytomas with various pathological grade, to evaluate the relationship between dying strength, precent of positive cell and the astromic maglinant degree. Results Negative expressional cases of P16 protein increased parallel with the elevation of astrocytomic malignant degree, and so decreased the positive dying cells. Conclusions This study suggests that the abnormal expression of negative interrelation between the level of astromic P16 protein expression and pathological grade in astrocytomas is an important factor which affect the occurence and development of astrocytomas.

  3. Tumor Suppressor Gene p16 and Genetherapy of Cancer%抑癌基因p16与肿瘤基因治疗

    Institute of Scientific and Technical Information of China (English)

    熊光武; 王世阆

    2002-01-01

    在肿瘤发生、发展过程中,癌基因的激活和抑癌基因的失活是细胞癌变的分子基础.p16基因是继p53和RB基因之后发现的又一重要的抑癌基因.本文就p16基因的结构、功能异常,及其相关的肿瘤基因治疗进行简要概述.

  4. 胰腺癌组织中p16基因缺失及其对p16蛋白表达的影响%Deletion of p16 gene and its impact on the expression of p16 protein in pancreatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    胡育新; 泽武纪雄; 渡边弘之

    2007-01-01

    目的 探讨胰腺癌组织中p16基因缺失状态及其对p16蛋白表达的影响.方法 采用聚合酶链反应技术分别检测经显微切割方法获取的p16蛋白免疫组化染色阳性和阴性的胰腺癌组织中p16基因纯合性缺失状态并将结果与p16蛋白表达之间的关系进行分析.结果 32例胰腺癌中分别有20例(62.5%)和21例(65.6%)表现为p16蛋白表达丢失和p16基因纯合性缺失,其中有5例发生于p16基因的第1外显子,12例缺失发生于第2外显子,1例发生于第3外显子,另有3例同时发生于第1和第2外显子.此外还发现无p16蛋白表达的胰腺癌组织发生p16基因纯合性缺失的比例(18/20,90.0%)高于有p16蛋白表达的胰腺癌(3/12,25.0%);在无p16蛋白表达并伴有p16基因缺失的7例胰腺癌病人中仅有1例生存期超过5mo,而二者均无异常的3例胰腺癌的生存期均超过8mo.结论 胰腺癌组织中的p16基因纯合性缺失可以影响p16蛋白的表达,促使胰腺癌病人的预后更差.

  5. Pioglitazone promotes preadipocyte proliferation by downregulating p16(Ink4a).

    Science.gov (United States)

    Hasan, Arif U; Ohmori, Koji; Hashimoto, Takeshi; Kamitori, Kazuyo; Hirata, Yuko; Ishihara, Yasuhiro; Okamoto, Naoko; Noma, Takahisa; Kosaka, Hiroaki; Tokuda, Masaaki; Kohno, Masakazu

    2011-07-29

    Pioglitazone, a synthetic ligand of peroxisome proliferator-activated receptor (PPAR)γ, causes preadipocyte proliferation through a mechanism which still remains elusive. Here, to address the mechanism, we investigated the effects of PPARγ and pioglitazone on the kinetics of cyclin-dependent kinase inhibitors, especially with p16(Ink4a) (p16) centered, by employing 3T3-L1 preadipocytes. Pioglitazone promoted preadipocyte proliferation by increasing S and G(2)/M cell-cycle entry, which was accompanied by decreased p16 mRNA expression. PPARγ overexpression along with the luciferase reporter assay confirmed that PPARγ was crucial for the downregulation of p16 mRNA transcription, and that the action was augmented by pioglitazone. Thus, pioglitazone exerted cell-cycle dependent promoting effect on preadipocyte proliferation, of which mechanisms include p16-downregulation through PPARγ. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Ageing as developmental decay: insights from p16(INK4a.).

    Science.gov (United States)

    Martin, Nadine; Beach, David; Gil, Jesús

    2014-12-01

    The p16(INK4a) cell cycle regulator is one of the best ageing biomarkers because it is suppressed in early embryogenesis and progressively induced during ageing. p16(INK4a) plays a crucial role in key cell fate decisions which contribute to ageing, such as cellular senescence and stem cell dynamics. Detailed examination of the pathways regulating p16(INK4a) expression has revealed an overlap with those regulating early development. We present the hypothesis that ageing might be primarily driven by gradual functional decay of developmental pathways. To support this, we summarise the role of p16(INK4a) in ageing and our current knowledge on p16(INK4a) regulation. The developmental decay hypothesis implies that the much-evidenced damage associated with all aspects of ageing might be secondary to such decay. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. EXPRESSION AND SIGNIFICANCE OF ONCOPROTEIN p16 AND FOS IN OSTEOSARCOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate p16, c-fos protein expression and theirrelationships in osteosarcoma. Methods: Immuno-histochemical technique (SABC) was used to detect p16 and C-fos protein expression in 41 cases of osteosarcoma. Results: The positive rates of p16 and C-fos protein expres-sion were 51.2% and 82.9% respectively. Their expression was not correlated to pathological subtype, but correlated to clinic grade, and the latter was associated with tumor metastasis. There was a negative correlation between p16 and C-fos protein expression. Conclusion: The alteration of p16 and C-fos protein expression may be related to the tumorigenesis and development of osteosarcoma, and C-fos proteins may take part in osteosarcoma metastasis. These data will offer useful helpness to determine the prognosis of osteosarcoma.

  8. Expression of p16 gene and Rb protein in gastric carcinoma and their clinicopathological significance

    Institute of Scientific and Technical Information of China (English)

    Xiu-Sheng He; Ying-Hui Rong; Qi Su; Qiao Luo; Dong-Mei He; Yan-Lan Li; Yan Chen

    2005-01-01

    AIM: To analyze the correlation between the protein expression of p16 and Rb genes in gastric carcinoma (GC),to investigate the role of p16 gene in invasion and lymph node metastasis of GC, and to examine the deletion and mutation in exon 2 of p16 gene in GC.METHODS: The protein expression of p16 and Rb genes was examined by streptavidin-peroxidase conjugated method (S-P) in normal gastric mucosa, dysplastic gastric mucosa and GC. The deletion and mutation of p16 gene were examined by polymerase chain reaction (PCR) and polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) respectively in normal gastric mucosa and GC.RESULTS: The positive rates of P16 and Rb protein expression respectively were 96% (77/80) and 99%(79/80) in normal gastric mucosa, 92% (45/50) and 80%(40/50) in dysplastic gastric mucosa, 48% (58/122) and 60% (73/122) in GC. The positive rates of P16 and Rb protein expression in GC were significantly lower than that in normal gastric mucosa and dysplastic gastric mucosa (P<0.05). The positive rate of P16 protein expression in mucoid carcinoma (10%, 1/10) was significantly lower than that in poorly differentiated carcinoma (51%, 21/41),undifferentiated carcinoma (58%, 15/26) and signet ring cell carcinoma (62%, 10/16) (P<0.05). The positive rates of P16 protein in 30 cases of paired primary and lymph node metastatic GC were 47% (14/30) and 17% (5/30)respectively, being significantly lower in the later than in the former (P<0.05). There was no mutation in exon 2 of p16 gene in the 25 freshly resected primary GCs. But five cases in the 25 freshly resected primary GCs displayed deletion in exon 2 of p16 gene. The positive rate of both P16 and Rb proteins was 16% (14/90), and the negative rate of both P16 and Rb proteins was 8% (7/90) in 90GCs. The rate of positive P16 protein with negative Rb protein was 33% (30/90). The rate of negative P16 protein with positive Rb protein was 43% (39/90). There was reverse correlation

  9. p16在食管癌变过程中的表达

    Institute of Scientific and Technical Information of China (English)

    刘海明

    2011-01-01

    目的探讨p16基因在食管癌变过程中的表达。方法应用免疫组织化学S-P法检测p16基因在17例癌变组和40例非癌变组中的表达。结果 p16在癌变组中的表达降低(P〈0.05)。结论 p16基因的表达和食管癌的发生有关,p16基因表达的变化可能是食管癌发生中的早期事件。

  10. Expression of Cyclin D1 and P16 in Esophageal Squamous Cell Carcinoma.

    Science.gov (United States)

    Dey, Biswajit; Raphael, Vandana; Khonglah, Yookarin; GiriLynrah, Kyrshanlang

    2015-10-01

    BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Many genes including cyclin D1 and p16 play important role in its carcinogenesis. We aimed to analyze the expressions of cyclin D1 and p16 with the various clinicopathological characteristics of ESCC. METHODS We examined 30 biopsy samples of ESCC for cyclin D1 and p16 protein expressions using immunohistochemistry. Immunointensity was classified as no immunostaining (-), weakly immunostaining (+), weak immunostaining (++) and strongly positive immunostaining (+++). RESULTS Out of the 30 cases, positive expression of cyclin D1 was detected in 26 cases (86.7%). The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in cyclin D1 positive tumors than in the cyclin D1 negative tumors. However no significant association was found between cyclin D1 expression and the different clinicopathological parameters.There were 22 cases of ESCC (73.3 %) which showed negativity for p16. The percentage of tumors with invasion to the adventitia (82.4%) and poorly differentiated tumors (92.9%) were higher in the p16 negative tumors than in the p16 positive tumors. There was significant association between the histological grade and p16 expression (p=0.012). However, there were no significant association with regard to site, size and lymph node status of the tumors and p16 expression. CONCLUSION The study shows that alterations of cyclin D1 and p16 play an important role in ESCC. Loss of p16 expression was associated with poor differentiation.

  11. Two distinct pathways of p16 gene inactivation in gallbladder cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To examine the mechanism of inactivation of the p16 gene in gallbladder cancer, and to investigate p16 alterations and their correlation with clinicopathological features.METHODS: Specimens were collected surgically from 51 patients with gallbladder cancer. We evaluated the status of protein expression, loss of heterozygosity (LOH),homozygous deletion and promoter hypermethylation using immunohistochemistry, microsatellite analysis,quantitative real-time polymerase chain reaction (PCR) and methylation-specific PCR, respectively. In addition,mutations were examined by direct DNA sequencing.RESULTS: Homozygous deletions of the p16 gene exon2, LOH at 9p21-22, p16 promoter hypermethylation, and loss of p16 protein expression were detected in 26.0% (13/50), 56.9% (29/51), 72.5% (37/51) and 62.7% (32/51), respectively. No mutations were found. LOH at 9p21 correlated with the loss of p16 protein expression (P < 0.05). Homozygous deletion of the p16 gene, a combination LOH and promoter hypermethylation, and multiple LOH at 9p21 were significantly correlated with the loss of pl6 protein expression (P < 0.05). LOH at 9p21 and promoter hypermethylation of the p16 gene were detected in 15.4% (2/13) and 92.3% (12/13) of the tumors with homozygous deletion of the pl6 gene,respectively. P16 alterations were not associated with clinicopathological features.CONCLUSION: Our results suggest that LOH and homozygous deletion may be two distinct pathways in the inactivation of the pl6 gene. Homozygous deletion, a combination of LOH and promoter hypermethylation, and multiple LOH are major mechanisms of p16 inactivation in gallbladder cancer.

  12. 白血病p16基因失活的研究

    Institute of Scientific and Technical Information of China (English)

    陈文明

    1998-01-01

    为探讨白血病p16基因失活的发生率及其与疾病预后的关系,对48例初发或复发的白血病进行了D16基因失活研究。首先应用多重聚合酶链反应(MPCR)方法扩增p16基因纯合子缺失,然后用限制性内切酶-PCR方法检测p16基因甲基化。研究结果表明,48例患者中有p16基因失活者10例(占20.4%),其中p16纯合子缺失者5例(2例伴有9p丢失),p16基因甲基化者5例。有p16基因失活者,病情进展迅速,治疗效果差,患者在短期内死亡。结论提示:p16基因失活在部分白血病的发生、发展中起重要作用;有p16基因失活者预后较差;p16基因失活的检测对于判断预后具有重要意义。

  13. p16 Expression and Biological Behavior of Flat Vulvar Low-grade Squamous Intraepithelial Lesions (LSIL).

    Science.gov (United States)

    Lewis, Natasha; Blanco, Luis Z; Maniar, Kruti P

    2017-09-01

    Flat low-grade squamous intraepithelial lesion (LSIL) of the vulva [vulvar intraepithelial neoplasia (VIN) 1, flat condyloma] is an uncommon entity with poorly understood biological behavior. We aimed to determine the risk of subsequent vulvar high-grade squamous intraepithelial lesion (HSIL) or carcinoma following a diagnosis of vulvar LSIL/VIN 1, as well as the frequency and predictive value of p16 immunohistochemical expression in this setting. Of the 51 included cases, p16 positivity (diffuse block staining) was identified in 2 (4%). Follow-up data were available in 34 cases, of which 2 (5.9%) developed subsequent vulvar HSIL, including 1/2 p16-positive cases and 1/32 p16-negative cases. The difference in HSIL frequency between p16-positive and p16-negative cases was not statistically significant (P=0.116 for VIN 2+, P=0.061 for VIN 3). For the 18 patients with treatment information available, 10 (56%) received medical or surgical treatment after biopsy. Our results indicate that flat vulvar LSIL is infrequently p16 positive, and that few patients with vulvar LSIL develop subsequent vulvar HSIL. Despite the use of destructive treatment in some cases, the data provide support for the nonpreneoplastic nature of the entity. Immunohistochemical expression of p16 may not be a predictor of HSIL risk in vulvar LSIL, although this result may also be related to the very low rates of both p16 positivity and subsequent vulvar HSIL in our sample. It is clear that vulvar LSIL is distinct from LSIL in other lower anogenital sites in terms of its behavior and p16 expression frequency.

  14. The study of p16 methylation and p16 protein expression in non-small cell lung cancers(NSCLC)%非小细胞肺癌(NSCLC)p16基因甲基化改变及p16蛋白表达研究

    Institute of Scientific and Technical Information of China (English)

    张文; 孙玉鹗; 蔡庆; 王桂洪; 卢光明

    2004-01-01

    目的分析非小细胞肺癌(NSCLC) 及癌周正常肺组织p16基因甲基化改变及p16蛋白表达情况. 方法选取各种病理类型的非小细胞肺癌(NSCLC)标本共40例作为研究对象,同时选取癌组织周围的正常肺组织作为对照.运用甲基化特异性PCR(MSP)方法检测肺癌标本及周围正常肺组织中p16基因的甲基化改变情况,运用免疫组化方法检测p16蛋白在肺癌标本及周围正常肺组织中的表达情况. 结果①40例肺癌标本中,29例发生了p16基因甲基化.而其周围正常肺组织只有5例发生了p16基因甲基化.二者有明显差异(P<0.01).②40例肺癌标本中,26例p16蛋白表达降低,而其周围正常肺组织只有5例蛋白表达降低,二者有明显差异(P<0.01).③29例p16基因发生了甲基化改变的肺癌标本中,有22例发生了p16蛋白表达降低.在11例未发生p16基因甲基化改变的肺癌标本中,有4例发生了p16蛋白表达降低. 结论 p16基因甲基化是导致非小细胞肺癌(NSCLC) p16蛋白表达降低的重要机制.

  15. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review

    Science.gov (United States)

    Grønhøj Larsen, C; Gyldenløve, M; Jensen, D H; Therkildsen, M H; Kiss, K; Norrild, B; Konge, L; von Buchwald, C

    2014-01-01

    Background: A significant proportion of squamous cell carcinomas of the oropharynx (OP-SCC) are related to human papillomavirus (HPV) infection and p16 overexpression. This subgroup proves better prognosis and survival but no evidence exists on the correlation between HPV and p16 overexpression based on diagnostic measures and definition of p16 overexpression. We evaluated means of p16 and HPV diagnostics, and quantified overexpression of p16 in HPV-positive and -negative OP-SCCs by mode of immunohistochemical staining of carcinoma cells. Methods: PubMed, Embase, and the Cochrane Library were searched from 1980 until October 2012. We applied the following inclusion criteria: a minimum of 20 cases of site-specific OP-SCCs, and HPV and p16 results present. Studies were categorised into three groups based on their definition of p16 overexpression: verbal definition, nuclear and cytoplasmatic staining between 5 and 69%, and ⩾70% staining. Results: We identified 39 studies with available outcome data (n=3926): 22 studies (n=1980) used PCR, 6 studies (n=688) used ISH, and 11 studies (n=1258) used both PCR and ISH for HPV diagnostics. The methods showed similar HPV-positive results. Overall, 52.5% of the cases (n=2062) were HPV positive. As to p16 overexpression, 17 studies (n=1684) used a minimum of 5–69% staining, and 7 studies (n=764) used ⩾70% staining. Fifteen studies (n=1478) referred to a verbal definition. Studies showed high heterogeneity in diagnostics of HPV and definition of p16. The correlation between HPV positivity and p16 overexpression proved best numerically in the group applying ⩾70% staining for p16 overexpression. The group with verbal definitions had a significantly lower false-positive rate, but along with the group applying 5–69% staining showed a worse sensitivity compared with ⩾70% staining. Conclusions: There are substantial differences in how studies diagnose HPV and define p16 overexpression. Numerically, p16 staining is better to

  16. 胃肠道间质瘤中P16基因甲基化和P16蛋白表达的临床意义%Prognostic value of P16 gene methylation and P16 protien expression in gastrointestinal stromal tumor

    Institute of Scientific and Technical Information of China (English)

    梁建芳; 郑绘霞; 李宁; 程彩霞; 肖虹; 王宏坤

    2007-01-01

    目的 探讨胃肠道间质瘤(GIST)中P16基因启动子区甲基化状态和P16蛋白在GIST中的表达及其意义.方法 对62例随访资料完整的GIST患者,应用甲基化特异性聚合酶链反应法和免疫组化EnVisionTM法,检测瘤组织中P16基因启动子区甲基化状态和P16蛋白的表达.结果 本组进展性疾病(PD)21例,非PD 41例.Fletcher分级:极低度侵袭危险性(Ⅰ级)13例;低度侵袭危险性(Ⅱ级)12例;中度侵袭危险性(Ⅲ级)19例;高度侵袭危险性(Ⅳ级)18例.P16甲基化19例,非甲基化43例.P16蛋白阳性细胞数小于50%20例,50%~75%15例,大于75%27例.在Fletcher分级中,P16基因启动子甲基化和P16蛋白表达差异有统计学意义(分别为P<0.05和P<0.01);Ⅳ级中P16基因启动子甲基化占50%,P16阳性细胞数小于50%者占65%.P16蛋白表达阳性不同强度之间PD值比较差异有统计学意义(P<0.01);P16阳性细胞数小于50%者PD占95%;而50%以上者组间PD值比较,P>0.05;差异无统计学意义.P16阳性细胞数小于50%者的肿瘤组织P16甲基化占75%,而P16阳性细胞数大于50%者P16甲基化仅占10%,两组间差异有统计学意义(P<0.01).结论 在GIST组织中,P16蛋白低表达、P16基因启动子甲基化预示肿瘤预后差.

  17. [Hypermethylation and downregulation of tumor suppressor gene p16 in benzene poisoning].

    Science.gov (United States)

    Xing, Caihong; Wang, Qianfei; Tian, Haoyuan; Li, Bin; Ni, Yune; Yin, Songnian; Guo, Xinbiao; Li, Guilan

    2012-03-01

    To investigate whether benzene negatively affects the expression of p16 through DNA methylation. We carried out a case-control study in Chinese occupational benzene poisoning patients. Eleven cases of BP and 8 controls who were matched for age (+/- 5 years), sex, working duration and job title with BP were recruited. Expression level was examined by quantitative real-time PCR. Bisulfite-PCR pyrosequencing was used to quantitate the level of DNA methylation. The expression levels of p16 are down-regulated in BP patients compared to the control group (0.53 versus 2.06, P = 0.064). The average percentage of methylated cytosines of p16 was higher in BP group than in controls (12.4%, 11.3%, respectively, P > 0.05). p16 mRNA level decreased with increasing methylation (Pearson r = -0.64, P > 0.05). The fourth CpG site in p16 promoter is located within the consensus binding sequence for olfactory neuron-specific transcription factor. A significant negative correlation between mRNA level and the fourth CpG site was exhibited (Pearson r = - 0.88, P p16 is significantly downregulated in BP patients. Hypermethylation in promoter CpG islands is likely to contribute to the downregulation of p16. Further in-depth studies, utilizing large number of samples, are needed to fully understand the molecular mechanism involved in the tumor-suppressor gene inactivation in benzene-related diseases.

  18. p16 Immunohistochemistry Interpretation by Nonpathologists as an Accurate Method for Diagnosing Cervical Precancer and Cancer.

    Science.gov (United States)

    Liao, Guang-Dong; Kang, Le-Ni; Chen, Wen; Zhang, Xun; Liu, Xiao-Yang; Zhao, Fang-Hui; Stoler, Mark H; Mills, Anne; Xi, Ming-Rong; Qiao, You-Lin; Castle, Philip E

    2015-07-01

    We conducted a pilot study of whether nonpathologists could accurately diagnose cervical precancer in biopsies using only a basic light microscope, evaluating p16 immunohistochemistry (p16 IHC) of biopsies, and video-based training for both. Using biopsies collected as part of a screening study conducted in rural China, we randomly selected 50 biopsies with a precancerous diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+) and 50 biopsies with diagnosis of CIN less severe than CIN2, and stained them for p16 using a commercial IHC kit. Twelve nonpathologists of varying educational backgrounds living in Beijing, China received video training and were assigned one of 4 sets of 25 CIN2+ and 25 CIN less severe than CIN2 for evaluation. A pathologist reviewed all 100 cases. The mean sensitivity and specificity of the p16 IHC staining scored by the nonpathologists were 91.7% and 94.1%, respectively, compared to scoring by the pathologist. The readers and the pathologist agreed on p16 IHC scoring for 42 (84%) of the 50 slides of CIN less severe than CIN2 and 37 (74%) of the 50 CIN2+ slides. The mean sensitivity and specificity for consensus CIN2+ of p16 IHC as scored by the readers were 88% and 87%, respectively, versus an overall sensitivity and specificity by the pathologist of 96% and 92%, respectively. We demonstrated that nonpathologists can accurately diagnose CIN2+ using p16 IHC alone.

  19. HPV-Positive Oropharyngeal Cancer Via p16 Immunohistochemistry in Japan.

    Science.gov (United States)

    Toman, Julia; Von Larson, Scott; Umeno, Hirohito; Kurita, Takashi; Furusaka, Tohru; Hasegawa, Hisashi; Prasad, Manju L; Sasaki, Clarence T

    2017-02-01

    Human papillomavirus (HPV) has emerged as a driving cause of head and neck cancer, but investigations outside the West are limited. A p16 immunohistochemistry is a commonly used biomarker for HPV cancers. We sought to investigate the pathology and rates of HPV head and neck oropharyngeal cancer in Japan via p16 immunohistochemistry at 2 institutions in Japan. Fifty-nine oropharyngeal specimens from 2 university hospitals in Japan were examined for morphology and p16 immunohistochemistry. The rate of p16 positivity was then determined, and the 2 groups were compared for differences in age, smoking history, gender, and stage of presentation and mortality. The rate of p16 positivity among the oropharyngeal specimens was 29.5%. There were important differences in the pathology compared to morphology usually seen in the US. The patients with p16+ cancer tended to be younger. There was no significant difference in smoking status. Patients with p16+ cancers trended toward better survival. There appears to be a geographical difference in HPV rates of oropharyngeal cancers with persistently lower rates in Asian countries when compared to Western Europe and the US. Conclusions about HPV head and neck squamous cell carcinoma (HNSCC) in Western countries may not be generalizable across the globe at this time.

  20. PROMOTER HYPERMETHYLATION OF p16 GENE AND DAPK GENE IN SERA FROM HEPATOCELLULAR CARCINOMA (HCC) PATIENTS

    Institute of Scientific and Technical Information of China (English)

    LIN Qing; CHEN Long-bang; TANG Yong-ming; WANG Jing

    2005-01-01

    Objective: To analyze the aberrant methylation of p16 gene and DAPK gene in sera from primary liver cancer patients ad to evaluate the clinical significance. Methods: A methylation-specific PCR was performed for the detection of promoter hypermethylation of p16 gene and DAPK gene in blood DNA from 64 cases of HCC patients, and to analyze the relation of the aberrant methylation of p16 gene and KAPK gene and the clinical pathological data. Results: 76.6%(49/64) of the sera from 64 cases of HCC patients showed hypermethylation for p16 promoter and 40.6% (26/64) for KAPK promoter, whereas no methylated p16 gene promoter and DAPK gene promoter were found in sera from benign liver diseases patients and normal control. Methylated p16 gene and KAPK gene promoters in sera did not strongly correlated with HBsAg, stage,metastasis and differentiation in HCC; but strongly correlated with AFP. Conclusion: Detection of the aberrant methylation of p16 gene and KAPK gene in blood DNA from HCC patients might offer an effective means for the earlier auxiliary diagnosis of the malignancy.

  1. p16 deficiency promotes nonalcoholic steatohepatitis via regulation of hepatic oxidative stress.

    Science.gov (United States)

    Lv, Fangqiao; Wu, Jun; Miao, Dengshun; An, Wei; Wang, Yutong

    2017-03-10

    Nonalcoholic steatohepatitis (NASH) is characterized by excess accumulation of lipids in liver, accompanied with hepatocyte injury, cell death and inflammation. Although p16 is known as tumor suppressor in multiple cancer types, it remains unclear whether p16 plays a critical role in NASH. To determine whether p16 could play a role in the pathogenesis of NASH, wild-type mice and p16(-/-) mice were fed on a methionine and choline-deficient (MCD) diet for 3 weeks, and liver steatosis, fibrosis, and inflammation were evaluated. Our data show that p16(-/-) mice fed with MCD diet displayed more significant hepatic steatosis, hepatocyte damage, increased oxidative stress and inflammatory cell infiltration compared to MCD-fed WT mice. It was also clear that the increased ROS and the accumulation of lipid in BEL-7402 cells occurred when p16 expression was depleted with siRNA. These findings indicate that p16 may play a critical role in the development of NASH by reining in ROS production and by inhabiting inflammatory response.

  2. Pioglitazone promotes preadipocyte proliferation by downregulating p16{sup Ink4a}

    Energy Technology Data Exchange (ETDEWEB)

    Hasan, Arif U. [Department of Cardiorenal Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Ohmori, Koji, E-mail: komori@med.kagawa-u.ac.jp [Department of Cardiorenal Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Hashimoto, Takeshi [Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Kamitori, Kazuyo; Hirata, Yuko [Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Ishihara, Yasuhiro; Okamoto, Naoko; Noma, Takahisa [Department of Cardiorenal Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Kosaka, Hiroaki [Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Tokuda, Masaaki [Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan); Kohno, Masakazu [Department of Cardiorenal Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan)

    2011-07-29

    Highlights: {yields} Mechanisms for preadipocyte hyperplasia by pioglitazone, a PPAR{gamma} agonist, are shown. {yields} Pioglitazone promotes cell-cycle of 3T3-L1 preadipocytes and increases their number. {yields} Pioglitazone downregulates a cyclin dependent kinase inhibitor, p16{sup Ink4a}. {yields} PPAR{gamma} transrepresses p16{sup Ink4a} gene in preadipocytes, which pioglitazone enhances. -- Abstract: Pioglitazone, a synthetic ligand of peroxisome proliferator-activated receptor (PPAR){gamma}, causes preadipocyte proliferation through a mechanism which still remains elusive. Here, to address the mechanism, we investigated the effects of PPAR{gamma} and pioglitazone on the kinetics of cyclin-dependent kinase inhibitors, especially with p16{sup Ink4a} (p16) centered, by employing 3T3-L1 preadipocytes. Pioglitazone promoted preadipocyte proliferation by increasing S and G{sub 2}/M cell-cycle entry, which was accompanied by decreased p16 mRNA expression. PPAR{gamma} overexpression along with the luciferase reporter assay confirmed that PPAR{gamma} was crucial for the downregulation of p16 mRNA transcription, and that the action was augmented by pioglitazone. Thus, pioglitazone exerted cell-cycle dependent promoting effect on preadipocyte proliferation, of which mechanisms include p16-downregulation through PPAR{gamma}.

  3. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion.

    Science.gov (United States)

    Helman, Aharon; Klochendler, Agnes; Azazmeh, Narmen; Gabai, Yael; Horwitz, Elad; Anzi, Shira; Swisa, Avital; Condiotti, Reba; Granit, Roy Z; Nevo, Yuval; Fixler, Yaakov; Shreibman, Dorin; Zamir, Amit; Tornovsky-Babeay, Sharona; Dai, Chunhua; Glaser, Benjamin; Powers, Alvin C; Shapiro, A M James; Magnuson, Mark A; Dor, Yuval; Ben-Porath, Ittai

    2016-04-01

    Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

  4. Expression of p16INK4A and p14ARF in hematological malignancies.

    Science.gov (United States)

    Taniguchi, T; Chikatsu, N; Takahashi, S; Fujita, A; Uchimaru, K; Asano, S; Fujita, T; Motokura, T

    1999-11-01

    The INK4A/ARF locus yields two tumor suppressors, p16INK4A and p14ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone marrow and lymph nodes expressed little or undetectable p16INK4A and p14ARF mRNAs, which were readily detected in 12 and 17 of 41 cell lines, respectively. Patients with hematological malignancies frequently lacked p16INK4A expression (60/137) and lost p14ARF expression less frequently (19/137, 13.9%). Almost all patients without p14ARF expression lacked p16INK4A expression, which may correspond to deletions of the INK4A/ARF locus. Undetectable p16INK4A expression with p14ARF expression in 41 patients may correspond to p16INK4A promoter methylation or to normal expression status of the p16INK4A gene. All patients with follicular lymphoma (FL), myeloma or acute myeloid leukemia (AML) expressed p14ARF while nine of 23 patients with diffuse large B cell lymphoma (DLBCL) lost p14ARF expression. Patients with ALL, AML or blast crisis of chronic myelogenous leukemia expressed abundant p16INK4A mRNAs more frequently than patients with other diseases (12/33 vs 6/104, P < 0.01). Patients with FL and high p14ARF expression had a significantly shorter survival time while survival for patients with DLBCL and increased p14ARF expression tended to be longer. These observations indicate that p16INK4A and p14ARF expression is differentially affected among hemato- logical malignancies and that not only inactivation but also increased expression may have clinical significance.

  5. Identification and characterization of Bmi-1-responding element within the human p16 promoter.

    Science.gov (United States)

    Meng, Sha; Luo, Min; Sun, He; Yu, Xin; Shen, Meili; Zhang, Quancang; Zhou, Rudan; Ju, Xiaofang; Tao, Wei; Liu, Di; Deng, Hongkui; Lu, Zhigang

    2010-10-22

    Bmi-1, the first functionally identified polycomb gene family member, plays critical roles in cell cycle regulation, cell immortalization, and cell senescence. Bmi-1 is involved in the development and progression of carcinomas and is a potent target for cancer therapy. One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16(Ink4a) and p19(Arf), as Bmi-1 represses the INK4a locus on which they are encoded. A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear. In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter. The BRE resided at bp -821 to -732 upstream of the p16 ATG codon. BRE alone was sufficient to allow Bmi-1-mediated regulation of the CMV promoter. Bmi-1 typically functions by forming a complex with Ring2; however, regulation of p16 was independent of Ring2. Chromatin immunoprecipitation sequencing of Bmi-1-precipitated chromatin DNA revealed that 1536 genes were targeted by Bmi-1, including genes involved in tissue-specific differentiation, cell cycle, and apoptosis. By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation. Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy.

  6. Expression of the p16 and Ki67 in Cervical Squamous Intraepithelial Lesions and Cancer.

    Science.gov (United States)

    Kanthiya, Kanjana; Khunnarong, Jakkapan; Tangjitgamol, Siriwan; Puripat, Napaporn; Tanvanich, Sujitra

    2016-01-01

    To evaluate the expression of p16 and Ki67 in cervical intraepithelial neoplasia (CIN) and cancer. We performed a immunohistochemical study of p16 and Ki67 in 243 cervical tissues 53 nondysplastic lesions, 106 CIN1, 61 CIN2/3 and 23 squamous cell carcinomas. The expression of p16 and Ki67 was interpreted independently by 2 researchers and the sensitivity and specificity to detect clinically significant lesions (≥ CIN2) were determined. The overall agreement results of positive or negative immunostaining of intrainter observer variability were 0.659 for p16 and 0.808 for Ki67. p16 expression was demonstrated in 91.3% of invasive carcinomas, 78.7% of CIN2/3, 10.4% of CIN1 and 9.4% of nondysplasic lesions. The corresponding Ki67 expression was: 100% of all invasive carcinomas, 75.4% of CIN2/3, 22.6% of CIN1, and 11.3% with nondysplasia. The expression was significantly different between CIN2/3 vs CIN1 for both p16 and Ki67 (pvalues cancer vs CIN2/3 for Ki67 (pvalue 0.008). The differences were not significant between CIN1 vs nondysplasia (pvalues 1.000 for p16 and 0.130 of Ki67), and cancer vs CIN2/3 for p16 (p value 0.219). The sensitivity and specificity to detect > CIN2 were 84.5% and 90.5% by p16 and 82.1% and 88.6% by Ki67. The rates for 16 and Ki67 expression were directly associated with the severity of cervical lesions. Significant differences in these markers expression may be useful in cases with equivocal histologic features among cervical intraepithelial lesions, but not between CIN1 and nondysplastic lesions. The two markers had high sensitivity and specificity in determining >CIN2.

  7. Expression of p16 and pRB in invasive breast cancer.

    Science.gov (United States)

    Shin, Eunah; Jung, Woo-Hee; Koo, Ja-Seung

    2015-01-01

    We aimed to assess protein expressions of p16 and pRB in breast cancer and explore the clinicopathologic implications. Tissue microarray (TMA) was constructed with 406 cases of breast cancer. The cases were subgrouped into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) based on the results of immunohistochemical stains for ER, PR, HER-2, and Ki-67 and fluorescent in situ hybridization (FISH) for HER-2. One hundred and sixty-eight cases were allocated to the subgroup luminal A; 87 cases to the luminal B; 32 cases to the HER-2; and 119 cases to the TNBC. The TNBC group showed the highest negative rate for p16, and the luminal B and HER-2 groups showed the highest positive rate for p16 (P pRB expression rate was the highest in the HER-2 group and lowest in the luminal A group. In addition, p16(+)/pRB(+) type was the most common in the luminal B group, p16(+)/pRB(-) in the luminal A group, and p16(-)/pRB(+) in the TNBC group (P pRB(+) and non-altered p16/pRB(+) type was the most common in the luminal B, and altered p16/pRB(-) and non-altered p16/pRB(+) type was the most common in the luminal A (P pRB positivity was correlated with PR negativity (P = 0.009), HER-2 positivity (P = 0.001), and higher Ki-67 LI (P pRB differ according to the molecular subgroups of breast cancer and they subsequently correlate with clnicopathologic factors.

  8. HPV L1 and P16 Expression in CIN1 to Predict Future CIN2.

    Science.gov (United States)

    Liu, Chong; Du, Hui; Wang, Chun; Belinson, Jerome L; Yang, Bin; Zhang, Wei; Tang, Jinlong; Wu, Ruifang

    2017-03-08

    To use the biomarkers human papillomavirus (HPV) L1 and p16 to develop an algorithm that could triage the individual patient with CIN1 for the risk of progression. A total of 82 patients initially diagnosed with CIN1 at Peking University Shenzhen Hospital in China had their initial and follow-up paraffin-embedded tissue blocks immune-stained for HPV L1 capsid protein and p16. For CIN1, any staining of abnormal epithelium was considered positive. All patients were followed until they developed CIN2+ or for ≥3 years. About 38 patients regressed (HPV-, Cytology-), 17 persisted (CIN1), and 27 progressed (≥CIN2+). At initial diagnosis, HPV L1 capsid protein was expressed in 42.7% of the CIN1 cases. There was no difference in L1 expression among the 3 groups. However, p16-positive staining in the progression group was significantly higher than in the regression group (Pp16- category was significantly higher than that in the progression group. In the progression group, when CIN1 lesions progressed to CIN2+, the L1-positive rate was significantly decreased from 51.9% to 18.5%, the p16+/HPV L1+ rate decreased from the initial (44.4%) to the final diagnosis (14.8%), and the p16+/HPV L1- rate increased from the initial (25.9%) to the final diagnosis (66.7%). P16 expression is a clear risk factor for the progression of CIN1. The p16-/HPV L1- pattern was significantly associated with the regression of CIN1. Moving from CIN1 to CIN2+ over time, p16+/HPV L1+ decreased, and p16+/HPV L1- increased. Unfortunately, our objective of finding a sensitive and specific triage algorithm for the individual patient with CIN1 was still not achieved.

  9. P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis

    OpenAIRE

    Cui, Chenghua; Gan, Ying; Gu, Liankun; Wilson, James; Liu, Zhaojun; Zhang, Baozhen; Deng, Dajun

    2015-01-01

    Background P16 DNA methylation is well known to be the most frequent event in cancer development. It has been reported that genetic inactivation of P16 drives cancer growth and metastasis, however, whether P16 DNA methylation is truly a driver in cancer metastasis remains unknown. Results A P16-specific DNA methyltransferase (P16-dnmt) expression vector is designed using a P16 promoter-specific engineered zinc finger protein fused with the catalytic domain of dnmt3a. P16-dnmt transfection sig...

  10. Northwestern Hawaiian Islands (NWHI) photo-quadrat monitoring data table : Site number MID P16

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This spreadsheet summarizes the number of corals photographed along a 50-meter transect line at Underwater Site P16 at Midway Atoll in the Northwestern Hawaiian...

  11. Northwestern Hawaiian Islands (NWHI) photo-quadrat monitoring data table : Site number FFS P16

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This spreadsheet summarizes the number of corals photographed along a 50-meter transect line at Underwater Site P16 off French Frigate Shoals in the Northwestern...

  12. Immunohistochemical overexpression of p16 protein associated with cervical cancer in Thailand

    National Research Council Canada - National Science Library

    Jedpiyawongse, Adisorn; Homcha-em, Patcharin; Karalak, Anant; Srivatanakul, Petcharin

    2008-01-01

    .... It has been demonstrated that p16 protein can be detected in cervical preneoplasia all high grade SIL or invasive cancers, whereas no expression was detected in normal, metaplastic or inflammatory cervical lesions...

  13. P16基因在喉癌中的表达

    Institute of Scientific and Technical Information of China (English)

    范井荣

    2006-01-01

    目的探讨P16基因的表达与喉癌的关系。方法采用RT—PCR方法检测喉癌中P16 mRNA表达情况。结果不同病理级别喉癌组织中P16 mRNA表达均有不同程度下降,Ⅱ~Ⅲ级患者下降比较明显。结论P16基因在喉癌中的表达明显低于正常喉黏膜组织,可能与喉癌的发生发展密切相关。

  14. A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway

    OpenAIRE

    Cimino-Mathews, Ashley; Hicks, Jessica L.; Sharma, Rajni; Vang, Russell; Illei, Peter B; De Marzo, Angelo; Emens, Leisha A.; Argani, Pedram

    2013-01-01

    Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb,...

  15. Risk stratification of early stage oral tongue cancers based on HPV status and p16 immunoexpression.

    Science.gov (United States)

    Ramshankar, Vijayalakshmi; Soundara, Viveka T; Shyamsundar, Vidyarani; Ramani, Prathiba; Krishnamurthy, Arvind

    2014-01-01

    Recent epidemiological data have implicated human papilloma virus (HPV) infection in the pathogenesis of head and neck cancers, especially oropharyngeal cancers. Although, HPV has been detected in varied amounts in persons with oral dysplasia, leukoplakias and malignancies, its involvement in oral tongue carcinogenesis remains ambiguous. HPV DNA prevalence was assessed by PCR with formalin fixed paraffin embedded sections (n=167) of oral tongue squamous cell carcinoma patients and the physical status of the HPV16 DNA was assessed by qPCR. Immunohistochemistry was conducted for p16 evaluation. We found the HPV prevalence in tongue cancers to be 51.2%, HPV 16 being present in 85.2% of the positive cases. A notable finding was a very poor concordance between HPV 16 DNA and p16 IHC findings (kappap16 overexpression showed that patients with tumours showing p16 overexpression had increased hazard of death (HR=2.395; p=0.005) and disease recurrence (HR=2.581; p=0.002) irrespective of their HPV 16 DNA status. Our study has brought out several key facets which can potentially redefine our understanding of tongue cancer tumorigenesis. It has emphatically shown p16 overexpression to be a single important prognostic variable in defining a high risk group and depicting a poorer prognosis, thus highlighting the need for its routine assessment in tongue cancers. Another significant finding was a very poor concordance between p16 expression and HPV infection suggesting that p16 expression should possibly not be used as a surrogate marker for HPV infection in tongue cancers. Interestingly, the prognostic significance of p16 overexpression is different from that reported in oropharyngeal cancers. The mechanism of HPV independent p16 over expression in oral tongue cancers is possibly a distinct entity and needs to be further studied.

  16. P16 gene hypermethylation and hepatocellular carcinoma: A systematic review and meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Jia-Jie Zang; Feng Xie; Jin-Fang Xu; Ying-Yi Qin; Rong-Xi Shen; Jia-Mei Yang; Jia He

    2011-01-01

    AIM: To quantitatively investigate the effect of p16 hypermethylation on hepatocellular carcinoma (HCC) and hepatocirrhosis using a meta-analysis of available casecontrol studies. METHODS: Previous studies have primarily evaluated the incidence of p16 hypermethylation in HCC and corresponding control groups, and compared the incidence of p16 hypermethylation in tumor tissues, pericancer liver tissues, normal liver tissues and non-tumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of p16 hypermethylation in both groups were collected from these studies and summarized. RESULTS: Fifteen studies, including 744 cases of HCC and 645 non-tumor cases, were identified for metaanalysis. Statistically significant odds ratios (ORs) of p16 hypermethylation were obtained from tumor tissues and non-tumorous liver tissues of HCC patients (OR 7.04, 95% CI: 3.87%-12.78%, P < 0.0001), tumor tissues of HCC patients and healthy liver tissues of patients with other diseases (OR 12.17, 95% CI: 6.64%-22.31%, P < 0.0001), tumor tissues of HCC patients and liver tissues of patients with non-tumorous liver diseases (OR 6.82, 95% CI: 4.31%-10.79%, P < 0.0001), and cirrhotic liver tissues and non-cirrhotic liver tissues (OR 4.96, 95% CI: 1.45%-16.96%, P = 0.01). The pooled analysis showed significantly increased ORs of p16 hypermethylation (OR 6.98, 95% CI: 4.64%-10.49%, P < 0.001) from HCC tissues and cirrhotic tissues. CONCLUSION: P16 hypermethylation induces the inactivation of p16 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC and liver cirrhosis.

  17. Correlation between p16 gene methylation and the expression of p16 and ER protein in breast cancer and its significance%乳腺癌组织中p16基因甲基化与p16、ER蛋白表达的相关性及意义

    Institute of Scientific and Technical Information of China (English)

    杨玉华; 吕小梅

    2010-01-01

    目的 探讨p16基因甲基化在乳腺癌发生、发展中的作用.方法 应用甲基化特异性PCR(MSP)联合测序检测58份乳腺癌及其癌旁组织中p16基因甲基化状态,应用免疫组化SP法检测p16及ER蛋白表达情况,对各指标间关系行Spearman相关分析.结果 p16基因在乳腺癌中甲基化率为29.3%(17/58),有淋巴结及远处转移者显著高于无转移者(P<0.05);p16甲基化及非甲基化者p16蛋白表达阻性(失表达)率分别为82.4%(14/17)、43.9%(18/41),ER蛋白失表达率分别为 76.5%(13/17)、24.4%(10/41),P均<0.05.结论 p16基因甲基化在乳腺癌发生、发展中具有重要作用,机制可能与调节p16和ER蛋白表达有关.

  18. TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.

    Science.gov (United States)

    Wang, L; Zhang, P; Molkentine, D P; Chen, C; Molkentine, J M; Piao, H; Raju, U; Zhang, J; Valdecanas, D R; Tailor, R C; Thames, H D; Buchholz, T A; Chen, J; Ma, L; Mason, K A; Ang, K-K; Meyn, R E; Skinner, H D

    2017-02-09

    Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.

  19. Overdiagnosis of HSIL on cervical biopsy: errors in p16 immunohistochemistry implementation.

    Science.gov (United States)

    Clark, Jennifer L; Lu, Dan; Kalir, Tamara; Liu, Yuxin

    2016-09-01

    In 2012, the lower anogenital squamous terminology (LAST) project introduced new nomenclature for human papillomavirus-related squamous lesions of the lower genital tract: low-grade and high-grade squamous intraepithelial lesion (LSIL and HSIL). Biomarker p16(INK4a) immunohistochemistry (IHC) was also recommended to assist classification: block-like positive staining supports the diagnosis of HSIL. We aim to assess the impact of LAST recommendations on our practice as well as to identify challenges and errors in p16 IHC implementation. We studied 262 cervical biopsies meeting 3 criteria: (1) HSIL diagnosis; (2) p16 IHC performed at time of diagnosis; and (3) patient's follow-up more than 12 months, including cervical cytology, biopsy, and excision. Among these patients, subsequent loop electrosurgical excision procedure and surveillance revealed 163 HSILs (62%), 28 LSILs (11%), and 71 "nondysplastic changes" (27%). We reviewed the latter 2 groups' original hematoxylin and eosin and p16 IHC slides. The diagnosis of HSIL was confirmed in 49 cases (49%), whereas 50 (51%) were reclassified as LSIL (n=46) or negative for dysplasia (n=4). These cases were initially overdiagnosed as HSIL because pathologists (1) overused p16 IHC on unequivocal LSIL (n=27) or (2) upgraded questionable lesions to HSIL based on nonblock p16 staining patterns (patchy or focal, n=23). To implement LAST recommendations successfully, we advocate judicious use of p16 in the designated circumstances and careful interpretation of staining patterns in the context of morphology. A standardized threshold for p16 positivity and supplementary guidance will help clarify the biomarker's utility and will facilitate LAST implementation in routine practice.

  20. Expression of cyclin D1 and p16 in psoriasis before and after phototherapy.

    Science.gov (United States)

    Abou EL-Ela, M; Nagui, N; Mahgoub, D; El-Eishi, N; Fawzy, M; El-Tawdy, A; Abdel Hay, R; Rashed, L

    2010-10-01

    Psoriasis vulgaris (PV) is characterized by keratinocyte hyperproliferation. Altered expression of cell-cycle regulatory genes involved in the cyclin D1 ⁄ p16 INK4-pRb pathway may contribute to this epidermal hyperproliferation. To assess the expression of cyclin D1 and p16 in psoriasis, and to evaluate the effect of phototherapy on their expression. The study population comprised 25 patients with PV and 10 healthy controls. Patients were treated with 24 sessions of either narrowband ultraviolet (UV) B or psoralen UVA. Skin biopsies were taken from the affected skin of each patient before and after treatment, and from the healthy controls, to examine cyclin D1 and p16 expression. Before phototherapy, the mean value of cyclin D1 concentration in patients was significantly greater than that in controls and the mean value of p16 concentration in patients was significantly lower than that in controls. Following treatment, we detected a significant decrease in cyclin D1 and a significant increase in p16. Cyclin D1 upregulation and p16 downregulation may play a role in the pathogenesis of psoriasis. Normalization of the levels of both parameters may be a mechanism by which phototherapy induces remission in psoriasis.

  1. Immunohistochemical comparison of cyclin D1 and P16 in odontogenic keratocyst and unicystic ameloblastoma.

    Science.gov (United States)

    Razavi, Seyed Mohammad; Poursadeghi, Hamid; Aminzadeh, Atousa

    2013-03-01

    The different growth mechanism and biologic behavior of the odontogenic keratocyst (OKC) compared to other odontogenic cysts might be related to the proliferating capacity of its epithelium. In this study, the aim was to evaluate and compare the distribution and staining intensity of P16 and cyclin D1 in OKC and unicystic ameloblastoma (UA). In this descriptive analytic study, hematoxylin- and eosin-stained slides of OKCs and UAs available from the archives of the oral pathology laboratory of the Esfahan School of Dentistry were examined. Twenty-five noninflamed solitary odontogenic keratocysts and 25 unicystic ameloblastomas (of either type) were selected and stained immunohistochemically. Distribution and staining intensity score (SID score) for P16- and cyclin D1-positive cells was calculated in both groups. Results were analyzed statistically with Wilcoxon, Friedman, and Mann-Whitney tests; P P16-positive cells was observed in the basal and suprabasal layers of keratocysts (P > 0.05) and central portions of UAs (P > 0.05). Expression of Cyclin D1 was higher in UAs compared to keratocyts (P P16 did not show a significant difference between the two study groups (P > 0.05). Cyclin D1 did show a higher staining intensity in UAs compared to the keratocysts, although the expression of P16 was similar in the studied groups. The invasive growth of OKC might be related to the state of expression of cyclin D1 and P16 in the epithelium of this cyst.

  2. Radionuclides in cigarettes may lead to carcinogenesis via p16{sup INK4a} inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Prueitt, Robyn L.; Goodman, Julie E. [Gradient Corporation, 20 University Road, Cambridge, MA 02138 (United States); Valberg, Peter A. [Gradient Corporation, 20 University Road, Cambridge, MA 02138 (United States)], E-mail: pvalberg@gradientcorp.com

    2009-02-15

    It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including {alpha}-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16{sup INK4a} (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

  3. Radionuclides in cigarettes may lead to carcinogenesis via p16(INK4a) inactivation.

    Science.gov (United States)

    Prueitt, Robyn L; Goodman, Julie E; Valberg, Peter A

    2009-02-01

    It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including alpha-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16(INK4a) (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

  4. Expression of p16 in Human Colorectal Cancer and its Clinical Signiifcance

    Institute of Scientific and Technical Information of China (English)

    HE Qian-qian

    2015-01-01

    Objective: To explore the expression of p16 in human colorectal cancer and its clinical signiifcance. Methods: Neoplastic tissues and autologous non-neoplastic tissues were taken from 30 patients with colorectal cancer immediately after the operation. The expression of p16 in these tissues was detected using immunohistochemistry, and then was conifrmed with HT-29 cell line by Western-blot assay. Results: The positive rate of p16 expression in neoplastic tissues was 23.3%, signiifcantly lower than that in non-neoplastic tissues (P<0.01). p16 expression was closely associated with Dukes’ staging (P<0.01), lymph node metastasis(P<0.05) and histological differentiation degrees (P<0.05). And western-blot assay showed that the p16 expression in HT-29 cells was consistent with that of human colorectal cancer. Conclusion:Abnormal expression of p16 may play an important role in the occurrence and progression of colorectal cancer, and hence, it would be associated with the prognosis of colorectal cancer.

  5. Influence of suppressor gene p16 on retinoic acid inducing cancer cell A549 differentiation

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To investigate the role of suppressor gene p16 in the process of differential regulation of retinoic acid (RA) on the A549 lung cancer cells.Methods Tumor suppressor gene p16 was transferred into A549 cells and the cells were treated with all-trans retinoic acid (ATR) at the dosage of 5×10-6 mol/L for 4 d. After that, the proliferation and differentiation of A549 cells were examined by growth curve and cytometry analysis, the change of lung lineage-specific marker MUC1 was tested by immunohistochemical staining. Meanwhile, Western blot was used to observe the change of p16 protein expression in A549 cells treated with ATRA.Results ATRA could obviously inhibit the growth and induce the differentiation of A549 Cells that were transferred with p16 gene. There were more cells arrested in G1/G0 phase and the expression of MUG1 was markedly down-regulated than in control cells. The expression of p16 protein was up-regulated in A549 cells treated with ATRA.Conclusion Suppressor gene p16 could enhance the effects of RA and proliferated suppression and differential induction of A549 cells.

  6. In situ PCR and immunohistochemical studies on p16 gene in pituitary adenomas

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To examine the occurrence of p16 gene deletion and to analyze p16 expression on paraffin-embedded human pituitary adenoma specimens. Efforts were made to optimize the technical conditions for in situ PCR. Methods: In situ PCR techniques and inimuno-histochemistry were used. Results: Immunohistochemically, p16-positive tumor cells were observed in all cases with various proportions. The majority of the stromal cells and part of tumor cells was devoid of p16 immunostaining, but signal of in situ PCR for p16 gene, exon 2, was displayed in these cells. Conclusion: The results implied that p16 gene might not be deleted in these pituitary adenomas. It also indicated that in situ PCR, both direct and indirect methods, proved feasible and informative to the aim of DNA detection. It is critical to overcome non-specific amplification in direct in situ PCR by means of higher annealing temperature, fewer cycle, lower magnesium concentration and stringent washing. A target DNA-deleted sample as the negative control is extremely necessary. For the indirect method, the way to improve the sensitivity is to loosen the conditions for amplification and washing, so that more amplification products are subject to hybridization, and signal detection is facilitated.

  7. Significance of p16 expression in head and neck cancer patients treated with radiotherapy and cetuximab

    Energy Technology Data Exchange (ETDEWEB)

    Heiduschka, Gregor; Thurnher, Dietmar [Medical University of Vienna, Department of Otorhinolaryngology - Head and Neck Surgery, Vienna (Austria); Grah, Anja; Kranz, Alexander; Selzer, Edgar [Medical University of Vienna, Department of Radiotherapy, Vienna (Austria); Oberndorfer, Felicitas; Wrba, Fritz [Medical University of Vienna, Department of Clinical Pathology, Vienna (Austria); Seemann, Rudolf [Medical University of Vienna, Department of Maxillofacial Surgery, Vienna (Austria); Kornek, Gabriela [Medical University of Vienna, Department of Medicine I - Division of Clinical Oncology, Vienna (Austria)

    2014-09-15

    HPV-infection, p16 positivity, and EGFR expression have been correlated with favorable responses of head and neck cancer patients treated with radiotherapy (RT) with or without chemotherapy. However, a possible correlation of HPV/p16 and EGFR status on the effect of RT in combination with cetuximab has not been sufficiently investigated. We analyzed tumor samples for p16 and EGFR expression and correlated these variables with treatment outcome. Cox-proportional-hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. Survival was estimated by the Kaplan-Meier method. Results were compared with an institutional historical control group treated without cetuximab and with published data. Expression of p16 was predominantly found in oropharyngeal squamous cell cancer patients (OPSCC; 36.6 % positivity; 92 % of all cases), while EGFR was expressed at high levels in all tumor subsites (82 %). p16 expression was associated with improved overall survival in irradiated OPSCC patients (2-year overall survival of 80 % in p16-positive vs. 33 % overall survival in p16-negative patients). In a multivariable analysis covering all tumor sites, nodal stage (> N2a vs. ≤ N2a) and tumor site (OPSSC vs. non-OPSCC) had an impact on overall survival. Our results show that p16 positivity is associated with a favorable outcome in OPSCC patients treated with RT and cetuximab. (orig.) [German] HPV-Infektion, p16-Positivitaet und EGFR-Expression wurden bei Kopf-Hals-Tumorpatienten, die mit einer Strahlentherapie (RT) mit oder ohne Chemotherapie behandelt wurden, mit einem besseren Ergebnis in Verbindung gebracht. Bis jetzt wurde eine solche Korrelation bei Patienten, die mit einer RT in Kombination mit Cetuximab therapiert wurden, nicht untersucht. Es wurden die p16- und die EGFR-Expression in Tumormaterial untersucht und die Daten mit dem Behandlungsergebnissen korreliert. Um die Sterberisiken zu vergleichen, wurden Cox

  8. GenBank

    Data.gov (United States)

    U.S. Department of Health & Human Services — GenBank is the NIH genetic sequence database, an annotated collection of all publicly available DNA sequences. GenBank is designed to provide and encourage access...

  9. GEN 499 Courses/sanptutorial

    OpenAIRE

    2015-01-01

    GEN 499 Week 1 DQ 1 Final Research Paper Topic and Plan GEN 499 Week 1 DQ 2 Social Media GEN 499 Week 2 DQ 1 Professional Resume and Cover Letter GEN 499 Week 2 Assignment Critiquing Internet Sources GEN 499 Week 3 DQ 1 Social Capital GEN 499 Week 3 DQ 2 Federal Policy GEN 499 Week 3 Assignment Annotated Bibliography GEN 499 Week 4 DQ 1 Call to Action GEN 499 Week 4 DQ 2 Final Research Paper Progress GEN 499 Week 4 Critical Thinking Quiz GEN 499 Week 5 ...

  10. GEN 480 Courses/sanptutorial

    OpenAIRE

    2015-01-01

    GEN 480 Week 1 Individual Assignment Ethics Awareness Inventory GEN 480 Week 1 DQ 1 GEN 480 Week 1 DQ 2 GEN 480 Week 1 DQ 3 GEN 480 Week 1 DQ 4 GEM 480 Week 1 Summary GEN 480 Week 2 Individual Assignment Ethics Awareness Inventory Analysis GEN 480 Week 2 Individual Assignment Professional Workplace Dilemma Paper GEN 480 Week 2 Learning Team Assignment Skills Assessment Paper and Matrix GEN 480 Week 2 DQ 1 GEN 480 Week 2 DQ 2 GEN 480 Week 2 DQ 3 ...

  11. GEN 480 UOP TUTORIAL / Uoptutorial

    OpenAIRE

    2015-01-01

    For more course tutorials visit www.uoptutorial.com           GEN 480 Week 1 DQ 1  GEN 480 Week 1 DQ 2  GEN 480 Week 1 DQ 3  GEN 480 Week 1 DQ 4  GEN 480 Week 1 Individual AssignmentEthics Awareness  GEN 480 Week 1 Summary  GEN 480 Week 2 DQ 1  GEN 480 Week 2 DQ 2  GEN 480 Week 2 DQ 3  GEN 480 Week 2 DQ 4  GEN 480 Week 2 Individual Assignment Ethics Awareness &...

  12. Expression of the p16{sup INK4a} tumor suppressor gene in rodent lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Swafford, D.S.; Tesfaigzi, J.; Belinsky, S.A.

    1995-12-01

    Aberrations on the short arm of chromosome 9 are among the earliest genetic changes in human cancer. p16{sup INK4a} is a candidate tumor suppressor gene that lies within human 9p21, a chromosome region associated with frequent loss of heterozygosity in human lung tumors. The p16{sup INK4a} protein functions as an inhibitor of cyclin D{sub 1}-dependent kinases that phosphorylate the retinoblastoma (Rb) tumor suppressor gene product enabling cell-cycle progression. Thus, overexpression of cyclin D{sub 1}, mutation of cyclin-dependent kinase genes, or loss of p16{sup INK4a} function, can all result in functional inactivation of Rb. Inactivation of Rb by mutation or deletion can result in an increase in p16{sup INK4a} transcription, suggesting that an increased p16{sup INK4a} expression in a tumor cell signals dysfunction of the pathway. The p16{sup (INK4a)} gene, unlike some tumor suppressor genes, is rarely inactivated by mutation. Instead, the expression of this gene is suppressed in some human cancers by hypermethylation of the CpG island within the first exon or by homozygous deletion: 686. Chromosome losses have been observed at 9p21 syntenic loci in tumors of the mouse and rat, two species often used as animal models for pulmonary carcinogenesis. Expression of p16{sup INK4a} is lost in some mouse tumor cell lines, often due to homozygous deletion. These observations indicate that p16{sup INK4a} dysfunction may play a role in the development of neoplasia in rodents as well as humans. The purpose of the current investigation was to define the extent to which p16{sup INK4a} dysfunction contributes to the development of rodent lung tumors and to determine the mechanism of inactivation of the gene. There is no evidence to suggest a loss of function of the p16{sup INK4a} tumor suppressor gene in these primary murine lung tumors by mutation, deletion, or methylation.

  13. [Clinical value of p16/Ki-67 immunocytochemical dual staining in cervical cancer screening].

    Science.gov (United States)

    Wang, H R; Liao, G D; Chen, W; Qiao, Y L; Jiang, Y

    2017-08-23

    Objective: to investigate the clinical value of p16/Ki-67 immunocytochemical dual staining (abbreviated as p16/Ki-67 dual staining) in cervical intraepithelial neoplasia (CIN) and cervical cancer screening. Methods: From July to November 2015, a total of 980 women attending cervical cancer screening and receiving high-risk human papillomavirus (HR-HPV) test and thinprep cytologic test (TCT) were included in the study. p16/Ki-67 immunocytochemical dual staining was performed on residual cytologic specimens and compared with histopathology results. Results: The expression risks of p16/Ki-67 in HPV16/18 group and another HR-HPV group were higher than HPV negative group, with an odds ratio of 10.64 (95%CI: 5.66~20.02) and 5.40 (95%CI: 3.62~8.04), respectively. The positive rate of p16/Ki-67 increased with the grade of TCT and histologic diagnosis, and was higher in both CIN2 and CIN3 groups than normal group (Pp16/Ki-67 to detect CIN2+ and CIN3+ lesions was 89.3% and 94.1%, respectively, and the specificity was 69.3% and 66.8%, respectively. The sensitivity of TCT to detect CIN2+ and CIN3+ lesions was 60.7% and 64.7%, respectively, and the specificity was 49.3% and 49.1%, respectively. Conclusions: Compared with TCT, p16/Ki-67 dual staining has higher sensitivity and specificity. It can identify high-grade cervical lesions and guide the classification of CIN. p16/Ki-67 dual staining in conjunction with HPV test may be considered as an efficient method for cervical cancer screening.

  14. Sp1 is essential for p16 expression in human diploid fibroblasts during senescence.

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    Junfeng Wu

    Full Text Available BACKGROUND: p16(INK4a tumor suppressor protein has been widely proposed to mediate entrance of the cells into the senescent stage. Promoter of p16(INK4a gene contains at least five putative GC boxes, named GC-I to V, respectively. Our previous data showed that a potential Sp1 binding site, within the promoter region from -466 to -451, acts as a positive transcription regulatory element. These results led us to examine how Sp1 and/or Sp3 act on these GC boxes during aging in cultured human diploid fibroblasts. METHODOLOGY/PRINCIPAL FINDINGS: Mutagenesis studies revealed that GC-I, II and IV, especially GC-II, are essential for p16(INK4a gene expression in senescent cells. Electrophoretic mobility shift assays (EMSA and ChIP assays demonstrated that both Sp1 and Sp3 bind to these elements and the binding activity is enhanced in senescent cells. Ectopic overexpression of Sp1, but not Sp3, induced the transcription of p16(INK4a. Both Sp1 RNAi and Mithramycin, a DNA intercalating agent that interferes with Sp1 and Sp3 binding activities, reduced p16(INK4a gene expression. In addition, the enhanced binding of Sp1 to p16(INK4a promoter during cellular senescence appeared to be the result of increased Sp1 binding affinity, not an alteration in Sp1 protein level. CONCLUSIONS/SIGNIFICANCE: All these results suggest that GC- II is the key site for Sp1 binding and increase of Sp1 binding activity rather than protein levels contributes to the induction of p16(INK4a expression during cell aging.

  15. Immunohistochemical study of p16 INK4A and survivin expressions in cervical squamous neoplasm

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    Tan Geok

    2010-01-01

    Full Text Available Introduction:Cervical cancer is the second most common cancer affecting Malaysian women. Despite the implementation of pap smear screening, many women are still diagnosed only in the advanced stage of cervical cancer. This could partly be due to failure of detection of its precursor lesions; hence the need to search for novel biomarkers to assist in the screening and diagnosis of cervical neoplasia. This study aims to determine the expression of p16INK4A and survivin as possible predictive biomarkers in cervical squamous neoplasm. Material and Methods: This is a retrospective study on 201 cases of cervical neoplasm comprising of 129 cervical intraepithelial neoplasia (CIN and 72 squamous cell carcinoma (SCC. All samples were evaluated by two independent observers using p16INK4A and survivin monoclonal antibodies. The p16 INK4A expression was graded as negative, focal and diffuse positivity. The intensity for survivin expression was graded as weak, moderate and intense. Results: It is seen that p16 INK4A expression in CIN 1, CIN 2 and CIN 3 were 25.4%, 42.9% and 95.9% respectively. Majority of SCC (98.6% showed p16 INK4A expression. Survivin expressions in CIN 1, CIN 2, CIN 3 and SCC were 56.7%, 33.4%, 87.5% and 98.6%. There was a linear relationship between increasing grade of CIN and p16 INK4A expressions. Conclusion: Our study showed that p16 INK4A expressions correlate well with the increasing grade of CIN. Although survivin does not correlate well to the increasing grade of CIN, it could be useful in differentiating CIN 3 from SCC.

  16. Use of p16 FISH for differential diagnosis of mesothelioma in smear preparations.

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    Nabeshima, Kazuki; Matsumoto, Shinji; Hamasaki, Makoto; Hida, Tomoyuki; Kamei, Toshiaki; Hiroshima, Kenzo; Tsujimura, Tohru; Kawahara, Kunimitsu

    2016-09-01

    Because most of malignant pleural mesothelioma (MPM) patients first present with pleural effusion, detection of mesothelioma cells on effusion smears is critical for early diagnosis. Recently, accumulating evidence indicating that the cytological diagnosis of MPM supported by ancillary techniques is as reliable as that based on histopathology has led to new guidelines for the cytopathologic diagnosis of MPM. Based on the guidelines, a combination of cytomorphological criteria and verification by ancillary techniques is required for the cytologic diagnosis of MPM. Detection of p16 homozygous deletion by fluorescence in situ hybridization (FISH) is the most reliable ancillary technique for differentiating MPM from reactive mesothelial cells (RMC) because of its relatively high sensitivity and extremely high specificity. We showed that the p16 deletion status of MPM cells in pleural effusions reflected that of the underlying invasive MPM tissues, indicating the usefulness of p16 FISH in effusion smear cytology for MPM diagnosis. Thus, for differentiating MPM from RMC, we propose to perform p16 FISH as often as possible. A positive p16 homozygous deletion supports the diagnosis of MPM. However, a negative result does not rule out the possibility of MPM. In such cases, a morphological assessment is critical. Therefore, we analyzed the morphological characteristics of p16 deletion-positive mesothelioma cells using a combination of virtual microscopy and p16 FISH, and identified three morphological characteristics useful for the differentiation, including cell-in-cell engulfment with or without hump formation, multinucleate cells, and larger berry-like cell aggregates. Diagn. Cytopathol. 2016;44:774-780. © 2016 Wiley Periodicals, Inc.

  17. Human papillomavirus DNA and p16 expression in Japanese patients with oropharyngeal squamous cell carcinoma.

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    Kawakami, Hisato; Okamoto, Isamu; Terao, Kyoichi; Sakai, Kazuko; Suzuki, Minoru; Ueda, Shinya; Tanaka, Kaoru; Kuwata, Kiyoko; Morita, Yume; Ono, Koji; Nishio, Kazuto; Nishimura, Yasumasa; Doi, Katsumi; Nakagawa, Kazuhiko

    2013-12-01

    Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.

  18. Acid-induced p16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S.

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    Hong, Jie; Resnick, Murray; Behar, Jose; Wang, Li Juan; Wands, Jack; DeLellis, Ronald A; Souza, Rhonda F; Spechler, Stuart J; Cao, Weibiao

    2010-09-01

    Inactivation of tumor suppressor gene p16 may play an important role in the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Hypermethylation of p16 gene promoter is an important mechanism inactivating p16. However, the mechanisms of p16 hypermethylation in EA are not known. Therefore, we examined whether acid increases methylation of p16 gene promoter and whether NADPH oxidase NOX5-S mediates acid-induced p16 hypermethylation in a Barrett's cell line BAR-T and an EA cell line OE33. We found that NOX5-S was present in BAR-T and OE33 cells. Acid-induced increase in H(2)O(2) production and cell proliferation was significantly reduced by knockdown of NOX5-S. Exogenous H(2)O(2) remarkably increased p16 promoter methylation and cell proliferation. In addition, acid treatment significantly increased p16 promoter methylation and decreased p16 mRNA level. Knockdown of NOX5-S significantly increased p16 mRNA, inhibited acid-induced downregulation of p16 mRNA, and blocked acid-induced increase in p16 methylation and cell proliferation. Conversely, overexpression of NOX5-S significantly decreased p16 mRNA and increased p16 methylation and cell proliferation. In conclusion, NOX5-S is present in BAR-T cells and OE33 cells and mediates acid-induced H(2)O(2) production and cell proliferation. NOX5-S is also involved in acid-induced hypermethylation of p16 gene promoter and downregulation of p16 mRNA. It is possible that acid reflux present in BE patients may activate NOX5-S and increase production of reactive oxygen species, which in turn increase p16 promoter methylation, downregulate p16 expression, and increase cell proliferation, thereby contributing to the progression from BE to EA.

  19. Human Papillomaviruses, p16INK4a and Akt expression in basal cell carcinoma

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    Paolini Francesca

    2011-11-01

    Full Text Available Abstract Background The pathogenic role of beta-HPVs in non melanoma skin cancer (NMSC, is not still completely understood, and literature data indicate that they might be at least cofactors in the development of certain cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell carcinoma (BCC. The HPVs interact with many cellular proteins altering their function or the expression levels, like the p16INK4a and Akt. Our study aimed to determine the presence of different beta -HPV types and the expression of p16INK4a and Akt in BCC, the commonest NMSC, in the normal appearing perilesional skin and in forehead swab of 37 immunocompetent patients. Methods The expression of p16INK4a and Akt, by immunohistochemistry, and the HPV DNA, by nested PCR, were investigated in each sample. Results No correspondence of HPV types between BCC and swab samples was found, whereas a correspondence between perilesional skin and BCC was ascertained in the 16,7% of the patients. In BCC, 16 different types of beta HPV were found and the most frequent types were HPV107 (15,4%, HPV100 (11,5% and HPV15 (11,5% all belonging to the beta HPV species 2. Immunohistochemistry detected significant p16INK4a expression in almost all tumor samples (94,3% with the highest percentages (> 30% of positive cells detected in 8 cases. A statistically significant (p = 0,012 increase of beta HPV presence was detected in p16INK4a strongly positive samples, in particular of species 2. pAkt expression was detected in all tumor samples with only 2 cases showing rare positive cells, whereas Akt2 expression was found in 14 out of 35 BCC (40%; in particular in HPV positive samples over-expressing p16INK4a. Conclusions Our data show that p16INK4a and pAkt are over-expressed in BCC and that the high expression of p16INK4a and of Akt2 isoform is often associated with the presence of beta-HPV species 2 (i.e. HPV 15. The association of these viruses with the up

  20. Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence.

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    Attema, J L; Pronk, C J H; Norddahl, G L; Nygren, J M; Bryder, D

    2009-06-04

    Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process-a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A). Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo.

  1. YY1 restrained cell senescence through repressing the transcription of p16.

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    Wang, Xiuli; Feng, Yunpeng; Xu, Liang; Chen, Yuli; Zhang, Yu; Su, Dongmei; Ren, Guoling; Lu, Jun; Huang, Baiqu

    2008-10-01

    The transcription factor YY1 has been implicated to play a role in cell growth control. In this report, we demonstrate that YY1 was able to suppress NCI-H460 cell senescence through regulating the expression of p16(INK4a), a cyclin-dependent kinase inhibitor. We also show that YY1 participated in the repression of p16(INK4a) expression in 293T cells through an epigenetic mechanism involving histone acetylation modification. Specifically, HDAC3 and HDAC4 inhibited the p16(INK4a) promoter activity. The chromatin immunoprecipitation (ChIP) assays verified that HDAC3 and HDAC4 were recruited to p16(INK4a) promoter by YY1. Moreover, co-immunoprecipitation assays revealed that these three protein factors formed a complex. Furthermore, knockdown of these factors induced cell enlargement and flattened morphology and significantly increased the SA-beta-gal activity, a biochemical marker of cell senescence. Overall, data from this study suggest that YY1, HDAC3 and HDAC4 restrained cell senescence by repressing p16(INK4a) expression through an epigenetic modification of histones.

  2. Hypermethylation of p16 tumor-suppressor gene in ameloblastic carcinoma, ameloblastoma, and dental follicles.

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    Khojasteh, Arash; Khodayari, Abbas; Rahimi, Farzaneh; Ghaderian, Mohamad Hossain; Jafarian, Mohamad; Nayebi, Alireza; Akbarzadeh Najar, Reza; Tabatabayipanah, Akram; Jahangirnia, Alireza

    2013-01-01

    The high rate of p16 gene alterations in malignant neoplasms suggests the important effect of this tumor-suppressor gene mutation on the malignant behavior of tumoral lesions. The present study investigated the possible methylation of the p16 tumor in ameloblastic carcinoma, ameloblastoma, and dental follicles. Eighteen samples of ameloblastic carcinoma, ameloblastoma, and dental follicles of mandibular impacted third molar were selected from available documents in the archives of the Department of Oral and Maxillofacial Pathology, Taleghani Hospital and the Department of Oral and Maxillofacial Pathology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. After confirming the initial diagnosis, 6-μm sections were used for DNA extraction. A CpG island methylation of p16 was identified by polymerase chain reaction. Although CpG methylation of p16 was observed in all ameloblastic carcinoma samples, only 1 ameloblastoma specimen exhibited the mutation. The mutation was not detected in other ameloblastoma specimens or in any dental follicle sample. The p16 alteration might play a role in the malignant progression of ameloblastic carcinoma. It is worth mentioning that ameloblastoma can be further differentiated from ameloblastic carcinoma based on molecular observations. Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  3. EXPRESSION OF P16 AND CYCLIN D1 IN THE COURSE OF CARCINOGENESIS OF THE STOMACH

    Institute of Scientific and Technical Information of China (English)

    CHEN Yu-long; XU Feng; LI Yan-jie

    1999-01-01

    Objective: To determine p16 and cyclin D1 expression in the specimen of gastric carcinoma, atypic hyperplasia, atrophic gastritis, superficial gastritis and normal gastric mucosa. Methods: Using immunohistochemical method (ABC), the samples of 58 adenocarcinomas, 22 atypic hyperplasias, 28 atrophic gastritis,27 superficial gastritis and 15 gastric epitheliums were analyzed. Results: Positive immunostaining rate for p16 protein was the highest in normal gastric mucosa and decreased with the lesions progressing from superficial gastritis to atrophic gastritis to atypital hyperplasia and to adenocarcinoma (85%, 78.6%, 31.8%,48.3% respectively); Positive immunostaining of cyclin D1 can observed in atrophic gastritis. With the lesions progressing from atrophic gastritis to atypical hyperplasia to adenocarcinoma, its expression rate increased (17.9%, 36.4%, 53.4% respectively), and there was a significant difference between adenocarcinoma and atrophic gastritis group (P<0.05). An interesting observation was that inverse expression between p16and cyclin D1, was shown in most of gastric cancer detected. Conclusion: It is indicated that p16 and cyclin D1 play an important role in the gastric carcinogenesis, the inverse expression between p16 and cyclin D1 suggested that there is a suppression trend in them.

  4. The diagnostic utility of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations.

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    Monaco, Sara E; Shuai, Yongli; Bansal, Mona; Krasinskas, Alyssa M; Dacic, Sanja

    2011-04-01

    Two promising ancillary tests used in the diagnosis of mesothelioma include GLUT-1 immunohistochemical analysis and fluorescence in situ hybridization (FISH) testing for the p16 deletion. This study compared the diagnostic usefulness of p16 FISH and GLUT-1 immunohistochemical analysis in the diagnosis of mesothelial proliferations in 158 cases with a diagnosis of benign (45.4%), atypical (10.4%), or malignant/mesothelioma (44.2%). Of the 70 benign cases, none had a deletion of p16 and 5 cases (7%) were positive for GLUT-1. Of the 68 mesotheliomas, 40 (59%) had a deletion of p16 (sensitivity, 59%; specificity, 100%) and 27 (40%) were positive for GLUT-1 (sensitivity, 40%; specificity, 93%). GLUT-1 showed lower sensitivity in pleural (56% vs 70%) and peritoneal (29% vs 51%) mesotheliomas (P = .004). Our results demonstrate that p16 FISH is a more sensitive and specific test than GLUT-1 immunohistochemical analysis and can be a more reliable ancillary tool to support the diagnosis of mesothelioma.

  5. Expression of P16 protein and Bcl-2 protein in malignant eyelid tumors

    Institute of Scientific and Technical Information of China (English)

    牛膺筠; 周占宇; 刘夫玲; 王红云

    2002-01-01

    Objective To investigate the relationship between P16 gene (the tumor suppressor gene) and the bcl-2 gene (the apoptosis inhibitor gene) and the incidence and development of malignant eyelid tumors. Methods The streptavidin-biotin-peroxidase complex immunohistochemistry method was used to study the expression of P16 gene and the bcl-2 gene in 96 cases of malignant eyelid tumors. Results Among the 96 cases, there were 40 basal cell carcinomas (BCCs), 33 squamous carcinomas and 23 sebaceous carcinoma, with P16 protein positive (nuclear staining) rates 70%, 54.6% and 56.5%, respectively. The P16 positive rate was negatively correlated with the degree of tumor histological differentiation, and the rate difference between the high differentiated carcinomas was significant (P<0.05). Positive Bcl-2 protein expression was detected in the cytoplasm. All 40 BCC cases were Bcl-2 positive, and nearly all of the tumor cells showed positive cytoplasmic expression, while in the 33 squamous cell carcinoma cases only one showed positive focal reaction, and the staining in the other 32 cases was relatively faint. None of the 23 sebaceous carcinomas expressed Bcl-2. Conclusions The expression of the P16 protein was related to the occurrence and degree of differentiation of malignant eyelid tumors. The overexpression of the Bcl-2 protein suggests that suppression of apoptosis might play a role in the tumorigenesis of BCC.

  6. FREQUENT DELETION OF MTS1/p16 GENE AND CORRELATION WITH CLINICOPATHOLOGICAL PARAMETERS IN ENDOMETRIAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    Zhou Chunxiao; Sun Jianheng; Lu Shixin; Jin Shunqian; Liu Hailing; Sheng Xiugui

    1998-01-01

    Objective:To investigate the possible relationship between deletion of MTS/p16 gene and progression of endometrial carcinoma. Methods: Forty-six primary endometrial carcinoma, 7 tumor-adjacent endometrial tissue, 10 normal endometrial tissue specimen and 5 xenografts from patients with endometrial carcinoma were examined for homozygous deletion of MTS/p16 gene by polymerase chain reaction-based analysis. Results: Of 46 endometrial cancer specimens, 9 showed homozygous deletion, no deletion was detected in the tumor-adjacent and normal endometial tissues. Nor was it detected in well-differentiated endometrial carcinoma and all xenografts. Conclusions: Deletion of MTS1/p16 gene might contribute to the progression of endometrial carcinoma and could be served as indicator for predicting prognosis.

  7. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

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    Schaefer, Inga-Marie; Wang, Yuexiang; Liang, Cher-wei; Bahri, Nacef; Quattrone, Anna; Doyle, Leona; Mariño-Enríquez, Adrian; Lauria, Alexandra; Zhu, Meijun; Debiec-Rychter, Maria; Grunewald, Susanne; Hechtman, Jaclyn F.; Dufresne, Armelle; Antonescu, Cristina R.; Beadling, Carol; Sicinska, Ewa T.; van de Rijn, Matt; Demetri, George D.; Ladanyi, Marc; Corless, Christopher L.; Heinrich, Michael C.; Raut, Chandrajit P.; Bauer, Sebastian; Fletcher, Jonathan A.

    2017-01-01

    KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs. PMID:28270683

  8. Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status.

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    Coordes, Annekatrin; Lenz, Klaus; Qian, Xu; Lenarz, Minoo; Kaufmann, Andreas M; Albers, Andreas E

    2016-08-01

    Data indicate a better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV and p16 detection are established markers for HPV-related HNSCC. Both are accepted as survival-independent predictors. Previous studies investigating the survival in HNSCC patients depending on HPV(+/-) and p16(+/-) status consistently found discordant results with p16(-)/HPV(+) and p16(+)/HPV(-). However, no meta-analysis regarding the survival according to combined HPV/p16 status has been performed yet. The objective of this study was to discriminate the impact of combined HPV(+/-) and p16(+/-) status on survival. Data sources were identification and review of publications assessing survival of the distinct subgroups with both p16 and HPV investigated in HNSCC until February, 2015. A meta-analysis was performed to classify survival and clinical outcomes. 18 out of 397 articles (4424 patients) were eligible for the meta-analysis. The percent proportion of the subgroups was 25 % for HPV(+)/p16(+), 61.2 % for HPV(-)/p16(-), 7.1 % for HPV(-)/p16(+) and 6.8 % for HPV(+)/P16(-). The meta-analysis showed a significantly improved 5-year overall survival (OS), 5-year disease-free survival and their corresponding hazard ratio for HPV(+)/p16(+) HNSCC in comparison to HPV(-)/p16(-), HPV(+)/p16(-) and HPV(-)/p16(+). The 5-year OS of the HPV(-)/p16(+) subgroup was intermediate while HPV(+)/p16(-) and HPV(-)/p16(-) HNSCC had the shortest survival. With current therapeutic strategies, survival of patients with HNSCC is better if associated with HPV(+)/p16(+) or HPV(-)/p16(+). Clinical trials are needed to confirm the distinct survival pattern and to investigate possible differences in survival for HPV(+)/p16(-) and HPV(-)/p16(+) HNSCC. To further differentiate p16(+) HNSCC, HPV testing may be advisable.

  9. Immunohistochemical expression of p16ink4a in inflammatory, preneoplastic and neoplastic cervical lesions

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    Gajanin Radoslav

    2015-01-01

    Full Text Available Introduction. High-risk human papilloma viruses play a main role in the development of cervical dysplasias and carcinomas. p16INK4a can be considered as a surrogate marker of active highrisk human papillomaviruses infection in dysplastic and neoplastic cells of the cervix. This study was aimed at determining the presence and level of p16INK4a expression in inflammatory, preneoplastic and neoplastic lesions of the cervix. Material and Methods. The study was performed on 109 samples of cervical biopsy. Cervical cancer was diagnosed in 36 patients, 34 patients had a preneoplastic change (dysplasia in stratified squamous cervix epithelium and a nonspecific inflammatory process was found in 39 patients. In all samples, immunohistochemical analysis using antibodies to p16INK4a was performed. Results. The expression of p16INK4a was verified in all cases of cervical cancer (100%, in 67.65% of dysplastic cervical lesions and in 38.5% of inflammatory lesions. A statistically highly significant difference was found in the presence and level of expression among neoplasic, dysplastic and inflammatory lesions of the cervix (χ² = 76.02, p < 0.001. The expression was more frequent and had a higher level in neoplastic and high grade dysplastic lesions compared to expression in inflammatory lesions and low grade dysplasias. Conclusion. The analysis of the presence of p16INK4a can differentiate non-neoplastic, high grade preneoplastic and neoplastic changes of the cervix. The use of p16INK4a in interpreting borderline lesions of the cervix can enable a rational therapeutic treatment of patients.

  10. Human Papillomavirus Infection and p16 Expression in Extragenital/Extraungual Bowen Disease in Immunocompromised Patients.

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    Švajdler, Marián; Mezencev, Roman; Kašpírková, Jana; Kacerovská, Denisa; Kazakov, Dmitry V; Ondič, Ondrej; Michal, Michal

    2016-10-01

    An increased rate of second nonmelanoma skin cancers is found in immunocompromised patients. Epidemiological and molecular data implicate ultraviolet radiation as the major risk factor. In addition, there is increasing evidence supporting the role of human papillomavirus (HPV) in the pathogenesis of premalignant and malignant skin lesions in both immunocompetent and immunocompromised patients. In a retrospective cross-sectional study, the authors examined the expression of p16 by immunohistochemistry and the presence of mucosal (α-genus) and cutaneous/epidermodysplasia verruciformis (β-genus) HPV DNA by polymerase chain reaction in 29 biopsy specimens of extragenital/extraungual Bowen disease (BD) from 24 Eastern European white immunocompromised patients. Furthermore, the author evaluated the association between the expression of p16 protein and the presence of HPV DNA. Among 25 specimens from 21 patients evaluable by polymerase chain reaction, HPV DNA was detected in 10 (40%) BD lesions from 9 patients. Beta-HPV predominated over alpha-HPV types. Among 29 immunohistochemically evaluable BD specimens, 22 lesions (∼76%) from 20 patients were scored as p16 positive. HPV DNA-positive and HPV DNA-negative lesions displayed the same proportion of p16 positivity (80%) and no correlation was found between the HPV DNA presence and the p16 expression status. Our pilot study demonstrated that β-HPV infections predominate in BD cases diagnosed among immunocompromised patients, although high- and low-risk mucosal (alpha) HPV genotypes may be detected in a minority of cases. In contrast to anogenital HPV-associated lesions, positive p16 expression is not a reliable marker of high-risk α-HPV infection in BD cases, as it can be also detected in β-HPV infected and HPV-negative cases.

  11. HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil.

    Science.gov (United States)

    Freitas, V G; Focchi, G R; Pereira, E R; Levi, J E; Speck, N M G; Ribalta, J C

    2016-09-16

    The association between high-risk human papillomavirus (HPV) genotypes and p16 expression in indigenous women from the Xingu Indigenous Park, Brazil, was unknown. This study evaluated p16 expression in women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) 3 or higher and correlated this expression with HPV genotypes to determine possible discrepancies in the expression of this marker. We evaluated 37 previously collected samples with different HPV genotypes and high-grade lesions diagnosed based on cytology, histology, and colposcopy. Immunohistochemical analysis was performed using paraffin-embedded tissue sections and the CINtec® Histology Kit. p16 protein expression was investigated by immunostaining with an anti-p16 antibody. HPV genotyping was performed by reverse hybridization. The age of the study population ranged from 22-75 years (43.81 ± 15.89 years) and parity ranged from 1-11 (5.92 ± 2.58). Thirteen different HPV genotypes were found using the INNO-LiPA kit. Single and multiple infections by HPV were found with prevalence of single infections (P = 0.029). Comparison between HPV genotype and simple or multiple infections was highly significant; it was observed more HPV 52 followed by HPV 16 in single infections (P p16 expression was predominantly diffuse, which was observed in 91.7% of lesions, whereas 8.3% were focal (P p16 expression in high-grade CIN was not influenced by the viral genotype; however, more studies are necessary to further our understanding of this restricted group.

  12. Decadal Changes in DIC Along P16 in the Pacific Ocean

    Science.gov (United States)

    Peng, T.

    2008-12-01

    As a result of CLIVAR CO2 Repeat Hydrographic program, P16S was reoccupied in 2005, and P16N in 2006. The P16 is a WOCE cruise line along longitude 150°W in the Pacific Ocean. The section selected for this analysis in the North Pacific includes data collected between Hawaii and Kodiak Island. In the South Pacific, only stations along 150°W occupied during 1991 as P16S and during 1992 as P16A are selected. These are stations that were reoccupied in 2005 as Repeat Hydro P16S. The DIC values are normalized to salinity of 35 after correction for AOU. Comparisons of these DIC values are made along isopycnal surfaces. The DIC increases vary in each isopycnal horizon, with 2.4 µmol/kg along 27.2 isopycnal, and 18.0 µmol/kg along 26.4 isopycnal. With the estimated thickness of isopycnal horizons between 15°N and 45°N, we obtained a mean DIC inventory change of 0.58 µmol/kg/yr in the North Pacifc between 1991 and 2006 (or 0.50 mol/m2/yr). For the South Pacific, DIC increase is apparently faster than that in the North Pacific. We have seen significant DIC increases along each isopycnal horizons, on the order of 20 µmol/kg for isopycnals 26.0 to 27.2. Based on the estimated thickness of isopycnal layers between 15°S and 40°S, the mean DIC inventory change is estimated to be 1.61 µmol/kg/yr from 1991 to 2005, which is equivalent to 1.57 mol/m2/yr.

  13. HYPERMETHYLATION STATUS OF E-CADHERIN AND p16INK4a IN GASTROINTESTINAL STROMAL TUMOR

    Institute of Scientific and Technical Information of China (English)

    LIANG Jian-fang

    2006-01-01

    Objective: To investigate the methylation status of CpG island in E-cadherin(CDH1), P16INK4a(P16)promoter region ,and to analyze their role in gastrointestinal stromal tumor (GISTs). Methods: A total of 56 surgically resected GISTs were obtained from January 2003 to December 2005. The routine H&E-stained sections and CD117, CD34-immunoreactions were reviewed to verify the morphologic diagnosis. Methylation status of the CDH1, P16INK4a promoter region was analyzed by methylation specific polymerase chain reaction (MSP) from chemically modified DNA after Na-bisulfite treatment. Results: The frequency of CDH1gene methylation was 32% (18 of 56) in GISTs. The rate was 9% (1 of 11), 21% (4 of 19), 41.6% (5 of 12), and 57% (8 of 14) for very low risk, low risk, intermediate risk, and high risk GISTs; P16INK4a methylation was found in 19 of 56(34%) cases. The rate was 0% (0 of 11), 16% (3 of 19), 50% (6 of 12), and 71% (10 of 14) for very low risk, low risk, intermediate risk, and high risk GISTs. Statistical analysis indicated that of the 56 cases, there was significant association of CDH1 and/or P16INK4a methylation status with tumor malignant behavior (methylation rate 23/56, 41%, P<0.01) and site (P<0.05). Conclusion: E-cadherin (CDH1) and/or P16INK4a promoter hypermethylation is strongly associated with risk grade, may be a useful biomarker for GISTs risk assessment, and may shed light on new therapeutic options to treat GISTs

  14. New measurements and phase shift analysis of p16O elastic scattering at astrophysical energies

    Science.gov (United States)

    Dubovichenko, Sergey; Burtebayev, Nassurlla; Dzhazairov-Kakhramanov, Albert; Zazulin, Denis; Kerimkulov, Zhambul; Nassurlla, Marzhan; Omarov, Chingis; Tkachenko, Alesya; Shmygaleva, Tatyana; Kliczewski, Stanislaw; Sadykov, Turlan

    2017-01-01

    The results of new experimental measurements of p16O elastic scattering in the energy range of 0.6-1.0 MeV at angles of 40°-160° are given. Phase shift analysis of p16O elastic scattering was made using these and other experimental data on differential cross sections in excitation functions and angular distributions at energies of up to 2.5 MeV. Supported by the Ministry of Education and Science of the Republic of Kazakhstan (0073/PCF-IS-MES)

  15. Expression and function of P16 in a rat model of oxygen-induced retinopathy

    Directory of Open Access Journals (Sweden)

    You Li

    2017-02-01

    Full Text Available AIM: To investigate the effect of p16 protein expression on the proliferation of retinal neovascularization in oxygen-induced retinopathy(OIR.METHODS: Totally 60 SD rats aged 7d were randomly divided into 4 groups: normal group, model group, intervention group and NS control group. Normal group was raised in a normal air feeding; model group at 75% high oxygen for 5d to establish the model of oxygen induced retinopathy; intervention group was given anti p16 methylation drug 5-aza-CdR(0.25 mg/kgintraperitoneal injection; NS control group was given the same volume NS intraperitoneal injection. The eyes were taken from each group and the left eyes were removed for observation of retinal neovascularization by HE staining, and immunohistochemistry and immunofluorescence were taken for observations of p16 protein expression. Right retina had been performed real time-PCR to analysis p16mRNA expression. RESULTS: The normal group were not found retinal neovascularization breaking through internal limiting mebrane. In model group and NS control group, the retinal tissue was obviously thickened, and a large number of new blood vessels were found. In the intervention group, a small amount of new blood vessels were found in the retina. The expression of p16 was low in the model group, the positive cell number was 19.52±2.67, and the number of the positive cells was 36.38±3.16 in the intervention group, the difference was statistically significant(P-△△ct=0.14±0.01, the expression of p16 mRNA in the intervention group rats retina was significantly higher than that of NS control group rat retina, there was significant difference between two groups(2-△△ct=0.68±0.08, PCONCLUSION: The abnormal expression of P16 may be closely related to the proliferation of retinal neovascularization. Inhibition of p16 methylation can decrease the proliferation of retinal neovascularization.

  16. Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation.

    OpenAIRE

    Nakao, Y.; Yang, X.; Yokoyama, M; Ferenczy, A.; Tang, S. C.; Pater, M M; Pater, A

    1997-01-01

    The p16 (MTS1) tumour-suppressor gene is a cyclin-dependent kinase (cdk) inhibitor that decelerates the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma tumour-suppressor gene (Rb) protein (pRb). In cervical cancers, pRb is inactivated by the HPV E7 oncoprotein or by mutations. The hypothesis of earlier reports was that the disruption of the p16/cdk-cyclin/Rb cascade is essential for malignant cervical transformation/carcinogenesis. We previously established in vitro ...

  17. Melanoma MAPK pathway proteins and associated tumour suppressors: p16 is an independent prognostic biomarker by tissue microarrays

    DEFF Research Database (Denmark)

    Lade-Keller, Johanne; Guldberg, Per; Hamilton-Dutoit, Stephen Jacques

    2013-01-01

    Melanoma MAPK pathway proteins and associated tumour suppressors: p16 is an independent prognostic biomarker by tissue microarrays......Melanoma MAPK pathway proteins and associated tumour suppressors: p16 is an independent prognostic biomarker by tissue microarrays...

  18. EFFECTS OF p16INK4 GENE ON CHEMOSENSITIVITY OF HUMAN GLIOMA U251 CELL LINE TO TENIPOSIDE

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To determine the effects on the cell growth, tumorigenicity and chemosensitivity of p16/CDK4I in human glioma. Methods: p16 gene was transfected into U251 cells by lipofectin. Expression of exogenous p16 gene was confirmed by immunohistochemistry and Northern blot. The effects of exogenous p16 gene on the growth and chemosensitivity to teniposide were examined. Results: Expression of exogenous p16 gene inhibited the growth dramatically in vitro. G1 arrest of tumor cells was observed. However, wt p16-positive U251 was less sensitive than control cell lines and the number of apoptotic cells after chemotherapy was reduced. Conclusion: The expression of exogenous p16 gene could inhibit the growth of glioma. On the other hand, the chemosensitivity to teniposide of p16-positive U251 was decreased.

  19. p16 controls epithelial cell growth and suppresses carcinogenesis through mechanisms that do not require RB1 function

    Science.gov (United States)

    Sen, M; Akeno, N; Reece, A; Miller, A L; Simpson, D S; Wikenheiser-Brokamp, K A

    2017-01-01

    The p16/RB1 tumor suppressor pathway is inactivated in the vast majority, if not all, human cancers. The current paradigm is that p16 and RB1 function in a linear pathway to suppress tumorigenesis; however p16 is preferentially lost in human cancers suggesting that p16 has critical tumor suppressive functions not mediated through RB1. Carcinomas arise from transformed epithelial cells and account for 80% of adult malignancies highlighting the need to understand p16/RB1 pathway function in organ epithelia. Lung cancer is the leading cause of cancer deaths and is associated with p16/RB1 pathway deregulation. We demonstrate that p16 is upregulated in the lung epithelium after Rb1 ablation in genetically engineered mouse models. In contrast to fibroblasts, loss of RB1 family proteins, p107 or p130, did not result in p16 induction, demonstrating that p16 suppression is a unique RB1 pocket protein function in the lung epithelium in vivo. p16 upregulation did not induce cellular senescence but rather promoted survival of RB1-deficient lung epithelial progenitor cells. Mechanistic studies show that p16 protects RB1-deficient cells from DNA damage. Consequently, additional loss of p16 led to genetic instability and increased susceptibility to cellular immortalization and transformation. Mice with combined RB1/p16-deficient lungs developed lung tumors including aggressive metastatic lung cancers. These studies identify p16 loss as a molecular event that causes genetic instability and directly demonstrate that p16 protects against DNA damage in the absence of RB1 function providing an explanation for why p16 is preferentially targeted in human cancers. PMID:28414317

  20. Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb-independent pathway

    Science.gov (United States)

    Li, Chelsea; Liu, Tong; Rutter, Jared; Grossman, Douglas

    2017-01-01

    The tumor suppressor p16INK4A (p16) inhibits cell cycle progression through the CDK4/Rb pathway. We have previously shown that p16 regulates cellular oxidative stress, independent of its role in cell cycle control. We investigated whether loss of p16 had a direct impact on the mitochondria. We found that p16-null primary mouse fibroblasts (PMFs) displayed increased mitochondrial mass and expression of mitochondrial respiratory subunit proteins compared to wild-type (WT) PMFs. These findings in p16-null PMFs were associated with increased expression of the mitochondrial biogenesis transcription factors PRC and TFAM. On the other hand, p16-deficient PMFs demonstrated reduced mitochondrial respiration capacity consistent with electron microscopy findings showing that mitochondria in p16-deficient PMFs have abnormal morphology. Consistent with increased mitochondrial mass and reduced respiratory capacity, p16-deficient PMFs generated increased mitochondrial superoxide. One biological consequence of elevated ROS in p16-deficient PMFs was enhanced migration, which was reduced by the ROS scavenger N-acetylcysteine. Finally, p16-deficient PMFs displayed increased mitochondrial membrane potential, which was also required for their enhanced migration. The mitochondrial and migration phenotype was restored in p16-deficient PMFs by forced expression of p16. Similarly, over-expression of p16 in human melanocytes and A375 melanoma cells led to decreased expression of some mitochondrial respiratory proteins, enhanced respiration, and decreased migration. Inhibition of Rb phosphorylation in melanocytes and melanoma cells, either by addition of chemical CDK4 inhibitors or RNAi-mediated knockdown of CDK4, did not mimic the effects of p16 loss. These results suggest that p16 regulates mitochondrial biogenesis and function, which is independent of the canonical CDK4/Rb pathway. PMID:28915557

  1. Relationship between HPV infection/p16 expression and radiotherapy prognosis in oropharyngeal squamous cell carcinoma%口咽鳞癌HPV感染与p16表达及放疗预后相关性研究

    Institute of Scientific and Technical Information of China (English)

    曲媛; 高黎; 易俊林; 黄晓东; 罗京伟; 张世平; 王凯; 徐国镇

    2014-01-01

    Objective To investigate the relationship between human papillomavirus (HPV) infection/p16 expression and radiotherapy prognosis in oropharyngeal squamous cell carcinoma (OSCC) and the prognostic value of p16 in OSCC patients treated with radiotherapy.Methods Tissue samples were collected from 42 patients newly diagnosed with OSCC in our hospital from January 1999 to December 2008.PCR was performed to detect HPV DNA,and p16 expression was measured by immunohistochemistry.The chi-square test was used to compare the local/regional control rate (CR) between HPV (+)/p16 (+) patients and HPV (-)/p16 (-) patients after radical radiotherapy and evaluate the association between HPV infection and p16 expression; the Kaplan-Meier method was used to calculate overall survival (OS),and the log-rank test was used for survival difference analysis.Results The follow-up rate was 100%.The HPV infection rate was 19%,and the positive rate of p16 was 43%.In patients who received radical radiotherapy,the local CR for HPV (+) patients was 100%,versus 54% for HPV (-) patients (P =0.026) ;the local CR for p16(+) patients was 92%,versus 44% for p16(-) patients (P =0.006) ;the locoregional CR for p16(+) patients was 69%,versus 22% for p16(-) patients (P =0.009).For high-risk patients,HPV infection was significantly associated with p16 expression (P =0.000).The 3-year OS rates for p16(+) and p16 (-) patients were 9 1% and 2 6 %,respectively (P =0.001).Conclusions The p16 expression is closely associated with HPV infection in OSCC patients,and it is expected to become one of the prognostic markers in OSCC patients treated with radiotherapy.%目的 探讨口咽鳞癌HPV感染与p16表达及放疗预后相关性,以及p16是否有预测放疗预后的价值.方法 对1999-2008年间本院42例初治口咽鳞癌组织标本采用PCR检测HPV-DNA,采用免疫组织化学法检测p16表达情况.对HPV、p16不同状态肿瘤根治性放疗后局部区域CR及HPV感染与p16

  2. The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence.

    Science.gov (United States)

    Lu, Yang; Ma, Wenlong; Li, Zhongwei; Lu, Jun; Wang, Xiuli

    2017-01-25

    Cyclin-dependent kinase inhibitor p16(INK4a) (p16) primarily functions as a negative regulator of the retinoblastoma protein (Rb) -E2F pathway, thus plays critical role in cell cycle progression, cellular senescence and apoptosis. In this study, we showed that the methylation of Arg 138 and the phosphorylation of Ser 140 on p16 were critical for the control of cell proliferation and apoptosis. Compared to wild type p16, mutant p16R138K possessed improved function in preventing cell proliferation and inducing apoptosis, while the Ser 140 mutation (p16S140A) exhibited the opposite alteration. We also demonstrated that H2O2 was able to induce the phosphorylation of p16, which facilitated the interaction between CDK4 (Cyclin-dependent protein kinase) and p16, in 293T (human emborynic kidney) cells. Furthermore, the elevated arginine methylation in p16S140A mutant and increased serine phosphorylation in p16R138K mutant suggest that a antagonizing mechanism coordinating Arg 138 methylation and Ser 140 phosphorylation to regulates p16 function as well as cellular apoptosis and senescence. These findings will therefore contribute to therapeutic treatment for p16-related gene therapy by providing theoretical and experimental evidence.

  3. French Frigate Shoals Site P16 9/14/2001 45-46M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 45 and 46 meters along a permanent transect.

  4. Arsenic exposure is associated with DNA hypermethylation of the tumor suppressor gene p16.

    Science.gov (United States)

    Lu, Guangming; Xu, Huiwen; Chang, De; Wu, Zhenglai; Yao, Xiaoyuan; Zhang, Shiying; Li, Zhenlong; Bai, Jieben; Cai, Qing; Zhang, Wen

    2014-01-01

    Occupational and environmental exposure to inorganic arsenic leads to development of cancer and represents a significant health hazard in more than 70 countries. The underlying mechanism for arsenic-induced carcinogenesis remains unclear. Laboratory studies suggest that arsenic is a poor mutagen but may cause epigenetic silencing of key tumor suppressor genes such as p16 through DNA hypermethylation. However, the evidence for an association between human arsenic exposure and abnormal DNA methylation of tumor suppressor genes is lacking. Paired case-control studies were conducted involving 40 individuals with high arsenic exposure and arsenicosis, 40 individuals with similarly high exposure to arsenic but without arsenicosis, and 40 individuals with normal exposure to arsenic. DNA methylation status of p16 was determined using methylation-specific PCR. Conditional logistic regression analysis showed that DNA hypermethylation of p16 gene was significantly associated with high arsenic exposure (Odds Ratio = 10.0, P = 0.0019) independently of the development of arsenicosis (Odds Ratio = 2.0, P = 0.1343). High exposure of arsenic in human is positively linked to DNA hypermethylation of p16 gene, suggesting that epigenetic silencing of key tumor suppressor may be an important mechanism by which arsenic promotes cancer initiation.

  5. p16(INK4a prevents centrosome dysfunction and genomic instability in primary cells.

    Directory of Open Access Journals (Sweden)

    Kimberly M McDermott

    2006-03-01

    Full Text Available Aneuploidy, frequently observed in premalignant lesions, disrupts gene dosage and contributes to neoplastic progression. Theodor Boveri hypothesized nearly 100 years ago that aneuploidy was due to an increase in centrosome number (multipolar mitoses and the resultant abnormal segregation of chromosomes. We performed immunocytochemistry, quantitative immunofluorescence, karyotypic analysis, and time-lapse microscopy on primary human diploid epithelial cells and fibroblasts to better understand the mechanism involved in the production of supernumerary centrosomes (more than two microtubule nucleating bodies to directly demonstrate that the presence of supernumerary centrosomes in genomically intact cells generates aneuploid daughter cells. We show that loss of p16(INK4a generates supernumerary centrosomes through centriole pair splitting. Generation of supernumerary centrosomes in human diploid epithelial cells was shown to nucleate multipolar spindles and directly drive production of aneuploid daughter cells as a result of unequal segregation of the genomic material during mitosis. Finally, we demonstrate that p16(INK4a cooperates with p21 through regulation of cyclin-dependent kinase activity to prevent centriole pair splitting. Cells with loss of p16(INK4a activity have been found in vivo in histologically normal mammary tissue from a substantial fraction of healthy, disease-free women. Demonstration of centrosome dysfunction in cells due to loss of p16(INK4a suggests that, under the appropriate conditions, these cells can become aneuploid. Gain or loss of genomic material (aneuploidy may provide the necessary proproliferation and antiapoptotic mechanisms needed for the earliest stages of tumorigenesis.

  6. Midway Atoll Site P16 12/3/2002 26-27M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 26 and 27 meters along a permanent transect.

  7. French Frigate Shoals Site P16 10/4/2002 40-41M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 40 and 41 meters along a permanent transect.

  8. French Frigate Shoals Site P16 10/4/2002 38-39M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 38 and 39 meters along a permanent transect.

  9. French Frigate Shoals Site P16 10/4/2002 14-15M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 14 and 15 meters along a permanent transect.

  10. Midway Atoll Site P16 12/3/2002 1-2M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 1 and 2 meters along a permanent transect.

  11. French Frigate Shoals Site P16 10/4/2002 23-24M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 23 and 24 meters along a permanent transect.

  12. Midway Atoll Site P16 12/3/2002 45-46M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 45 and 46 meters along a permanent transect.

  13. French Frigate Shoals Site P16 9/14/2001 8-9M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 8 and 9 meters along a permanent transect.

  14. French Frigate Shoals Site P16 9/14/2001 6-7M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 6 and 7 meters along a permanent transect.

  15. French Frigate Shoals Site P16 10/4/2002 37-38M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 37 and 38 meters along a permanent transect.

  16. French Frigate Shoals Site P16 10/4/2002 13-14M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 13 and 14 meters along a permanent transect.

  17. French Frigate Shoals Site P16 9/14/2001 31-32M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 31 and 32 meters along a permanent transect.

  18. French Frigate Shoals Site P16 9/14/2001 23-24M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 23 and 24 meters along a permanent transect.

  19. French Frigate Shoals Site P16 9/14/2001 18-19M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 18 and 19 meters along a permanent transect.

  20. French Frigate Shoals Site P16 9/14/2001 48-49M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 48 and 49 meters along a permanent transect.

  1. French Frigate Shoals Site P16 10/4/2002 11-12M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 11 and 12 meters along a permanent transect.

  2. French Frigate Shoals Site P16 10/4/2002 24-25M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 24 and 25 meters along a permanent transect.

  3. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology

    DEFF Research Database (Denmark)

    Ikenberg, Hans; Bergeron, Christine; Schmidt, Dietmar

    2013-01-01

    Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections...

  4. Expression of P16 in NUT carcinomas with no association with human papillomavirus (HPV).

    Science.gov (United States)

    Salles, Paulo Guilherme de Oliveira; Moura, Rafael de Deus; Menezes, Letícia M; Bacchi, Carlos E

    2014-04-01

    NUT carcinoma (NC) is a rare malignant neoplasm usually located in the midline, including the upper aerodigestive tract. NC is an aggressive and highly lethal type of carcinoma. It is defined by the rearrangement of the nuclear protein in the testis (NUT) gene on chromosome 15q14. In most cases, the NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4-NUT fusion gene. The relationship between the human papillomavirus (HPV), p16, and upper aerodigestive tract cancer has been long postulated. In this study, we evaluated the relationship of the p16 expression in 4 cases of NCs and its eventual association with HPV. All 4 cases presented typical histopathologic findings with nuclear positivity of the NUT protein and strong expression for p16. None of these cases, however, showed an association with HPV evaluated by polymerase chain reaction. Despite the expression of p16, this negative result for HPV indicates that HPV infection probably does not play a role in the pathogenesis of NC.

  5. Midway Atoll Site P16 12/3/2002 33-34M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 33 and 34 meters along a permanent transect.

  6. Third-Generation Partnerships for P-16 Pipelines and Cradle-through-Career Education Systems

    Science.gov (United States)

    Lawson, Hal A.

    2013-01-01

    Amid unprecedented novelty, complexity, turbulence, and conflict, it is apparent that a new education system is needed. Focused on a new outcome--postsecondary education completion with advanced competence--heretofore separate systems for early childhood, K-12 schools, and postsecondary education are being joined in P-16 pipelines and…

  7. French Frigate Shoals Site P16 9/14/2001 28-29M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 28 and 29 meters along a permanent transect.

  8. French Frigate Shoals Site P16 10/4/2002 18-19M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 18 and 19 meters along a permanent transect.

  9. French Frigate Shoals Site P16 10/4/2002 9-10M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 9 and 10 meters along a permanent transect.

  10. French Frigate Shoals Site P16 9/14/2001 2-3M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 2 and 3 meters along a permanent transect.

  11. French Frigate Shoals Site P16 10/4/2002 6-7M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 6 and 7 meters along a permanent transect.

  12. French Frigate Shoals Site P16 10/4/2002 30-31M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 30 and 31 meters along a permanent transect.

  13. French Frigate Shoals Site P16 10/4/2002 1-2M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 1 and 2 meters along a permanent transect.

  14. French Frigate Shoals Site P16 10/4/2002 12-13M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 12 and 13 meters along a permanent transect.

  15. French Frigate Shoals Site P16 9/14/2001 4-5M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 4 and 5 meters along a permanent transect.

  16. French Frigate Shoals Site P16 10/4/2002 4-5M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 4 and 5 meters along a permanent transect.

  17. French Frigate Shoals Site P16 9/14/2001 42-43M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 42 and 43 meters along a permanent transect.

  18. French Frigate Shoals Site P16 9/14/2001 47-48M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 47 and 48 meters along a permanent transect.

  19. French Frigate Shoals Site P16 9/14/2001 10-11M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 10 and 11 meters along a permanent transect.

  20. Midway Atoll Site P16 12/3/2002 32-33M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 32 and 33 meters along a permanent transect.

  1. French Frigate Shoals Site P16 9/14/2001 33-34M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 33 and 34 meters along a permanent transect.

  2. French Frigate Shoals Site P16 9/14/2001 22-23M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 22 and 23 meters along a permanent transect.

  3. French Frigate Shoals Site P16 9/14/2001 27-28M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 27 and 28 meters along a permanent transect.

  4. French Frigate Shoals Site P16 9/14/2001 38-39M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 38 and 39 meters along a permanent transect.

  5. French Frigate Shoals Site P16 10/4/2002 10-11M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at French Frigate Shoals, site P16 (23.857 N, 166.271 W), between 10 and 11 meters along a permanent transect.

  6. Midway Atoll Site P16 12/3/2002 41-42M

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P16 (28.277 N, 177.368 W), between 41 and 42 meters along a permanent transect.

  7. Immunochemical assessment of p16 and HPV L1 capsid protein in cervical squamous intraepithelial lesions.

    Science.gov (United States)

    Balan, Raluca; Giuşcă, Simona; Căruntu, Irina Draga; Gheorghiţă, V; Neacşu, D; Amălinei, Cornelia

    2010-01-01

    The behavior of the cervical squamous intraepithelial lesions cannot be predicted, many of them, particularly of the low grade type, may disappear without treatment. Invasive cervical carcinoma occurs in approximately 10% of the intraepithelial precursor lesions, being strongly associated with HPV infection. The aim of this study was to make a comparative assessment between immunohistochemical and immunocytochemical expression of p16 and L1 HPV capsid protein respectively, in low grade and high grade cervical squamous intraepithelial lesions. The study involved 20 patients with cytological diagnosis of LSIL/CIN1 (low grade squamous intraepithelial lesion/cervical intraepithelial neoplasia) and HSIL (CIN2 and CIN3) (high grade squamous intraepithelial lesion), which underwent a subsequent cervical biopsy. The conventional smears were evaluated for the immunoexpression of L1HPV protein and the corresponding biopsies for the immunoexpression of p16. The HPV L1 capsid protein was expressed in 46% of LSIL and 24% of HSIL. P16 was positive in 68% of LSIL, 84% of CIN2 and 100% of CIN3. The correlative analysis of p16 status and protein L1HPV expression can be very useful in the assessment of progression risk of cervical squamous intraepithelial lesions.

  8. EXPRESSION OF p16, CYCLIN D1 AND RB PROTEIN IN GASTRIC CARCINOMA AND PREMALIGNANT LESIONS

    Institute of Scientific and Technical Information of China (English)

    缪林; 赵志泉; 季国忠; 范志宁; 金宁; 刘政; 张平; 程铁华

    2003-01-01

    Objective: To investigate the expression of p16, cyclin D1 and Rb protein in gastric carcinoma and premalignant lesions including dysplastic gastric mucosa and intestinal metaplasia gastric mucosa. Methods: Using SP immunohistochemical methods, the expression of pl6, cyclin D1 and Rb proteins was detected in 10 specimens of normal gastric mucosa, 15 specimens of dysplastic gastric mucosa, 15 specimens of intestinal metaplasia gastric mucosa, 30 specimens of gastric carcinoma. The clinical characteristics of the 30 patients with gastric carcinoma were analysed to explore the relationship between the parameter detected and biological action of gastric cancer. Results: Expression of p16 protein was detected in 90% of normal gastric mucosa, 86.67% of dysplastic gastric mucosa, 86.67% of intestinal metaplasia gastric mucosa, 36.67% of gastric carcinoma. The positive rate of p16 protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.01). Expression of cyclin D1 protein was detected in 10% of normal gastric mucosa, 20% of dysplastic gastric mucosa, 20% of intestinal metaplasia gastric mucosa, 53.33% of gastric carcinoma. The positive rate of cyclin D1, protein expression in gastric carcinoma is significantly higher than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.05). Expression of Rb protein was detected in 90% of normal gastric mucosa, 80% of dysplastic gastric mucosa, 80% of intestinal metaplasia gastric mucosa, 50% of gastric carcinoma. The positive rate of Rb protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa (P<0.05). The expression of p16, cyclin D1 gene were associated with the degree of differentiation of gastric carcinoma, lymphnodes metastasis and distant metastasis. Conclusion: p16, Cyclin D1 and Rb gene play important role in gastric carcinoma genesis. The expression of p16, cyclin D1 and Rb gene

  9. Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients.

    Science.gov (United States)

    Erdem, Beril; Küçükyıldırım, Sibel; Sağlar, Emel; Polat, Zülfikar; Mergen, Hatice

    2014-10-01

    Cancer is a consequence of the disruption of cellular regulation. Epigenetic is one of the reasons of this disruption. Epigenetic factors play a role in the carcinogenesis by affecting proto-oncogenes and tumor suppressor genes and it is one of the most popular research areas in recent years. DNA methylation, which is an epigenetic mechanism, occurs in the early stages of tumorigenesis. Promoter methylation which causes the silence of tumor suppressor genes have been studied extensively in various tumor types. The aim of this study was to investigate promoter methylation of certain tumor suppressor genes, Cyclin-dependent kinase inhibitor 2A (p16) and Adenomatous polyposis coli (APC), which take part in gastrointestinal tumorigenesis. To detect the promoter methylation of p16 and APC genes, tissue samples from 20 gastrointestinal cancer patients and peripheral blood samples from 15 healthy individuals were collected for Methylation-Specific Polymerase Chain Reaction (MSP) analysis. According to the statistical analysis, in tumor tissue, positive methylation ratio of p16 and APC genes was found respectively 30% (6/20) and 50% (10/20). The difference of promoter methylation of these genes between tumor tissues and control group was significantly observed (p=0.02 and 0.001, respectively). An alteration of promoter methylation of APC gene according to tumor localization was found (p=0.007), but there was no significant difference observed in p16. In our study, promoter methylation which was considered to be occurred as an early event in gastrointestinal carcinogenesis was observed in p16 and APC genes.

  10. CREG1 enhances p16(INK4a) -induced cellular senescence.

    Science.gov (United States)

    Moolmuang, Benchamart; Tainsky, Michael A

    2011-02-01

    Cellular senescence is an irreversible growth arrest that is activated in normal cells upon shortening of telomere and other cellular stresses. Bypassing cellular senescence is a necessary step for cells to become immortal during oncogenic transformation. During the spontaneous immortalization of Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes 1) expression was decreased during immortalization and increased in senescence. Moreover, we found that repression of CREG1 expression occurs via an epigenetic mechanism, promoter DNA methylation. Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines, cancers commonly seen in Li-Fraumeni Syndrome. In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16 (INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition. In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16 (INK4a) -induced senescence by transcriptional repression of cell cycle-regulated genes.

  11. Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts.

    Science.gov (United States)

    Ding, Ye; Chen, Jie; Okon, Imoh Sunday; Zou, Ming-Hui; Song, Ping

    2016-02-01

    Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, delays aging process. However, the molecular mechanisms by which AMPKα isoform regulates cellular senescence remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to the accelerated cell senescence by inducing p16(INK4A) (p16) expression thereby arresting cell cycle. The markers of cellular senescence, cell cycle proteins, and reactive oxygen species (ROS) were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1(-/-), AMPKα2(-/-)) mice by Western blot and cellular immunofluorescence staining, as well as immunohistochemistry (IHC) in skin tissue of young and aged mice. Deletion of AMPKα2, the minor isoform of AMPKα, but not AMPKα1 in high-passaged MEFs led to spontaneous cell senescence demonstrated by accumulation of senescence-associated-β-galactosidase (SA-β-gal) staining and foci formation of heterochromatin protein 1 homolog gamma (HP1γ). It was shown here that AMPKα2 deletion upregulates cyclin-dependent kinase (CDK) inhibitor, p16, which arrests cell cycle. Furthermore, AMPKα2 null cells exhibited elevated ROS production. Interestingly, knockdown of HMG box-containing protein 1 (HBP1) partially blocked the cellular senescence of AMPKα2-deleted MEFs via the reduction of p16. Finally, dermal cells senescence, including fibroblasts senescence evidenced by the staining of p16, HBP1, and Ki-67, in the skin of aged AMPKα2(-/-) mice was enhanced when compared with that in wild type mice. Taken together, our results suggest that AMPKα2 isoform plays a fundamental role in anti-oxidant stress and anti-senescence.

  12. Co-expression of p16 and p53 characterizes aggressive subtypes of ductal intraepithelial neoplasia.

    Science.gov (United States)

    Bechert, Charles; Kim, Jee-Yeon; Tramm, Trine; Tavassoli, Fattaneh A

    2016-12-01

    In the USA alone, approximately 61,000 new diagnoses of ductal intraepithelial neoplasia 1c-3 (DIN) are made each year. Around 10-20 % of the patients develop a recurrence, about 50 % of which are invasive. Prior studies have shown that invasive breast carcinomas positive for p16 or p53 have a higher frequency of recurrence and a more aggressive course; however, the co-expression of these markers across the entire spectrum of DIN and its potential correlation with grade of the lesions has not been studied previously. Immunohistochemical staining for p16 and p53 was evaluated on 262 DIN lesions from 211 cases diagnosed between 1991 and 2008. The lesions ranged from DIN1b (atypical intraductal hyperplasia) to DIN3 (DCIS, grade 3) and included 45 cases with associated invasive carcinoma. Frequency of staining for both p16 and p53 increased with increasing grade of DIN. Strong co-expression was found exclusively in higher grade DIN lesions (DIN2 and DIN3) particularly those associated with periductal stromal fibrosis and lymphocytic infiltrate. Strong co-expression was seen in 8 of 12 DIN3 lesions (67 %) associated with invasive carcinoma. In conclusion, co-expression of p16 and p53 increases with advancing grade of DIN and is maximal in high grade DIN lesions associated with invasive carcinoma, indicating a more aggressive phenotype. A distinctive variant of DIN with periductal fibrosis and lymphocytic infiltrate invariably falls into the high-grade category, based on either morphology or marker expression. Co-expression of p16/p53 may be of help in distinguishing between high-grade and low-grade DIN lesions.

  13. The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence

    OpenAIRE

    Lu, Yang; Ma, Wenlong; Li, Zhongwei; Lu, Jun; Wang, Xiuli

    2017-01-01

    Cyclin-dependent kinase inhibitor p16INK4a (p16) primarily functions as a negative regulator of the retinoblastoma protein (Rb) -E2F pathway, thus plays critical role in cell cycle progression, cellular senescence and apoptosis. In this study, we showed that the methylation of Arg 138 and the phosphorylation of Ser 140 on p16 were critical for the control of cell proliferation and apoptosis. Compared to wild type p16, mutant p16R138K possessed improved function in preventing cell proliferatio...

  14. Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki-67 in epithelial cells.

    Science.gov (United States)

    Reuschenbach, Miriam; Seiz, Mirjam; von Knebel Doeberitz, Christina; Vinokurova, Svetlana; Duwe, Alexander; Ridder, Ruediger; Sartor, Heike; Kommoss, Friedrich; Schmidt, Dietmar; von Knebel Doeberitz, Magnus

    2012-01-15

    Diffuse overexpression of p16(INK4a) in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus-mediated transformation. Focal p16(INK4a) expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16(INK4a) triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16(INK4a) , i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16(INK4a) -positive cells in epithelia displaying focal p16(INK4a) expression pattern do not coexpress proliferation-associated Ki-67 protein, while p16(INK4a) -positive cells in lesions with diffuse p16(INK4a) expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16(INK4a) and Ki-67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16(INK4a) , and in all of these lesions p16(INK4a) -positive cells were found to be negative for Ki-67 expression. Diffuse expression of p16(INK4a) was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki-67 immunoreactivity in a large proportion of p16(INK4a) -positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16(INK4a) and Ki-67. Coexpression of Ki-67 and p16(INK4a) in the same cell is entirely restricted to cervical lesions displaying diffuse p16(INK4a) expression, whereas in lesions with focal p16(INK4a) expression, p16(INK4a) -expressing cells are negative for Ki-67. Thus, diffuse expression of p16(INK4a) reflects lesions with proliferation-competent cells, while p16(INK4a) -expressing cells associated with focal expression patterns are cell cycle arrested.

  15. p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer.

    Science.gov (United States)

    Lebok, Patrick; Roming, Magdalena; Kluth, Martina; Koop, Christina; Özden, Cansu; Taskin, Berivan; Hussein, Khakan; Lebeau, Annette; Witzel, Isabell; Wölber, Linn; Geist, Stefan; Paluchowski, Peter; Wilke, Christian; Heilenkötter, Uwe; Müller, Volkmar; Schmalfeldt, Barbara; Simon, Ronald; Sauter, Guido; Terracciano, Luigi; Krech, Rainer Horst; von der Assen, Albert; Burandt, Eike

    2016-12-06

    Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, is linked to unfavorable tumor phenotype and poor prognosis in breast cancer. To better understand these contradictory observations, and to clarify the prognostic impact of p16 expression and 9p21 deletion, a tissue microarray (TMA) with 2,197 breast cancers was analyzed by fluorescence in-situ hybridization and immunohistochemistry (FISH) for 9p21 deletion and p16 expression. p16 immunostaining was weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 evaluable cancers. Strong p16 staining was linked to advanced tumor stage (p = 0.0003), high-grade (p p16 expression was absent in cancers harboring homozygous 9p21 deletions, but no difference in p16 expression was found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p = 0.0256). In summary, p16 expression is unrelated to partial 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High-level p16 expression is a strong predictor of unfavorable disease course in breast cancer.

  16. THE EXPRESSION OF p16 AND CYCLIN D1 IN PROLIFERATIVE ENDOMETRIUM AND ENDOMETRIAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To studythe role of p16 and cyclin in the genesis and development of endometrial car-cinoma. Methods 12 cases of normal endometrium, 22 cases of proliferative endometrium and 41 cases of endome- trial carcinoma were detected for the expression of p16 and cyclin D1 by means of immunohistochemical S-P. Results In normal endometrium p16 was expressed while cyclm D1was almost negative in the proliferative phase, but both of them were negative in the secretory phase. Among the groups of the simple and compound hyperplasia, the atypical hyperplasia and the endometrial carcinoma,the expression of p16 showed a descending tendency, while the expression of cyclin showed an ascending tendency. In endometrial carcinomas the expression of p16 was significantly lower than that of normal endometrium and proliferative endometrium (P<0. 01 ,P<0.05). However, the expression of cy- clin in proliferate endometrium and endometrial carcinoma was significantly higher than that in normal endometri- un (P<0. 05,P<0. 01). The overexpression of cyclin D1 in the atypical hyperplasia group was obviously different from that in the simple and compound hyperplasia group (P<0.01). In endometrial carcinoma,the expression of p16 was decreasing with the descending of cell differentiate degree, on the opposite, the expression of cyclin was in-creased and there existed a negative correlation between them. It was also observed that the overexpression of cyclin was significant different between and ( P <0. 01 ). Conclusion p1 6 is a negative regulating factor of cell cycle in endometrial carcinoma, while cyclin is a positive one. Both of them are important in the genesis and devel-opment of endometrial carcinoma. The Iow expression of p1 6 and the overexpression of cyclin are related with the malicious biological behaviors of endometrial carcinoma and maybe play an important role in the judgement of prog- nosis. Overexpression of cyclin may be an earlier molecular event in the genesis of

  17. p16(INK4a) /Ki-67 co-expression specifically identifies transformed cells in the head and neck region.

    Science.gov (United States)

    Prigge, Elena-Sophie; Toth, Csaba; Dyckhoff, Gerhard; Wagner, Steffen; Müller, Franziska; Wittekindt, Claus; Freier, Kolja; Plinkert, Peter; Hoffmann, Jürgen; Vinokurova, Svetlana; Klussmann, Jens Peter; von Knebel Doeberitz, Magnus; Reuschenbach, Miriam

    2015-04-01

    p16(INK4a) immunohistochemical overexpression is an overall reliable surrogate marker of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). However, cases of ambiguous p16(INK4a) overexpression are regularly detected in the head and neck: p16(INK4a) expression can be observed in non-malignant tissue, such as tonsillar crypt epithelium and a proportion of branchial cleft cysts. Additionally, diverse patterns of p16(INK4) expression can complicate interpretation of "p16(INK4a) -positivity". These aspects impede the unrestricted application of p16(INK4a) as a diagnostic marker in the head and neck. We hypothesized that combined detection of p16(INK4a) and the proliferation marker Ki-67 could support clarification of ambiguous p16(INK4a) expression in the head and neck by specifically indicating p16(INK4a) -expressing cells with proliferative activity. p16(INK4a) /Ki-67 co-expression in a combined staining procedure was correlated to distinct p16(INK4a) expression patterns and HPV status (HPV DNA followed by E6*I oncogene mRNA detection) in 147 HNSCC and 50 non-malignant head and neck samples. p16(INK4a) /Ki-67 co-expression only occurred in transformed cells of the head and neck. Co-expression was never detected in non-transformed cells. Combined p16(INK4a) /Ki-67 expression was stringently associated with a diffuse p16(INK4a) expression pattern. All HPV oncogene-expressing HNSCC showed p16(INK4a) /Ki-67 co-expression. We demonstrate that p16(INK4a) /Ki-67 co-expression occurs exclusively in transformed cells of the head and neck. Our findings indicate a substantial impact of combined p16(INK4a) /Ki-67 expression in the assessment of ambiguous p16(INK4a) expression in the head and neck by specifically identifying p16(INK4a) -expressing cells with proliferative activity. This property will be of considerable significance for head and neck histo- and cytopathology.

  18. The relationship between the expression of P16 and the prognosis of oesophagus cancer%食管癌P16表达与患者预后的关系

    Institute of Scientific and Technical Information of China (English)

    林小辉; 林兴悦; 江丽瑜; 陈远存; 周宇

    2008-01-01

    目的 探讨P16蛋白的表达与食管癌恶性潜能和进展密切相关.方法 检测56例食管癌患者癌组织P16的表达,并进行随访.结果 P16蛋白表达阳性率越低,食管癌术后生存率也越代,反之也然.结论 P16蛋白表达率能较好地反映食管癌预后,P16表达缺失或下调是食管癌恶性潜能和进展晚期的一种特异表现.P16蛋白表达与食管癌患者预后有一定的关系.%Objective Previons studies showed that,the gene of P16 is a kind of gene suppressing the cancer.its function once lose,the cell may change to cancer.Methods The expression of P16 has a closely relation with the malignant latent and evolve of the oesophagus cancer.ResulIs This research explored the relation between the P16 expression and the prognosis of oesophagus cancer,the results showed the positive rate of the expression of P16 is more low the rate ofexistence is more low,it in dicates the expression rate of P16 can reflect the prognosis of oesophagus cancer cell.Conclusion The expression of P16 missing or descending is closely rehted with the aggravate and evolve of oesophagus cancer,therefore the expression of P16 had a relation with the prognosis of oesophagus cancer.

  19. Prognostic value of HMGA2, P16, and HPV in oral squamous cell carcinomas

    DEFF Research Database (Denmark)

    Loeschke, Siegfried; Ohlmann, Anne Katharina; Bräsen, Jan Hinrich

    2016-01-01

    Purpose Molecular markers are only occasionally used in diagnostics of oral squamous cell carcinoma (OSCC), even though they could influence decision making in individually designed cancer therapies. We analyzed the predictive value of the markers HPV, p16, and HMGA2 and the TNM classification in...... and N were correlated. Conclusion Our results suggest that HMGA2 expression may have the potential to allow a more precise prognosis on survival in patients with OSCC. © 2016 European Association for Cranio-Maxillo-Facial Surgery...... in regard to survival and recurrence rates. Material and methods A total of 91 OSCC cases were included in this study, with a follow up of up to 131 months. HPV-DNA was present in 7 carcinomas. p16 was detected by immunohistochemical staining in 14 samples. HMGA2 expression was determined by real...

  20. Bmi1 promotes prostate tumorigenesis via inhibiting p16 and p14 expression

    OpenAIRE

    Fan, Catherine; He, Lizhi; Kapoor, Anil; Gillis, Aubrey; Rybak, Adrian P.; Cutz, Jean-Claude; Tang, Damu

    2008-01-01

    Bmi1 promotes prostate tumorigenesis via inhibiting p16INK4A and p14ARF expression correspondence: Corresponding authors. Anil Kapoor is to be contacted at Tel.: +1 (905) 522 1155, ext. 33218; fax: +1 (905) 521 6195. Damu Tang, T3310, St. Joseph?s Hospital, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6. Tel.: +1 (905) 522 1155, ext. 35168; fax: +1 (905) 521 6181. (Kapoor, Anil) correspondence: Corresponding authors. Anil Ka...

  1. Alterations of FHIT Gene and P16 Gene in Nickel Transformed Human Bronchial Epithelial Cells

    Institute of Scientific and Technical Information of China (English)

    WEI-DONG JI; JIA-KUN CHEN; JIA-CHUN LU; ZHONG-LIANG WU; FEI YI; SU-MEI FENG

    2006-01-01

    To study the alterations of FHIT gene and P16 gene in malignant transformed human bronchial epithelial cells induced by crystalline nickel sulfide using an immoral human bronchial epithelial cell line, and to explore the molecular mechanism of nickel carcinogenesis. Methods 16HBE cells were treated 6 times with different concentrations of NiS in vitro, and the degree of malignant transformation was determined by assaying the anchorage-independent growth and tumorigenicity. Malignant transformed cells and tumorigenic cells were examined for alterations of FHIT gene and P16 gene using RT-PCR, DNA sequencing, silver staining PCR-SSCP and Western blotting. Results NiS-treated cells exhibited overlapping growth. Compared with that of negative control cells, soft agar colony formation efficiency of NiS-treated cells showed significant increases (P<0.01) and dose-dependent effects. NiS-treated cells could form tumors in nude mice, and a squamous cell carcinoma was confirmed by histopathological examination. No mutation of exon 2 and exons 2-3, no abnormal expression in p16 gene and mutation of FHIT exons 5-8 and exons 1-4 or exons 5-9 were observed in transformed cells and tumorigenic cells. However, aberrant transcripts or loss of expression of the FHIT gene and Fhit protein was observed in transformed cells and tumorigenic cells. One of the aberrant transcripts in the FHIT gene was confirmed to have a deletion of exon 6, exon 7, exon 8, and an insertion of a 36 bp sequence replacing exon 6-8. Conclusions The FHIT gene rather than the P16 gene, plays a definite role in nickel carcinogenesis. Alterations of the FHIT gene induced by crystalline NiS may be a molecular event associated with carcinogen, chromosome fragile site instability and cell malignant transformation. FHIT may be an important target gene activated by nickel and other exotic carcinogens.

  2. The cell cycle regulator protein P16 and the cellular senescence of dental follicle cells.

    Science.gov (United States)

    Morsczeck, Christian; Hullmann, Markus; Reck, Anja; Reichert, Torsten E

    2017-08-02

    Cellular senescence is a restricting factor for regenerative therapies with somatic stem cells. We showed previously that the onset of cellular senescence inhibits the osteogenic differentiation in stem cells of the dental follicle (DFCs), although the mechanism remains elusive. Two different pathways are involved in the induction of the cellular senescence, which are driven either by the cell cycle protein P21 or by the cell cycle protein P16. In this study, we investigated the expression of cell cycle proteins in DFCs after the induction of cellular senescence. The induction of cellular senescence was proved by an increased expression of β-galactosidase and an increased population doubling time after a prolonged cell culture. Cellular senescence regulated the expression of cell cycle proteins. The expression of cell cycle protein P16 was up-regulated, which correlates with the induction of cellular senescence markers in DFCs. However, the expression of cyclin-dependent kinases (CDK)2 and 4 and the expression of the cell cycle protein P21 were successively decreased in DFCs. In conclusion, our data suggest that a P16-dependent pathway drives the induction of cellular senescence in DFCs.

  3. Lymph node melanocytic nevi: pathogenesis and differential diagnoses, with special reference to p16 reactivity.

    Science.gov (United States)

    Piana, Simonetta; Tagliavini, Elena; Ragazzi, Moira; Zanelli, Magda; Zalaudek, Iris; Ciarrocchi, Alessia; Valli, Riccardo

    2015-05-01

    Lymph node nevi (NN) have been occasionally described, yet little is currently known on their origin. According to a theoretical model of nevogenesis, the dissemination of nevus progenitor cells through lymphatic routes is responsible for the development of both nodal and skin nevi. The true incidence of NN is largely unknown but it has been reported to vary from 0.017% to as high as 22%. The frequency of NN nevi has increased since the introduction of sentinel lymph node mapping as a routine prognostic procedure in breast cancer and melanoma. The aim of this study was to analyze the frequency and morphological findings of NN, to discuss possible pathogenetic pathways in their evolution, and to verify the consistency of p16 immunostaining in the critical differential approach between NN and melanoma metastases. We therefore morphologically and immunohistochemically evaluated a series of 60 NN from 58 patients. In 21 patients, the lymph nodes had been removed during the staging for a skin melanoma; in all these patients NN immunostaining with p16 was strongly positive and p16 proved to be a reliable marker for the crucial differential diagnosis between NN and melanoma metastasis, strongly reacting in NN and lacking in melanoma deposits. A deeper knowledge on NN could help to clarify some important topics such as lymph node metastatic melanoma with unknown primary and the current debate on the lymph node involvement from atypical spitzoid tumors.

  4. Aberrant cytological localization of p16 and CDK4 in colorectal epithelia in the normal adenoma carcinoma sequence

    Institute of Scientific and Technical Information of China (English)

    Po Zhao; Xin Mao; Ian C Talbot

    2006-01-01

    AIM: To study the correlation between the patterns of subcellular expression of p16 and CDK4 in colorectal epithelia in the normal-adenoma-carcinoma sequence.METHODS: Paraffin sections of 43 cases of normal colorectal epithelia and corresponding adenomas as well as carcinomas were analysed immunocytochemically for subcellular expression of p16 and CDK4 proteins.RESULTS: Most carcinomas showed more cytoplasmic overexpression for p16 and CDK4 than the adenomas from which they arised or the adjacent normal mucosa.Most normal or non-neoplastic epithelia showed more p16 and CDK4 expression in the nucleus than their adjacent adenomas and carcinomas. There was a significant difference between the subcellular expression pattern of p16 and CDK4 in normal-adenoma-carcinoma sequence epithelia (P < 0.001). Neither p16 nor CDK4 subcellular patterns correlated with histological grade or Dukes' stage.CONCLUSION: Interaction of expression of p16 and CDK4 plays an important role in the Rb/p16 pathway.Overexpression of p16 and CDK4 in the cytoplasm, as well as loss expression of p16 in the nucleus might be important in the evolution of colorectal carcinoma from adenoma and, of adenoma from normal epithelia.

  5. Assessing p16 Status of Oropharyngeal Squamous Cell Carcinoma by Combined Assessment of the Number of Cells Stained and the Confluence of p16 Staining: A Validation by Clinical Outcomes.

    Science.gov (United States)

    Barasch, Samuel; Mohindra, Pranshu; Hennrick, Kenneth; Hartig, Gregory K; Harari, Paul M; Yang, David T

    2016-09-01

    Human papillomavirus-related oropharyngeal squamous cell carcinoma (OPSCC) has favorable prognosis relative to other head and neck squamous cell carcinomas. Criteria for predicting human papillomavirus status based upon p16 staining, including difficult cases with partial staining patterns, have been developed; however, clinical validation of these criteria and the clinical significance of partial p16 staining have not been reported. Eighty-one archival OPSCC cases were initially stained for p16 by immunohistochemistry with clone G175-405. The percentage of p16 cells and percentage of confluence of p16 cells were categorized as 25%, 26% to 75%, or >75%. Of all cases, 16 (20%) had partial p16 expression, with 26% to 75% p16 cells. Applying previously developed criteria of >75% p16 cells or >50% positive cells with >25% confluence, 48 (59%) patients were categorized p16 and demonstrated expected clinical characteristics and superior disease-free survival and overall survival (Pp16 patients. By themselves, the partial staining patients had intermediate outcomes; however, separating the partial staining cases by degree of confluence showed that those with >75% confluence had superior disease-free survival (P=0.042). When the 16 original partial staining cases were re-stained with the alternative anti-p16 E6H4 clone, p16 status remained concordant for all cases, but only 3 of the 16 were interpreted as demonstrating partial staining. This report shows that the prevalence of partial p16 staining varies with the antibody utilized and clinically validates the application of a graded evaluation of both the number as well as confluence of positive cells for risk stratification of patients with OPSCC.

  6. Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma.

    Science.gov (United States)

    Hu, Shi-Lian; Kong, Xiang-Yong; Cheng, Zhao-Dong; Sun, Yu-Bei; Shen, Gan; Xu, Wei-Ping; Wu, Lei; Xu, Xiu-Cai; Jiang, Xiao-Dong; Huang, Da-Bing

    2010-01-01

    Transcriptional silencing induced by hypermethylation of CpG islands in the promoter regions of genes is believed to be an important mechanism of carcinogenesis in human cancers including gastric cancer. A number of reports on methylation of various genes in gastric cancer have been published, but most of these studies focused on cancer tissues or only a single gene. In this study, we determined the promoter hypermethylation status and mRNA expression of 4 genes: p16, Runx3, DAPK and CHFR. Methylation-specific polymerase chain reaction (MSP) was used to determine the methylation status of p16, Runx3, DAPK and CHFR gene promoters in cancer and adjacent normal gastric mucosa specimens from 70 patients with gastric cancer, as well as normal gastric biopsy samples from 30 people without cancer serving as controls. In addition, the mRNA expression of p16, Runx3, DAPK and CHFR was investigated in 34 gastric cancer patients by RT-PCR. Bisulfite DNA sequence analysis was applied to check the positive samples detected by MSP. When carcinoma specimens were compared with adjacent normal gastric mucosa samples, a significant increase in promoter methylation of p16, Runx3, DAPK and CHFR was observed, while all 30 histologically normal gastric specimens were methylation free for all 4 genes. The methylation rate of the 4 genes increased from normal stomach tissue to tumor-adjacent gastric mucosa to gastric cancer tissue. Concurrent methylation in 2 or more genes was found in 22.9% of tumor-adjacent normal gastric mucosa and 75.7% of cancer tissues. No correlation was found between hypermethylation and other clinicopathological parameters such as sex, age, and tumor location. However, the frequency of DAPK and CHFR methylation in cancer tissues was significantly associated with the extent of differentiation and lymph node metastasis (P p16, Runx3, DAPK and CHFR is frequent in gastric cancer. DAPK and CHFR promoter hypermethylation may be an important help in evaluating the

  7. Methylation and Immunoexpression of p16(INK4a) Tumor Suppressor Gene in Primary Breast Cancer Tissue and Their Quantitative p16(INK4a) Hypermethylation in Plasma by Real-Time PCR.

    Science.gov (United States)

    Lee, Jae Jun; Ko, Eunkyung; Cho, Junhun; Park, Ha Young; Lee, Jeong Eon; Nam, Seok Jin; Kim, Duk-Hwan; Cho, Eun Yoon

    2012-12-01

    The p16(INK4a) gene methylation has been reported to be a major tumorigenic mechanism. We evaluated the methylation status of the p16(INK4a) genes in 231 invasive breast cancer and 90 intraductal carcinoma specimens using a methylation-specific polymerase chain reaction and p16 protein expression using immunohistochemistry. The quantity of cell-free methylated p16(INK4a) DNA in the plasma samples of 200 patients with invasive breast cancer was also examined using a fluorescence-based real-time polymerase chain reaction assay. The frequencies of p16(INK4a) methylation in invasive and intraductal tumors were 52.8% (122/231) and 57.8% (52/90), respectively. The p16 protein was overexpressed in 145 of the 231 invasive carcinomas (62.8%) and 63 of the 90 intraductal carcinomas (70%). High p16 expression in invasive carcinomas correlated significantly with a high histologic grade, a negative estrogen receptor and progesterone receptor status, p53 immunoreactivity and high Ki-67 expression with immunohistochemistry. In addition, the methylation index of p16(INK4a) was significantly higher in the cancer patients than the normal controls (pp16 immunoreactivity correlated with a loss of differentiation in breast carcinomas and high frequency of p16(INK4a) promoter methylation in both invasive and intraductal carcinomas, suggesting it may be involved in the pathogenesis of breast cancer.

  8. Novel frameshift mutation in the p16/INK4A tumor suppressor gene in canine breast cancer alters expression from the p16/INK4A/p14ARF locus.

    Science.gov (United States)

    Lutful Kabir, Farruk M; Agarwal, Payal; Deinnocentes, Patricia; Zaman, Jishan; Bird, Allison Church; Bird, R Curtis

    2013-01-01

    The INK4 family of cyclin-dependent kinase inhibitors (CKI) encode important cell cycle regulators that tightly control cell cycle during G1 to S phase. These related genes are considered tumor suppressors as loss of function contributes to the malignant phenotype. Expression of CKIs p16, p14ARF, or p15 were defective in six different canine mammary tumor (CMT) cell lines compared to normal thoracic canine fibroblasts. This suggests CKI defects are frequently responsible for neoplastic transformation in canine mammary carcinomas. p16 and p14ARF are two alternatively spliced products derived from the canine p16/INK4A/p14ARF gene locus. Despite omissions in the published p16 transcript and canine genome and the presence of GC-rich repeats, we determined the complete coding sequence of canine p16 revealing a deletion and frameshift mutation in p16 exon 1α in CMT28 cells. In addition, we determined canine p14ARF mRNA and protein sequences. Mapping of these mutations uncovered important aspects of p16 and p14ARF expression and defects in CMT28 cells shifting the p16 reading frame into p14ARF making a fusion protein that was predicted to be truncated, unstable and devoid of structural and functional integrity. This data describes an important neoplastic mechanism in the p16/INK4A/p14ARF locus in a spontaneous canine model of breast cancer. Copyright © 2012 Wiley Periodicals, Inc.

  9. Significance of Study on P16 Gene Loss in Primary Transitional Cell Carcinomas of Urinary Bladder%原发性膀胱移行细胞癌P16基因缺失研究

    Institute of Scientific and Technical Information of China (English)

    杨志伟; 郑新民; 胡礼泉; 李世文

    2001-01-01

    目的:探讨原发性膀胱移行细胞癌中P16基因缺失及P16蛋白的表达。方法:应用PCR和免疫组化方法对38例膀胱移行细胞癌标本P16基因缺失和P16蛋白的表达进行分析。结果:原发性膀胱移行细胞癌P16基因缺失率为18.42%,缺失率明显低于培养的膀胱癌细胞系;P16蛋白的阳性表达率为52.63%。结论:肿瘤细胞自原体转入培养环境的适应阶段P16基因缺失可能有助于肿瘤细胞的增殖,在膀胱肿瘤的发生中起重要作用。%To explore the loss of P16 gene and expression of P16 protein in primary transitional cell carcinomas(TCCs) of bladder.Methods:PCR and immunohistochemical methods were used to detect the loss of P16 gene and expression of P16 protein in 38 specimens of primary TCCs of urinary bladder.Results:The loss rate of P16 gene was 18.42% in 38 TCCs specimens and the positive rates of P16 expression were 52.63%. Conclusion:There are apparently an lower frequency of P16 loss and mutation in primary bladder cancer compared with the culture tumor counterparts.The loss of P16 gene confers a selective growth advantage during adaptation of tumor cells to culture and hence is probably important in the generation of bladder cancer cell lines.The loss of P16 gene makes a significant contribution to bladder cancer oncogeness.

  10. The hypermethylation of p16 gene promoter region and the expression of p16 mRNA in condyloma ac-cuminatum%尖锐湿疣皮损中p16基因启动子区高甲基化及其mRNA的表达

    Institute of Scientific and Technical Information of China (English)

    许辉; 马红; 闵敏; 顾文涛; 李遇梅

    2015-01-01

    目的::明确尖锐湿疣组织中p16基因启动子区高甲基化与p16 mRNA表达的关系。方法:采用甲基化特异性PCR技术检测30例尖锐湿疣组织及20名正常对照组织p16基因启动子区CpG岛甲基化状态,用RT-PCR法检测p16 mRNA的表达。结果:尖锐湿疣组织p16基因启动子高甲基化率为26.67%(8/30),正常对照组高甲基化率为0,差异具有统计学意义(P<0.05)。高甲基化的尖锐湿疣组织p16 mRNA的表达高于未甲基化的尖锐湿疣组织p16 mRNA的表达和高于正常对照组织p16 mRNA的表达。结论:尖锐湿疣组织皮损中p16基因启动子区甲基化不导致p16 mRNA表达的缺失。%Objective:To determine the relationship between the hypermethylation of the p16 gene promot-er region and the expression of p16 mRNA in condyloma accuminatum ( CA) tissue. Methods: The hyperm-ethylation of p16 gene promoter CpG island and the expression of p16 mRNA were detected by methylation-specific PCR and RT-PCR respectively in CA tissue from 30 patients and 20 healthy controls. Results: The rates of the hypermethylation of p16 gene promoter in CA tissue and normal skin were 26.67% (8/30) and 0, with a significant difference ( P<0.05) . The expression of p16 mRNA in hypermethylation CA tissue was high-er than that in unmethylated CA tissue and normal tissue. Conclusion:The hypermethylation of p16 gene pro-moter region does not lead to the loss of p16 mRNA expression in CA tissue.

  11. Exogenous p16 gene therapy combined with X-ray irradiation suppresses the growth of human glioma cells

    Institute of Scientific and Technical Information of China (English)

    Hongbing Ma; Zhengli Di; Minghua Bai; Hongtao Ren; Zongfang Li

    2011-01-01

    In this study, we infected human glioma U251 cells with a replication-defective recombinant adeno-virus carrying the p16 gene. This adenovirus constructed was able to transfect exogenous p16 into the human glioma cells efficiently, and direct a high level of p16 protein expression. Tumor-inhibition experiments demonstrated that treatment with the adenovirus-p16 significantly inhibited the growth of glioma cells in vitro as well as the in vivo development of tumors in nude mice bearing a brain glioma. The combination of adenovirus-p16 gene treatment and X-ray irradiation resulted in a greater inhibition of tumor growth. Adenovirus-mediated p16 gene therapy conferred a significant antitumor effect against human glioma cells both in vitro and in vivo, and that there was a synergistic effect when X-ray irradiation was also used.

  12. 鼻咽癌p16基因表达与突变的对比研究及意义%Relationship between p16 protein expression and mutation in nasopharyngeal carcinoma (NPC)

    Institute of Scientific and Technical Information of China (English)

    李建萍; 张小清; 左克强; 李植源

    2005-01-01

    [Objective] To explore the influencing factor on p16 protein expression and p16 gene mutation in NPC, and to investigate the correlation between NPC and p16 gene. [Methods] The expression of p16 protein in NPC by immunochemical technique; and the possible delection of p16 gene in exon 2 in NPC by multiplex-PCR.[Results] The delection rates of p16 protein expression were 55.3%(26/47)in NPC, 8% (2/25) cases in chronic inflammation of nasopharyngeal epithelium (CINE) respectively (P<0.001); The deletion rates of p16 gene exon 2 were34% in NPC, Which were not detected in all the tumor-adjacent tissues(P<0.001); The positive expression rate of p16 protein in NPC was higher than deletion rates of p16 gene. [Conclusion] We found the development of NPC was closely associated with the loss of p16 gene; and p16 protein down-expression may play an important role in the process.%目的探讨p16蛋白表达与p16基因突变在鼻咽癌发生中的作用,以确定两者之间的联系及意义.方法运用免疫组化二步法检测鼻咽癌中p16蛋白表达状况;采用多重PCR法检测鼻咽癌中p16基因第二外显子可能的缺失突变.结果p16蛋白表达缺失率:鼻咽癌组中55.3%(26/47),慢性鼻咽炎8%(2/25),鼻咽癌组中p16蛋白表达缺失率高于慢性鼻咽炎组(P<0.001);p16基因第二外显子缺失突变:鼻咽癌组中纯合缺失突变率34%,而相应的癌旁组织未检出(P<0.001);鼻咽癌p16蛋白表达缺失率高于p16基因外显子2缺失率.结论鼻咽癌的发生不仅与p16基因表达缺失和突变密切相关,而且p16蛋白表达下调可能是鼻咽癌发生发展的主要原因.

  13. Deoxyribonucleic acid (DNA) methyltransferase contributes to p16 promoter CpG island methylation in lung adenocarcinoma with smoking.

    Science.gov (United States)

    Sun, Rongju; Liu, Jiahong; Wang, Bo; Ma, Lingyun; Quan, Xiaojiao; Chu, Zhixiang; Li, Tanshi

    2015-01-01

    In this study, the relationship between CpG island methylation and smoking and DNA methyltransferase in the occurrence and development of lung adenocarcinoma was explored by detecting p16 promoter methylation status. Protein and mRNA levels of p16 were detected by immunohistochemistry and in situ hybridization assays. p16 gene promoter and exon 1 CpG island locus Hap II sites methylation status was analyzed with the methylation-specific PCR. Only 4 of 40 p16-positive cases were detected to methylate on CpG islands with 10% methylating rate whereas 18 of p16-negative cases were methylated up to 36.73% of methylating rate. The methylating rates of both p16-positive and p16-negative groups were significantly different. 17 of 50 cases with smoking from total 89 lung adenocarcinoma cases were detected to methylate on CpG islands while only 5 of the remaining 39 non-smokers to methylate. The difference of the methylating rates in both smokers and non-smokers was significant to suggest the closely association of CpG island methylation of p16 with smoking. Furthermore, p16 promoter CpG islands were detected to methylate in 15 of 35 cases with higher DNA methyltransferase activity whereas only 7 detected to methylate in the remaining 54 cases with lower DNA methyltransferase activity. p16 promoter CpG island methylation likely made p16 expressing silence thus contributed to the tumorigenesis of lung adenocarcinoma. Smoking is likely to promote p16 CpG island methylation or by its effect of the activity and metabolism of DNA methyltransferase 1 (DNMT) on CpG island methylation status.

  14. p16 Gene Methylation and Expression in Esophageal Squamous Cell Carcinoma%食管鳞癌中p16基因启动子区甲基化及其表达

    Institute of Scientific and Technical Information of China (English)

    宋长山; 谭家驹; 崔金环; 徐致祥; 杨光; 司建华

    2008-01-01

    目的 探讨食管鳞癌(ESCC)p16基因甲基化的状况及其表达与食管鳞癌临床病理特征之间的关系.方法 采用甲基化特异性PCR方(MSP)分别检测75例食管癌组织、癌旁组织和切缘组织p16基因启动子区域CpG岛甲基化状态.采用Envision免疫组化法检测食管癌组织及癌旁组织的p16蛋白的表达.结果 75例标本中,食管癌组织、癌旁组织和切缘组织p16基因甲基化率分别为41.3%(31/75)、13.3%(10/75)和6.67%(5/75).癌组织和癌旁组织P16蛋白的阳性表达率分别为29.3%(22/75)和56.7%(17/30).31例癌组织p16基因甲基化阳性标本中有2例(6.4%)检测到P16蛋白的表达,而44例癌组织p16基因甲基化阴性标本中有20例(45.5%)检测到P16蛋白的表达.食管癌组织p16基因甲基化率显著高于癌旁组织和切缘组织(P<0.01),P16蛋白表达与p16基因甲基化呈负相关.p16基因启动子区甲基化与食管癌的组织学分级、肿瘤部位无明显相关,与临床分期、淋巴转移密切相关.结论 p16基因甲基化在食管癌发生发展中起着重要作用,食管鳞癌的分期和淋巴结转移与p16基因甲基化之间有密切关系.

  15. 垂体腺瘤组织P16蛋白表达缺失及原因分析%Study on deletion of P16 protein expression and its causes in pituitary adenomas

    Institute of Scientific and Technical Information of China (English)

    魏新亭; 张亚卓; 罗世祺

    2001-01-01

    目的: 探讨垂体腺瘤组织中p16的表达及表达缺失的原因.方法:取尸体解剖正常垂体标本6例,临床病理证实的垂体腺瘤标本40例,采用蛋白杂交技术检测P16蛋白的表达;核酸杂交分析p16基因的纯和性缺失;单链构象多态性分析筛选p16基因突变;甲基化分析检测无纯和性缺失和突变的30例肿瘤组织p16基因启动子的甲基化状态.结果:40例垂体腺瘤组织中P16蛋白表达缺失.核酸杂交40例标本10例出现p16基因的纯和性缺失,该10例MRI表现为侵袭性垂体腺瘤.单链构像多态性分析,30例无p16纯合性缺失标本血与肿瘤DNA配对扩增电泳筛选p16第一和第二外显子碱基突变,未发现p16的主要编码区第一、第二外显子存在突变.对无p16纯合性缺失和突变的30例进行甲基化分析发现p16基因启动子存在甲基化.结论:垂体腺瘤的发生与p16的表达缺失有关,其缺失的原因包括p16基因的纯和性缺失和启动子的甲基化,p16基因的纯和性缺失是侵袭性垂体腺瘤的分子标志之一.

  16. p16蛋白和PCNA在子宫内膜癌中的表达及其意义%Expression of p16 protein and PCNA in endometrial carcinomas

    Institute of Scientific and Technical Information of China (English)

    林国志

    2004-01-01

    Objective: To investigate the effect of multiple tumor suppressor gene(p16/MTS1) and proliferating cell nuclear antigen(PCNA) in the carcinogenesis of human endometrial carcinoma. Methods: The expressions of the PCNA and p16 protein were investigsted by immunohistochemical method in 8 normal endometrial tissues, 22atypical endometrial hyperplasia(AEH) and 42 endometrial carcinoma tissues. Results: The positive rate of p16 expression decreased from normal endometrial tissues and AEH to endometrial carcinoma, while the PCNA index showed inversely. The expression of p16 related to histological grade ( P<0.05) and Lymph node metastasis. The prognosis of patients with p16 negetive-expression was poor. PCNA index was associated with histological grade and surgical stage of endometrial carcinoma. PCNA index in tumors with p16 positive-expression was higher than in tumors with p16 negetive expression ( P<0.05). Conclusion: It is suggested that the inactivation of p16 gene may be involved in the carcinogenesis of endometrial carcinoma, and the expression of p16 protein may be a useful prognosticator of endometrial carcinoma.%目的探讨p16基因和PCNA在子宫内膜癌发生发展中的作用.方法采用免疫组化技术检测子宫内膜癌组织中p16蛋白和PCNA的表达.结果子宫内膜癌组织p16蛋白表达阳性率低于正常内膜组织(P《0.05),而PCNA表达高于正常内膜组织(P《0.01),p16蛋白表达与子宫内膜癌组织学分级、淋巴转移相关(P《0.05,P《0.05),PCNA指数与子宫内膜癌的临床分期、组织学分级、淋巴转移相关.p16蛋白表达阴性者预后差.结论p16基因和PCNA可能参与子宫内膜癌的发生发展,p16蛋白检测可做为子宫内膜癌的预后指标.

  17. p16 Gene Expression in Salivary Gland Adenoid Cystic Carcinoma%抑癌基因P16在涎腺腺样囊性癌中的表达意义

    Institute of Scientific and Technical Information of China (English)

    郑雄伟; 许磊; 陈刚

    2001-01-01

    [目的]探讨抑癌基因p16与涎腺腺样囊性癌的发生发展的关系。[方法]采用免疫组织化学法检测30例腺样囊性癌中p16基因表达情况。[结果]腺样囊性癌组织中阳性表达率为76 6%,p16蛋白阳性率在腺样囊性癌的腺样型、管状型、混合型、实体型中分别为90%、100%、75%、42.9%,显示p16蛋白表达阳性率随恶性程度的上升而降低,p16阳性与阴性之间的5年生存率则无明显差异。[结论]抑癌基因p16的表达与肿瘤的病理类型有关,而腺样囊性癌预后好于其它肿瘤可能与其p16缺失少有关。%[ Purpose ] To explore the relationship between gene p 16 and genesis as well as development of adenoid cystic carcinoma. [ Method ]The SP immunohistochemieal method was used .The expressions of p16 gene protein in 30 cases of salivary gland adenoid cystic carcinoma (SGACC) were studied. [ Results]The positive expression for p 16 gene protein was 76.6%. The positive rates of p 16 gene in SGACC classic cribriform, tubular, mixed and solid patterns were 90%, 100%, 75%and 42.9% respoctively.The positive rate of p16 gene protein expression markedly reduced with the in crease of pathologic grade.There was no significant difference between p16 positive and p16 negative expression cases in 5-year survival.[Conclusion]The expression of suppressor gene p16 relates to pathologic types of tumor.The prognosis of adenoid cystic carcinoma is better than those of other tumors. It may be correlated with the loss of p16 gene protein.

  18. Inhibition of Hypoxia-Induced Cell Motility by p16 in MDA-MB-231 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Liyuan Li, Yi Lu

    2010-01-01

    Full Text Available Our previous studies indicated that p16 suppresses breast cancer angiogenesis and metastasis, and downregulates VEGF gene expression by neutralizing the transactivation of the VEGF transcriptional factor HIF-1α. Hypoxia stimulates tumor malignant progression and induces HIF-1α. Because p16 neutralizes effect of HIF-1α and attenuates tumor metastatic progression, we intended to investigate whether p16 directly affects one or more aspects of the malignant process such as adhesion and migration of breast cancer cells. To approach this aim, MDA-MB-231 and other breast cancer cells stably transfected with Tet-on inducible p16 were used to study the p16 effect on growth, adhesion and migration of the cancer cells. We found that p16 inhibits breast cancer cell proliferation and migration, but has no apparent effect on cell adhesion. Importantly, p16 inhibits hypoxia-induced cell migration in breast cancer in parallel with its inhibition of HIF-1α transactivation activity. This study suggests that p16's ability to suppress tumor metastasis may be partially resulted from p16's inhibition on cell migration, in addition to its known functions on inhibition of cell proliferation, angiogenesis and induction of apoptosis.

  19. Perbedaan Ekspresi P16INK4a dan HPVL1 pada Cervical Intraepithelial Neoplasia 1, Cervical Intraepithelial Neoplasia 2, Cervical Intraepithelial Neoplasia 3 dan Squamous Cell Carcinoma Serviks Uteri

    Directory of Open Access Journals (Sweden)

    Arlene Elizabeth Padang

    2014-09-01

    Full Text Available Human papillomavirus (HPV memegang peranan penting dalam proses karsinogenesis kanker serviksuteri; namun hanya sebagian kecil wanita yang terinfeksi tersebut akan berkembang menjadi kankerserviks yang invasif. Cervical intraepithelial neoplasia (CIN merupakan spektrum dari lesi servikalyang mewakili lesi prekursor dari squamous cell carcinoma (SCC serviks uteri yang dikategorikanmenjadi CIN1, CIN2, CIN3. Interaksi protein HPV (E6 dan E7 dengan protein pengatur selular (pRbdan p53 akan menyebabkan up regulation protein P16INK4a. P16INK4a merupakan tumor supresorprotein cyclin dependen kinase inhibitor yang menghambat cyclin dependent kinase 4 dan 6 yangmerupakan produk dari gen INK4a yang terlibat dalam fosforilasi protein retinoblastoma (pRb.Human papillomavirus-late 1 (HPVL1 merupakan protein kapsid yang terekspresi pada saat awalfase produktif karsinogenesis serviks uteri. Tujuan dari penelitian ini adalah untuk mengetahuiperbedaan ekspresi protein P16INK4a dan HPVL1 pada CIN1, CIN2, CIN3, dan SCC serviks uteri,dimana ekspresi P16INK4a dapat membantu untuk membedakan berbagai derajat displasia serviksuteri dan ekspresi HPVL1 dapat membantu untuk memprediksi progresivitas dari berbagai derajatdisplasia serviks uteri, sehingga penanganan pasien menjadi lebih tepat. [MEDICINA 2013;44:77-81].

  20. p16蛋白在食管鳞癌中的表达及其意义%Expression of p16 Protein in Human Esophageal Squamous Cell Carcinoma

    Institute of Scientific and Technical Information of China (English)

    廖琼; 孙维纲

    2001-01-01

    目的:研究p16蛋白表达与食管鳞癌生物学行为的关系.方法:应用免疫组化LSAB法检测52例食管鳞癌p16蛋白表达.结果:21例食管鳞癌p16蛋白表达阳性,阳性率为40.4%.随着恶性程度增加及病程进展,p16蛋白阳性率逐渐下降;p16蛋白阳性与淋巴结转移有关.p16蛋白阴性患者死亡率明显高于p16蛋白阳性者,且存活时间短.结论:检测食管鳞癌组织p16蛋白表达,有助于综合判断食管鳞癌恶性程度、转移潜能和预后.

  1. PTEN and p16 genes as epigenetic biomarkers in oral squamous cell carcinoma (OSCC): a study on south Indian population.

    Science.gov (United States)

    Sushma, P S; Jamil, Kaiser; Kumar, P Uday; Satyanarayana, U; Ramakrishna, M; Triveni, B

    2016-06-01

    Phosphatase and tensin homolog (PTEN) and p16INK4a (p16) genes are tumor suppressor genes, associated with epigenetic alterations. PTEN and p16 promoter hypermethylation is a major epigenetic silencing mechanism leading to cancer. The cooperation between PTEN and p16 in pathogenesis of cancers suggest that their combination might be considered as potential molecular marker for specific subgroups of patients. Hence, the present study aimed to investigate whether PTEN and p16 promoter methylations were involved in oral squamous cell carcinoma (OSCC) in south Indian subjects. DNA methylation quantitative analyses of the two candidate tumor suppressor genes PTEN and p16 were performed by methylation-specific polymerase chain reaction (MSP). Fifty OSCC biopsy samples and their corresponding non-malignant portions as controls were studied comparatively. The methylation status was correlated with the clinical manifestations. Twelve out of 50 patients (24 %) were found to be methylated for PTEN gene, whereas methylation of the p16 gene occurred in 19 out of 50 cases (38 %). A statistically significant result was obtained (P = p16 genes. PTEN and p16 promoter methylation may be the main mechanism leading to the low expression of PTEN and p16 genes indicating the progress of tumor development. Our data suggest that a low PTEN and p16 expression due to methylation may contribute to the cancer progression and could be useful for prognosis of OSCC. Therefore, analysis of promoter methylation in such genes may provide a biomarker valuable for early detection of oral cancer.

  2. Clinicopathological significance of p16, cyclin D1, Rb and MIB-1 levels in skull base chordoma and chondrosarcoma

    Institute of Scientific and Technical Information of China (English)

    Jun-qi Liu; Qiu-hang Zhang; Zhen-lin Wang

    2015-01-01

    Objective: To investigate the expression of p16, cyclin D1, retinoblastoma tumor suppressor protein (Rb) and MIB-1 in skull base chordoma and chondrosarcoma tissues, and to determine the clinicopathological significance of the above indexes in these diseases.Methods: A total of 100 skull base chordoma, 30 chondrosarcoma, and 20 normal cartilage tissue samples were analyzed by immunohistochemistry.The expression levels of p16, cyclinD1,Rb and MIB-1 proteins were assessed for potential correlation with the clinicopathological features.Results: As compared to normal cartilage specimen (control), there was decreased expression of p16, and increased expression of cyclin D1, Rb and MIB-1 proteins, in both skull base chordoma and chondrosarcoma specimens.MIB-1 LI levels were significantly increased in skull base chordoma specimens with negative expression of p16, and positive expression of cyclin D1 and Rb (P < 0.05).Significantly elevated MIB-1 LI was also detected in skull base chondrosarcoma tissues, while there was negative expression of p16, cyclin D1 and Rb (P < 0.05).In skull base chordoma, p16 negatively correlated with cyclin D1 and Rb, while cyclin D1 positively correlated with Rb.Additionally, p16, cyclin D1, Rb, or MIB-1 expression showed no correlation with age, gender, or pathological classification of patients with skull base chordoma (P > 0.05).However, p16 and MIB-1 levels correlated with the intradural invasion, and expression of p16, Rb and MIB-1 correlated with the number of tumor foci (P < 0.05).Further, the expression of p16 and MIB-1 appeared to correlate with the prognosis of patients with skull base chordoma.Conclusions: The abnormal expression of p16, cyclin D1 and Rb proteins might be associated with the tumorigenesis of skull base chordoma and chondrosarcoma.

  3. Persistent infection of hepatitis B virus is involved in high rate of p16 methylation in hepatocellular carcinoma.

    Science.gov (United States)

    Jicai, Zhang; Zongtao, Yü; Zongtao, Yu; Jun, Lü; Jun, Lu; Haiping, Li; Jianmin, Wu; Lihua, Hu

    2006-07-01

    High rate of chronic hepatitis B virus (HBV) infection and p16 promoter methylation were found in the majority of hepatocellular carcinoma (HCC). To investigate the potential linkage between high rate of p16 methylation and HBV infection, p16 methylation was detected with methylation-specific polymerase chain reaction (PCR), and HBV markers were examined with real-time PCR and immunologic method. p16 methylation was detected in 5.5% of patients with hepatitis B, 9.1% of noncancerous liver, 36.6% of cirrhotic liver tissue, and 70.5% of cancerous tissue of HCC, primarily in cirrhotic (46.7%) and cancerous tissue (90.6%) with HBV infection. In noncancerous tissue, p16 methylation could only be detected in samples with HBV infection, although no significant difference, the frequency of p16 methylation in noncancerous tissue with HBV infection was higher than those without it. The results showed that, in cancerous, cirrhotic, or noncancerous tissues, the frequency of p16 methylation in samples with HBV infection was higher than those without it, suggesting possible association between HBV infection and p16 methylation. The result of HBV-DNA analysis showed that 96.1% (49/51) samples with p16 methylation also showed detectable HBV-DNA; it signifies that replication and/or integration of HBV may contribute to high rate of p16 methylation in hepatocarcinogenesis. Generally, these results indicate that persistent HBV infection may be associated with high rate of p16 methylation, and involved in development of HCC through this way.

  4. 垂体腺瘤p16基因启动子甲基化分析%Analysis of the hypermethylation of p16 gene promotor in pituitary adenomas

    Institute of Scientific and Technical Information of China (English)

    魏新亭; 罗世祺

    2001-01-01

    目的:探讨垂体腺瘤p16基因表达缺失的原因.方法;对无p16基因纯合性缺失的肿瘤标本进行甲基化分析.结果:30例标本甲基化敏感性内切酶SmaI消化后p16基因第一外显子扩增片段消失,表明存在p16启动子的甲基化.结论:垂体腺瘤p16基因的表达缺失与该基因启动子的甲基化有关.

  5. Expression and clinical significance of p16 protein in cervical neoplasms%p16蛋白在宫颈病变中的表达及其临床意义

    Institute of Scientific and Technical Information of China (English)

    魏喆强; 朱明月; 过晓艳

    2010-01-01

    目的 研究p16蛋白在宫颈病变中的表达及其临床意义.方法 用免疫组化技术检测p16基因蛋白在139例不同级别宫颈病变中的表达情况.结果 p16的表达:WNL<CIN1<CIN2<CIN3<CC.病理变化和p16蛋白表达呈正相关(P<0.01).结论 p16基因蛋白检测在宫颈病变筛查和确诊中具有重要意义.

  6. p16蛋白在脑胶质瘤中的表达及其临床意义%Expression of p16 protein in brain glioma and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    王东军; 赵革灵

    2004-01-01

    目的:探讨抑癌基因 p16 蛋白在脑胶质瘤发生、分化过程中的作用及其与预后的关系经.方法:采用免疫组化的方法检测 54 例脑胶质瘤患者病理标本中的 p16 蛋白,分析 p16 蛋白的缺失与病理分级、患者预后之间的关系.结果:全组共有 29 例(53.7%)标本 p16 蛋白表达阴性,Ⅲ、Ⅳ级胶质瘤的 p16 蛋白的阴性率明显高于Ⅰ、Ⅱ级(P<0.05).p16 蛋白表达阳性患者的复发率明显低于 p16 蛋白表达阴性者(P<0.05),分别为20.0% 和 55.2%.结论: p16 蛋白的缺失与脑胶质瘤的恶性程度有关,恶性程度越高,p16 蛋白的缺失率越高;p16 蛋白的缺失与预后相关,其缺失率越高,患者复发率越高.

  7. Photometric observation of HAT-P-16b in the near-UV

    CERN Document Server

    Pearson, Kyle A; Sagan, Thomas A G

    2014-01-01

    We present the first primary transit light curve of the hot Jupiter HAT-P-16b in the near-UV photometric band. We observed this object on December 29,2012 in order to update the transit ephemeris, constrain its planetary parameters and search for magnetic field interference. Vidotto et al. (2011a) postulate that the magnetic field of HAT-P-16b can be constrained if its near-UV light curve shows an early ingress compared to its optical light curve, while its egress remains unchanged. However, we did not detect an early ingress in our night of observing when using a cadence of 60 seconds and an average photometric precision of 2.26mmag. We find a near-UV planetary radius of Rp=1.274+-0.057RJup which is consistent with its near-IR radius of Rp=1.289+-0.066RJup (Buchhave et al., 2010). We developed an automated reduction pipeline and modeling package to process our data. The data reduction package synthesizes a set of IRAF scripts to calibrate images and perform aperture photometry. The modeling package utilizes ...

  8. Differential effects of adenovirus-p16 on bladder cancer cell lines can be overcome by the addition of butyrate.

    Science.gov (United States)

    Lee, C T; Seol, J Y; Park, K H; Yoo, C G; Kim, Y W; Ahn, C; Song, Y W; Han, S K; Han, J S; Kim, S; Lee, J S; Shim, Y S

    2001-01-01

    High frequency of p16 alteration and high local recurrence rate of bladder cancer make this cancer an ideal target for p16 gene therapy. However, a low transduction rate of p16 via adenoviral vector causes an inconsistent result. In this study, we have tested adenovirus-p16 in several bladder cancer cell lines and investigated a way of improving the low transduction rate. Adenovirus-p16 showed a strong antitumor effect on bladder cancer cell lines (253J and T24) with strong Coxackie-adenoviral receptor (CAR) expression but little antitumor effect on bladder cancer cell lines (J82 and HT1376) with little CAR expression. In this study, we suggest a simple way of overcoming the differential effects of the adenovirus. The addition of butyrate to media was found to increase the transduction rate of adenovirus remarkably and increase the antitumor effect of adenovirus-p16 in bladder cancer cell lines with little CAR expression. Butyrate effects were related with increased CAR expression on the cell surface as well as increased transgene expression from adenoviral vector. From these observations, application of adenovirus-p16 gene therapy with butyrate can overcome the obstacle of low gene transfer and enhance the antitumor effect of adenovirus-p16 in bladder cancer.

  9. The synergic effect of HPV infection and epigenetic anomaly of the p16 gene in the development of cervical cancer.

    Science.gov (United States)

    Ahmad, Arif; Raish, Mohammad; Shahid, Mohammad; Batra, Swaraj; Batra, Vineeta; Husain, Syed Akhtar

    2017-07-04

    Cervical cancer is the most common cancer in Indian women. Infection with a high-risk human papillomavirus (HR-HPV) is the greatest risk factor for developing cervical cancer. The genetic and epigenetic changes in the tumor suppressor p16 gene is play an important role in the development of cervical cancer. To evaluate the expression and promoter methylation of p16 gene in HR-HPV infected squamous cell carcinoma of the uterine cervix. To find out p16INK4a expression and methylation status 105 squamous cell carcinoma of the uterine cervix were investigated by using immunohistochemistry and Methylation Specific PCR techniques. HPV16/18 was amplified in 83.8% cases of the cervix. 80% of them were positive for HPV type 16, while only 3.8% were positive for HPV type 18. Promoter CpG island hypermethylation of p16 gene was detected in 20.9% tissue samples of cervical carcinoma. Of these hypermethylated samples 90.9% cases showed nil/very low p16INK4a expression (P= 0.001). Overexpression of p16INK4a was observed in 73.3% cases of HR-HPV infected squamous cell carcinoma of the cervix. An association between p16 methylation, expression, and HR-HPV infection suggested the compliance of HPV infection and aberration of p16 gene have a synergic effect on initiation and progression of cervical carcinoma.

  10. p16 expression in patients with cervical cancer and its prognostic significance: meta-analysis of published literature.

    Science.gov (United States)

    Huang, K; Li, L-A; Meng, Y-G; Fu, X Y

    2014-12-01

    p16, a tumour suppressor, is unable to express its suppressive effects following interaction with E7-retinoblastoma protein. Previous reports have suggested that p16 immunostaining allows precise identification of cervical intra-epithelial neoplasia and cervical cancer lesions in biopsies. The prognostic value of p16 expression in cervical cancers has been evaluated for several years, but the results remain controversial. As such, the authors undertook a systematic review and meta-analysis of studies assessing the impact of p16 expression on overall survival and disease-free survival. Medline, Embase and China National Knowledge Infrastructures were searched to identify studies on the prognostic impact of p16 expression in patients with cervical cancer. In total, 1070 patients from 10 eligible studies were included in the analysis. Pooled risk ratios (RRs) with 95% confidence intervals (95% CI) were calculated. A significant association was found between p16 expression and increased disease-free survival (RR 0.60; 95% CI 0.44-0.82; p=0.001). However, no significant association was found between p16 and overall survival. p16 expression may be predictive of a favourable prognosis in patients with cervical cancer. However, large-scale, multicentre and well-matched cohort studies are warranted to confirm this finding. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Assessment of inverse correlation of p16 and pRb expression in carcinoma ex pleomorphic adenoma.

    Science.gov (United States)

    Tarakji, B; Alenzi, F; Al-Khuraif, A A

    2013-06-01

    Published data indicate that an inverse correlation has been identified in some tumours such as ovarian cancer and laryngeal squamous carcinoma. This study aimed to characterize alteration in the immunohistochemical expression of p16 and p Rb in carcinoma ex pleomorphic adenoma, and to assess the inverse correlation between p16 and pRb in carcinoma ex pleomorphic adenoma. A selected series of 27 cases of carcinoma ex pleomorphic adenoma were examined at Alfarabi Dental School in 2012. The results showed an inverse correlation between p16 (normal expression) and pRb (mutated) in 15 cases. Also 3 cases showed an inverse correlation between p16 (mutated) and pRb (normal expression). p16 and pRb (both proteins with normal expression) were identified in 3 cases. p16 and pRb (both proteins inactivated) were identified in 6 cases. This study suggests the alteration of p16 and pRb expression has been detected in carcinoma ex pleomorphic adenomas. They mentioned that if the function of one gene such as p16 or pRb was abrogated the other gene would be overexpressed or unaffected ini 18 out of 27 cases.

  12. Significance of p16 and pRb Expression in Children Rhabdomyosarcoma%儿童横纹肌肉瘤中p16和pRb蛋白的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    胡晓丽; 詹江华; 王学文; 宋兰云; 宁培儒

    2003-01-01

    目的探讨横纹肌肉瘤(RMS)中p16和pRb的蛋白表达及其与RMS的发生、浸润和转移的关系.方法应用免疫组化方法检测30例RMS病人中p16和pRb蛋白的表达情况.结果 30例RMS中,无1例p16和pRb两种蛋白表达均正常.9例p16阴性的RMS中,有4例pRb呈强阳性表达;4例p16弱阳性病例,pRb均呈强阳性;17例p16中-强阳性病例中,有3例pRb阴性表达,12例弱阳性表达.而5例pRb阴性RMS中,3例p16强阳性表达.在21例p16蛋白阳性的病例中,有5例发生转移,而在p16蛋白阴性的9例中有7例发生转移.在p16阴性和阳性组之间P=0.0125,有显著性差异.pRb阳性的25例中,有10例发生转移,在pRb阴性的5例中有2例转移.在pRb阴性和阳性组之间,P=1.0000,无显著性差异.结论 (1)p16、pRb异常与RMS的发生密切相关;(2)p16与pRb表达呈负相关关系;(3)p16的表达缺失与RMS的广泛浸润和转移有关.

  13. 胃良、恶性病变中p16蛋白表达的研究%To Study the Expression of p16 in Benign and Malignant Gastric Lesions

    Institute of Scientific and Technical Information of China (English)

    范开席; 王绍平; 唐基栋; 王哲海

    2001-01-01

    目的 探讨p16蛋白在胃良、恶性病变中的表达及其与胃癌的发生、发展的关系。方法应用免疫组化LSAB方法,对10例正常胃粘膜、35例良性病变和65例胃癌中p16的表达进行了检测。结果 p16蛋白在正常胃粘膜中的阳性率为100%,在良性病变中的阳性率自75%至87.5%不等,在胃癌中的阳性率为30.8%。在高、中分化胃癌中p16的阳性表达率高于低、未分化者(P<0.05),p16的阳性表达与TNM分期密切相关。结论 p16参与了胃癌的发生、发展过程,对预后的判断有意义。%Objective To study the expression of p16 suppressor gene inbenign and malignant gastric lesions and its correlation with occurrence and development of gastric cancer.Methods p16 was observed in 10 normal gastric tissue、35 benign lesions and 65 gastric cancer with LSAB immunohistochemical methods.Results The positive expression rate of p16 in the normal gastric tissue was 100%,the rate of benign lesions was 75%~87.5%,the rate of gastric cancer was 30.8%.The positive expression rate of p16 was higher in high and middle differentiation than low and small cell carcinoma (P<0.05),The positive expression of p16 was significantly correlated with TNM stage.Conclusion p16 may play some roles in the development of gastric cancer, the expression of p16 may assess the prognosis in gastric cancer.

  14. Role of quantitative p16(INK4A) mRNA assay and digital reading of p16(INK4A) immunostained sections in diagnosis of cervical intraepithelial neoplasia.

    Science.gov (United States)

    Vasiljević, Nataša; Carter, Paul D; Reuter, Caroline; Warman, Rhian; Brentnall, Adam R; Carton, James R; Cuzick, Jack; Lorincz, Attila T

    2017-08-15

    Visual interpretation of cervical biopsies is subjective and variable, generally showing fair to moderate inter-reader agreement in distinguishing high from low grade cervical intraepithelial neoplasia (CIN). We investigated the performance of two objective p16 quantitative tests in comparison with visual assessment: (i) p16-mRNA assay and (ii) digital analysis of sections stained for p16 protein. The primary analysis considered 232 high-risk human papilloma virus positive (HPV+) samples from diagnostic cervical specimens. A p16 RT-qPCR (p16-mRNA assay) was run on mRNA extracted from formalin-fixed paraffin-embedded sections. Two p16 immunohistochemistry (IHC) readings, a visual read by a histopathologist (Visual IHC) and a digital read of a high-resolution scan (Digital IHC), were done on adjacent sections. The worst reviewed CIN grade (agreed by at least two histopathologists) from up to two biopsies and a loop excision was taken, with CIN2/3 as the primary endpoint. Visual IHC attained a specificity of 70% (95%CI 61-77) for 85% (95%CI 77-91%) sensitivity. The four-point Visual IHC staining area under the curve (AUC) was 0.77 (95%CI 0.71-0.82), compared with 0.71 (95%CI 0.64-0.77) for p16-mRNA and 0.67 (95%CI 0.60-0.74) for Digital IHC. Spearman rank-order correlations were: visual to p16-mRNA 0.41, visual to digital 0.49 and p16-mRNA to digital: 0.22. The addition of p16-mRNA assay to visual reading of p16 IHC improved the AUC from 0.77 to 0.84 (p = 0.0049). p16-mRNA testing may be complementary to visual IHC p16 staining for a more accurate diagnosis of CIN, or perhaps a substitute in locations with a lack of skilled pathologists. © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

  15. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer

    DEFF Research Database (Denmark)

    Lassen, Pernille; Eriksen, Jesper Grau; Hamilton-Dutoit, Stephen

    2010-01-01

    BACKGROUND: HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved...... the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC. MATERIALS AND METHODS: Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated...... by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5 years after radiotherapy. RESULTS: Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio...

  16. P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells.

    Science.gov (United States)

    Hu, Huanzhang; Li, Zhigang; Chen, Jie; Wang, Duanming; Ma, Juming; Wang, Weiguo; Li, Jiang; Wu, Hongping; Li, Linfang; Wu, Mengchao; Qian, Qijun; Chen, Jingbo; Su, Changqing

    2011-05-01

    Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re-expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy.

  17. Reliability of the CINtecTM p16INK4a immunocytochemical test in screening cervical precancerous lesions

    Directory of Open Access Journals (Sweden)

    Jović Milena

    2008-01-01

    Full Text Available Background/Aim. Overexpression of p16INK4a has been found to be linked with genomic integration of high-risk human papillomavirus (HPV and the developement of precancerous cervical intraepithelial lesions. The aim of this study was to examine is there a higher positive level of correlation between grade of histological dysplasia and p16INK4a level of expression in cervical smear, compared to results of Papanicolaou test. We also examined the correlation between HPV type, p16INK4a expression and Papanicolau test results. Methods. A total of 48 women with precanceorous cervical lesions and HPV cervicitis and 10 healthy women were enrolled in the study. Papanicolaou test, CINtecTM p16INK4a citological immunohistochemical test, polymerase chain reaction (PCR HPV 16, 18, 31, 33 analysis and histopathology of the lesion were performed in all the patients. Results. Comparing the results of Papanicoulaou test and the grade of histological dysplasia, low-grade squamous intraepithelial lesion (LSIL was confirmed in 38%, and high-grade squamous intraepithelial lesion (HSIL in 69.2% of the patients (p > 0.05. Significant positive correlation was found between p16 overexpression and grade of histological dysplasia (p = 0.000. Overexpression p16 was found in 70% of LSIL and 94.4% of HSIL. Positive correlation was found between p16 overexpression and grade of dysplasia in Papanicolaou test (p = 0.011. In 38% of LSIL and 15% of HSIL cases p16 was not expressed. The most frequently found HPV type in PCR analysis was HPV16. Analysing the results of p16 test according to HPV status and Papanicolaou test rather heterogenous results were obtained. Conclusion. In the patients with precancerous cervical lesions a higher level of correlation was found between the grade of histological dysplasia and p16INK4a level of expression in the cervical smear, compared to the results of Papanicolaou test.

  18. 骨巨细胞瘤中p16和Rb蛋白表达及其意义

    Institute of Scientific and Technical Information of China (English)

    邹继彬; 张炽新

    2002-01-01

    目的:探讨骨巨细胞瘤中p16和Rb蛋白的表达、相互关系及其意义。方法:应用免疫组织化学SP法检测60例骨巨细胞瘤患者组织中p16和Rb蛋白的表达情况。结果:60例骨巨细胞瘤中,p16和Rb总异常表达率良性为13.0%,恶生为86.5%;P16和Rb阳性率,良性(I级)分别为91.3%、87.0%;恶性(K级和II级)分别为32.4%、54.1%。肿瘤分化越差,p16及Rb阳性率越低。P16和Rb蛋白均阳性的肿瘤术后复发率低。结论:骨巨细胞瘤的发生发展与p16和Rb蛋白缺失有关;瘤组织分化程度越差,p16和助蛋白丢失越多;p16和Rb蛋白均阳性的肿瘤术后复发率低;p16和助蛋白的表达具有负相关系,两者共同作用才能阻止瘤细胞的增殖。

  19. Usefulness of p16(INK4a) staining for managing histological high-grade squamous intraepithelial cervical lesions.

    Science.gov (United States)

    Miralpeix, Ester; Genovés, Jordi; Maria Solé-Sedeño, Josep; Mancebo, Gemma; Lloveras, Belen; Bellosillo, Beatriz; Alameda, Francesc; Carreras, Ramon

    2017-02-01

    p16(INK4a) (p16) tumor-suppressor protein is a biomarker of human papillomavirus (HPV) oncogenic activity that has revealed a high rate of positivity in histological high-gade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 2 (HSIL/CIN2) lesions. However, there is a paucity of data regarding p16 status as a surrogate marker of HSIL/CIN2 evolution. The aim of this study was to evaluate the outcome of HSIL/CIN2 patients followed up without treatment for 12 months according to p16 immunohistochemical staining. Patients diagnosed with HSIL/CIN2 colposcopy-directed biopsy, were recruited prospectively between December 2011 and October 2013. p16 staining was performed in all HSIL/CIN2 diagnostic biopsies. Follow-up was conducted every 4 months by cytology, colposcopy and biopsy if suspicion of progression and once the 12 months of follow-up completed. Complete regression, partial regression, persistence, and progression rates of HSIL/CIN2 were defined as a final outcome. A total of 96 patients were included in the analysis. The rate of spontaneous regression was 64%, while 28% had persistent disease, and 8% progressed at 12 months of follow-up. p16 was positive in 81 (84%) initial HSIL/CIN2 biopsies. Regression was observed in all 15 p16 negative cases and in 46 of 81 (57%) p16 positive cases (P=0.001). In conclusion, patients with p16 negative HSIL/CIN2 biopsy had a high rate of regression during first 12 months of follow-up. Status of p16 staining could be considered for HSIL/CIN2 management.

  20. 胃癌细胞p16和CDK4的表达及调控的分子机制%Molecular mechanism of p16 and CDK4 expression and regulation in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    马炬明; 王伟国; 胡慧珍; 施正杰

    2011-01-01

    目的 通过腺病毒携带p16基因感染胃癌细胞,研究p16功能恢复对CDK4表达的调节作用.方法 构建携带p16基因的重组腺病毒AdCMV-p16感染胃癌细胞系.Western blotting检测p16和CDK4的表达,MTT法检测癌细胞的增殖活性,DAPI染色计数癌细胞的凋亡比例.结果 胃癌细胞感染腺病毒载体AdCMV-p16后获得p16表达,对细胞整体CDK4表达无影响,但可明显降低细胞核CDK4的表达量;AdCMV-p16感染后引起癌细胞增殖活性下降,当感染复数(MOI)为1、10、20时,细胞存活率已经分别低于50%、20%和5%;p16表达可诱导癌细胞凋亡,细胞凋亡率达(13.86±4.65)%.结论 p16功能恢复后核CDK4含量减少,可能是诱导细胞周期阻滞和细胞凋亡、抑制癌细胞生长的主要分子机制.%Objective To investigate the regulation of CDK4 expression by reactivating p16 function through adenovirus vector in gastric cancer. Methods The adenovirus vector carrying p16 gene of AdCMV-p16 was constructed and used to infect gastric cancer cell lines. Western blotting was used to detect the expression of p16 and CDK4, MTT assay was used to detect the proliferation activity of cancer cells, and DAPI was used to stain and count the percentages of cancer cell apoptosis. Results After reactivation of p16 in gastric cancer cells, the expression level of CDK4 in whole cell extracts was not affected, but the nuclear CDK4 was decreased obviously. This phenomenon resulted in the depression of cancer cell proliferation activity, with the cell viability of lower than 50% ,20%, or 5% when MOl was 1, 10 or 20, respectively. p16 expression induced gastric cancer cells apoptosis with the apoptotic rate of ( 13. 86 ±4. 65)%. Conclusion The reactivation of p16 function in gastric cancer cells resulted in the decrease of nuclear CDK4,which may be the main molecular mechanism of pl6-induced cell cycle arrest and p16-mediated inhibition of cancer cell proliferation.

  1. Immunohistochemical Study of p16 Gene Alteration in Colorectal Cancer%大肠腺癌p16抑癌基因改变的免疫组化研究

    Institute of Scientific and Technical Information of China (English)

    陈玉英; 易静; 杨小妹; 吴平平

    2000-01-01

    目的:研究大肠腺癌中抑癌基因p16的表达情况.方法:用免疫组化LSAB法检测71例结肠癌和直肠癌存档标本中p16蛋白的表达.结果:36例(50.70%)标本呈p16阳性,阳性细胞往往比阴性细胞有更明显的异型性,p16阳性与临床病理分级有关.结论:大肠癌的p16基因改变表现出异质性,即一部分肿瘤细胞为p16失活或表达不增高,另一部分则为p16过度表达.p16阳性肿瘤细胞在形态上的异型性特征以及p16阳性标本数在低分化大肠癌中明显增高,均提示p16过度表达可能与细胞的异常增殖分化有关.

  2. DOFFEREMTIAL EXPRESSION OF CELLULAR SENESCENCE- ASSOCIATED GENES INDUCED BY p16INK4A%p16INK4A诱导的衰老相关基因表达差异

    Institute of Scientific and Technical Information of China (English)

    韩晓琳

    2005-01-01

    目的检测衰老主导基因p16与衰老相关基因p21、CSIG、TOM1间的相互关系.方法正、反义p16转染人胚肺2倍体成纤维细胞(2BS)后,用RT-PCR检测p21、CSIG、TOM1的表达,用WesternBlot检测p21蛋白的表达.结果p16对p21存在转录后调控作用,正义p16转染细胞TOM1高表达,反义p16转染细胞CSIG高表达.结论衰老主导基因p16与衰老相关基因p21、CSIG、TOM1间存在相互作用,进一步说明了p16在衰老中的主导地位.

  3. The Significance of p16 Protein Expression in Children Rhabdomyosarcoma%儿童横纹肌肉瘤中p16蛋白的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    胡晓丽; 王学文; 宋兰云; 宁培儒

    2003-01-01

    目的:探讨横纹肌肉瘤(RMS)中p16蛋白表达及其与RMS的发生、浸润和转移的关系.方法:应用免疫组化方法检测30例RMS病人中p16蛋白的表达情况.结果:30例RMS中p16蛋白表达异常为26例,正常表达4例,与正常组比较,有非常显著性差异(P=0.0001).在21例p16蛋白阳性的病例中,有5例发生转移,而在p16蛋白阴性的9例中有7例发生转移,两组之间有显著性差异(P=0.0125).p16蛋白在胚胎性RMS(ERMS)和腺泡状RMS(ARMS)中的表达无显著性差异(P=1.0000).结论:(1)p16蛋白的异常表达与RMS的发生密切相关.(2)p16蛋白的表达缺失与RMS的广泛浸润和转移有关.(3)p16蛋白在不同类型RMS中的表达无明显差异.

  4. Relationship between the expression of p16 gene and the phenotypes of human gastric carcinomas%p16基因表达与胃癌组织类型的关系

    Institute of Scientific and Technical Information of China (English)

    孙华林

    2001-01-01

    目的 研究p16基因的表达与人胃癌组织类型的关系.方法 选择30例病理确诊胃癌患者的胃癌组织及相应正常胃粘膜组织,用蛋白质免疫印迹(Westem blot)技术检测p16基因在两种组织中的表达.结果 30例胃癌组织中,7例无p16基因表达的癌组织为低分化腺癌或印戒细胞癌;2例p16基因表达可疑;分化较高的6例p16基因表达增多;其余15例p16基因的表达与相应正常组织无区别.结论 p16基因在胃癌组织中的表达既可减低,也可增加,相当一部分胃癌组织p16基因的表达同相应正常组织无明显区别;p16基因表达减低的病例,其病理诊断往往属于恶性程度较高的低分化腺癌或印戒细胞癌,可能与患者的预后有一定关系.

  5. 胃癌组织中p16、 Cyclin D1和Survivin的表达及其相关性%Expression and correlation of p16, Cyclin D1 and Survivin in gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    魏卓文; 党冬梅

    2014-01-01

    目的 研究p16、Cyclin D1和Survivin在胃癌中的表达及其相关性.方法 应用免疫组化S-P法检测正常胃黏膜组织、不典型增生和胃癌组织中p16、Cyclin D1和Survivin的表达.结果 正常胃黏膜和不典型增生组织中p16的表达率高于Cyclin D1和Survivin的表达,胃癌组织中p16的表达率低于二者;p16、Cyclin D1和Survivin的表达与胃癌患者年龄、性别均无关;p16的表达与淋巴结转移相关(P<0.05);Cyclin D1的表达与组织分化程度、淋巴结转移相关(P <0.001;P <0.05);Survivin的表达与组织分化程度相关(P<0.05).且p16与Cyclin D1在胃癌组织中的表达呈负相关(r=-0.486),p16与Survivin也呈负相关(r=-0.518),Cyclin D1与Survivin呈正相关(r=0.431).结论 p16、Cyclin D1和Survivin与胃癌的发生发展和预后关系密切.

  6. The abnormalities of p16 gene expression and the methylation status of p16 gene promotor in gastric cancer%原发胃癌中p16基因及其甲基化状态、表达异常的研究

    Institute of Scientific and Technical Information of China (English)

    孔祥东; 张思仲; 胡建坤; 肖翠英; 孙岩

    2001-01-01

    目的检测胃癌组织中p16基因及启动子甲基化状态和p16蛋白表达情况.方法选择p16基因及启动子区域,用PCR-SSCP、MSP(甲基化特异的PCR)法、测序和免疫组化等方法对100例胃癌患者的癌组织和癌旁组织进行检测.结果 71%的病例p16表达阴性,54%的病例具有p16基因启动子区的高甲基化,50%的病例同时有p16表达阴性和p16基因启动子区的高甲基化,无突变和纯合缺失检出.结论提示p16基因启动子区域高甲基化是胃癌中p16基因失活的主要原因.

  7. Imunolocalização das proteínas dos genes supressores de tumores TP53 e p16CDKN2 no front invasivo do carcinoma epidermóide de cavidade bucal Immunolocalization of TP53 and p16CDKN2 tumour suppressor genes proteins in invasive front of oral epidermoid carcinoma

    Directory of Open Access Journals (Sweden)

    Alfredo Maurício Batista De-Paula

    2006-08-01

    Full Text Available INTRODUÇÃO: A carcinogênese bucal é um processo multipassos no qual eventos genéticos promovem o rompimento de vias regulatórias normais que controlam funções celulares básicas. O carcinoma epidermóide de cavidade bucal (CECB surge como conseqüência de múltiplos eventos moleculares induzidos pelos efeitos de vários carcinógenos influenciados por fatores ambientais contra um quadro de resistência ou suscetibilidade herdada geneticamente. OBJETIVO: Avaliar a importância clínica e morfológica da imunoexpressão das proteínas p53 e p16 na região do front invasivo de uma série de 35 casos rotineiramente processados de CECB. MATERIAL E MÉTODOS: Amostras de CECB primários tratados exclusivamente por cirurgia foram investigadas. O sistema TNM foi empregado para o estadiamento clínico dos pacientes. Para a gradação morfológica das lesões foi adotado o sistema de gradação do front invasivo. A técnica de imuno-histoquímica foi realizada nas lesões fixadas em formalina tamponada a 10% e emblocadas em parafina para identificação das proteínas p53 e p16. As contagens foram realizadas e submetidas a tratamentos estatísticos específicos. RESULTADOS: As taxas de imunolocalização para as proteínas p53 e p16 foram de 63% e 66%, respectivamente, nas 35 amostras de carcinoma estudadas. Não houve relação entre as expressões das proteínas p53 e p16 com os parâmetros clínico-morfológicos analisados. Não houve correlação entre a expressão imuno-histoquímica das proteínas p53/p16. CONCLUSÃO: A expressão das proteínas p53 e p16 não influenciou os parâmetros clínico-morfológicos analisados neste estudo e aparentemente não representa base molecular para o significado biológico da região do front invasivo tumoral. A ausência de forte correlação entre as expressões imuno-histoquímicas das proteínas p53 e p16 sugere que as mesmas podem participar de atividade biológicas do controle do ciclo celular por

  8. P16表达在宫颈上皮内病变中的诊断价值%Diagnostic Value of P16 Expression in Cervical Intraepithelial Lesions

    Institute of Scientific and Technical Information of China (English)

    程涛; 沈红; 邱学芳

    2016-01-01

    Objective To investigate the expression of p16 protein in cervical intraepithelial lesions diagnostic value. Methods Convenient from Zhaotong City of Yunnan Province in 2004 to 2015 the first people's Hospital cervical speci-mens of 180 cases as the research object, using immunohistochemistry SP method to detect the expression of 180 cases of benign cervical lesions and cervical intraepithelial lesion in p16 protein, and the expression and significance of analysis. Results Cervical benign lesions of p16 expression rate was 0%, the rate of p16 expression in LSIL is 45%and is focal point to express and largely confined to the middle and the surface, p16 expression in HSIL rate more than 100% and for ribbon strong positive expression, the significant difference between groups (P<0.05). Conclusion P16 can be used as a differential diagnosis between cervical benign lesions, LSIL and HSIL a useful marker.%目的:探讨p16蛋白表达在宫颈上皮内病变中的诊断价值。方法方便选取云南省昭通市第一人民医院2004-2015年间的宫颈标本180例作为研究对象,采用免疫组化SP法检测180例宫颈良性病变及宫颈上皮内病变中p16蛋白的表达,并对其表达和意义进行分析。结果宫颈良性病变中p16表达率为0%,LSIL中p16表达率为45%且多为点灶状表达并主要局限于中间及表层,HSIL中p16表达率100%且多为带状强阳性表达,各组之间差异有统计学意义(P<0.05)。结论 p16可以作为宫颈良性病变、LSIL及HSIL之间鉴别诊断的一个有用的标记物。

  9. A study on p16 protein expression and p16 gene deletion in primary hepatocellula r carcinoma%原发性肝细胞癌中p16蛋白的表达及其基因的缺失性研究

    Institute of Scientific and Technical Information of China (English)

    赵向前; 冯玉泉; 赵霖; 邓心新

    2001-01-01

    Objective To study the p16 protein expression and p16 gene deletion in hepatocellular carcinoma(HCC), and to evaluate the relati onship between p16 gene and HCC.  Methods Using immunohistochemistry and polymerase chain reaction (PCR), we exam ined the expression of p16 protein and the deletion of p16 gene in 25 cases of H CC. Results The loss of p16 protei n expression was observed in 17 cases of HCC (68%,17/25) and in 1 case of tumor adjacent tissues (4%,1/25), respectively (P<0.01). The loss of p16 prot ein expression was closely correlated with poor histological differentiation of the tumor (P<0.05), but not related to the size of the tumor, nor the serum AFP level(P>0.05).The deletion rate of p16 gene in HCC(28%, 7/25) w as significantly different from that in tumor adjacent hepatic tissues(4%,1/2 5). The deletion rate of p16 gene was not correlated with the histological dif ferentiation, nor with the size of the tumor and serum AFP level (P>0.0 5). Conclusions There was a close relationship between hepatocarcinogenesis and p16 gene inactivation. The expres sion of p16 protein may be an useful index to predict the prognosis.%目的 研究原发性肝细胞癌中p16蛋白的表达及其基因的缺失 情况,探讨p16基因与肝癌的关系。 方法 采用回顾性调查研究方法,收集我院原发性肝癌25例,用免疫组织化学SP法、聚合酶链反应 (PCR)方法检测肝癌及癌旁组织中p16蛋白的表达及其基因的扩增情况。 结果25例肝癌中,p16蛋白阴性表达率为68%(17/25),癌 旁组织中p16蛋白阴性表达率为4%(1/25)。两者差异有显著意义(P0.05)。p16基因在癌组织中的缺失率(28%,7/25)显著高于癌旁组 织(4%,1/25)(P0.05)。 结论 p16基因失活与肝 癌发生关系密切。除了基因缺失之外,还有其他引起p16基因失活的因素存在。p16蛋白的检 测可能是预测病人预后的一个指标,但尚需进一步证实。

  10. GenBank

    Science.gov (United States)

    Benson, Dennis A.; Cavanaugh, Mark; Clark, Karen; Karsch-Mizrachi, Ilene; Lipman, David J.; Ostell, James; Sayers, Eric W.

    2017-01-01

    GenBank® (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive database that contains publicly available nucleotide sequences for 370 000 formally described species. These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole genome shotgun (WGS) and environmental sampling projects. Most submissions are made using the web-based BankIt or the NCBI Submission Portal. GenBank staff assign accession numbers upon data receipt. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through the NCBI Nucleotide database, which links to related information such as taxonomy, genomes, protein sequences and structures, and biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. Recent updates include changes to policies regarding sequence identifiers, an improved 16S submission wizard, targeted loci studies, the ability to submit methylation and BioNano mapping files, and a database of anti-microbial resistance genes. PMID:27899564

  11. Tissue microarray evidence of association between p16 and phosphorylated eIF4E in tonsillar squamous cell carcinoma.

    Science.gov (United States)

    Fury, Matthew G; Drobnjak, Marija; Sima, Camelia S; Asher, Marina; Shah, Jatin; Lee, Nancy; Carlson, Diane; Wendel, H Guido; Pfister, David G

    2011-09-01

    Expression of p16 is a marker for human papillomavirus (HPV)-related carcinogenesis in head and neck cancer. The purpose of this study is to determine if p16 immunoreactivity is associated with aberrant expression of components of the PI3 kinase pathway. A tissue microarray (TMA) was constructed for 46 archived tonsillar squamous cell carcinoma specimens. Clinical demographics of these patients were analyzed, and the TMA was interrogated with antibodies directed against p16, phosphorylated Akt(Ser473), phosphorylated S6(Ser240/244), phosphorylated S6(Ser235/236), phosphorylated 4E-BP1(Thr37/46), phosphorylated eIF4E(Ser209), PTEN, p21, and p53. There was a significant correlation between history of tobacco abuse (>10 pack/years) and absence of p16 expression (p = .01). Expression of p16 was significantly associated with immunoreactivity of p21 (p = .02), PTEN (p = .02), and phosphorylated eIF4E (p = .03). There was no evidence of association between p16 status and expression of phosphorylated S6, phosphorylated 4E-BP1, or p53. p16 positive tonsillar squamous cell carcinoma is characterized by expression of phosphorylated eIF4E that may occur via a mammalian target of rapamycin (mTOR)-independent mechanism. Copyright © 2010 Wiley Periodicals, Inc.

  12. p16 Immunohistochemistry in Colposcope-Directed and Random Cervical Biopsies of CIN2 and CIN3.

    Science.gov (United States)

    Arvizo, Cynthia; Chen, Qing; Du, Hui; Wang, Chun; Tang, Jinlong; Yang, Bin; Pretorius, Robert G; Wu, Ruifang; Belinson, Jerome Leslie

    2016-07-01

    The aim of this study was to determine if there is a different p16 expression pattern between colposcope-directed and random (colposcope-undetectable) biopsies of cervical intraepithelial neoplasia (CIN2) and CIN3. Cervical biopsies that were positive for CIN2 or CIN3 were selected from a database of samples acquired during a large population-based clinical trial in Guangdong Province in China (Shenzhen Cervical Cancer Screening Study II). Blocks were recut, reread, and then immunostained for p16. Biopsies were categorized as either colposcope-directed or random biopsies. Diffuse staining was considered p16 positive, whereas focal or no staining was considered p16 negative. Differences were determined by the Fisher exact test. Among the patients with CIN3, there were 232 individual biopsies of CIN3. Sixty were randomly collected, and 172 were colposcopy directed. p16 positivity for the colposcope-directed and random biopsies was 97.7% and 91.7%, respectively (p = 0.052). Like the CIN3 biopsies, colposcope-directed and random CIN2 samples expressed p16 similarly (86.8% [46/53] and 82.6% [19/23], p = .73, respectively). Based on our data, even small colposcope-undetectable biopsies of CIN3 are significant. Random biopsies of CIN2 or CIN3 demonstrate similar p16 positivity as visible lesions and therefore might be expected to have a similar natural history.

  13. p53 and p16 in oral epithelial dysplasia and oral squamous cell carcinoma: A study of 208 cases

    Directory of Open Access Journals (Sweden)

    Juan C Cuevas Gonzalez

    2016-01-01

    Full Text Available Background: The use of p16 and p53 as biomarkers of malignant transformation of oral epithelial dysplasia (OED and biological behavior of oral squamous cell carcinoma (OSCC is controversial. Aim: To determine the immunoexpression of p16 and p53 in OED and OSCC and to establish their possible relation to histopathological grading of OED/OSCC. Materials and Methods: Ninety-six OEDs (40 mild, 36 moderate, and 20 severe dysplasia; and 112 OSCCs (64 well-differentiated, 38 moderately differentiated, and 10 poorly differentiated coming from archives of four centers of oral pathology were included. Histological slides from all cases were processed with immunohistochemical technique using anti-p53 and anti-p16 antibodies. The intensity of the immunoreactivity were classified using the ImageLab®MCM systemas follows: 60–90 strong. Forstatistical purposesa χ2 test (P 0.05. Statistical association of p16-positive and p53-positive cells to basal stratum of OED (P = 0.0008; P = 0.0000, respectively and p16-positive cells and p53-positive cells to perivascular zone of OSCC (P = 0.001; P = 0.0000, respectively was found. Conclusions: p16 and p53 could be not specific enough to identify patients suffering OED with high risk to malignancy; however, the evaluation of the presence of p16 and p53 in the tumoral invasive front of OSCC could contribute to establish the tumor progression.

  14. Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a

    Science.gov (United States)

    Boquoi, Amelie; Arora, Sanjeevani; Chen, Tina; Litwin, Sam; Koh, James; Enders, Greg H

    2015-01-01

    The cyclin-dependent kinase (Cdk) inhibitor p16Ink4a (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. PMID:25481981

  15. Double positivity for HPV DNA/p16 in tonsillar and base of tongue cancer improves prognostication

    DEFF Research Database (Denmark)

    Garnaes, Emilie; Frederiksen, Kirsten; Kiss, Katalin

    2016-01-01

    of tongue squamous cell carcinoma (BSCC) when stratifying for HPV DNA status, p16 expression and combined HPV/p16 status. We included all patients (n = 797) diagnosed with TSCCs and BSCCs in Eastern Denmark as registered in the Danish Head and Neck Cancer Group (DAHANCA) database and the Danish Pathology...... Databank, 2000–2010. Patients were treated according to national guidelines (radiotherapy +/− concomitant cisplatin). All specimens were analysed using HPV DNA PCR and p16 immunohistochemistry. Clinical information was retrieved from the DAHANCA database and the Danish National Patient Registry....... Information on vital status was obtained from the Danish Civil Registration System. We observed improved OS for HPV+/p16+ BSCCs compared to HPV−/p16− (hazard ratio for death [HR], 0.15; 95% CI, 0.09–0.24). Among STSCCs, HPV+/p16+ showed the lowest HR (0.19, 95% CI, 0.13–0.29); whereas, HPV−/p16+ showed...

  16. p16(INK4A) enhances the transcriptional and the apoptotic functions of p53 through DNA-dependent interaction.

    Science.gov (United States)

    Al-Khalaf, Huda H; Nallar, Shreeram C; Kalvakolanu, Dhananjaya V; Aboussekhra, Abdelilah

    2017-02-20

    p16(INK4A) and p53 are two important tumor suppressor proteins that play essential roles during cell proliferation and aging through regulating the expression of several genes. Here, we report that p16(INK4A) and p53 co-regulate a plethora of transcripts. Furthermore, both proteins colocalize in the nucleus of human primary skin fibroblasts and breast luminal cells, and form a heteromer whose level increases in response to genotoxic stress as well as aging of human fibroblasts and various mouse organs. CDK4 is also present in this heteromeric complex, which is formed only in the presence of DNA both in vitro using pure recombinant proteins and in vivo. We have also shown that p16(INK4A) enhances the binding efficiency of p53 to its cognate sequence presents in the CDKN1A promoter in vitro, and both proteins are present at the promoters of CDKN1A and BAX in vivo. Importantly, the fourth ankyrin repeat of p16(INK4A) and the C-terminal domain of p53 were necessary for the physical association between these two proteins. The physiologic importance of this association was revealed by the inability of cancer-associated p16(INK4A) mutants to interact with p53 and to transactivate the expression of its major targets CDKN1A and BAX in the p16-defective U2OS cells expressing either wild-type or mutated p16(INK4A) . Furthermore, the association between p16(INK4A) and p53 was capital for their nuclear colocalization, the X-ray-dependent induction of p21 and Bax proteins as well as the induction of apoptosis in various types of cells. Together, these results show DNA-dependent physical interaction between p16(INK4A) and p53.

  17. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis.

    Science.gov (United States)

    Nuovo, G J; Plaia, T W; Belinsky, S A; Baylin, S B; Herman, J G

    1999-10-26

    We have developed a technique, methylation-specific PCR in situ hybridization (MSP-ISH), which allows for the methylation status of specific DNA sequences to be visualized in individual cells. We use MSP-ISH to monitor the timing and consequences of aberrant hypermethylation of the p16 tumor suppresser gene during the progression of cancers of the lung and cervix. Hypermethylation of p16 was localized only to the neoplastic cells in both in situ lesions and invasive cancers, and was associated with loss of p16 protein expression. MSP-ISH allowed us to dissect the surprising finding that p16 hypermethylation occurs in cervical carcinoma. This tumor is associated with infection of the oncogenic human papillomavirus, which expresses a protein, E7, that inactivates the retinoblastoma (Rb) protein. Thus, simultaneous Rb and p16 inactivation would not be needed to abrogate the critical cyclin D-Rb pathway. MSP-ISH reveals that p16 hypermethylation occurs heterogeneously within early cervical tumor cell populations that are separate from those expressing viral E7 transcripts. In advanced cervical cancers, the majority of cells have a hypermethylated p16, lack p16 protein, but no longer express E7. These data suggest that p16 inactivation is selected as the most effective mechanism of blocking the cyclin D-Rb pathway during the evolution of an invasive cancer from precursor lesions. These studies demonstrate that MSP-ISH is a powerful approach for studying the dynamics of aberrant methylation of critical tumor suppressor genes during tumor evolution.

  18. Protein p 16INK4A expression in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of uterine cervix

    Directory of Open Access Journals (Sweden)

    Gupta Ruchi

    2010-01-01

    Full Text Available The association of human papilloma virus (HPV infection and cervical intraepithelial neoplasia (CIN is well recognized. Interaction of HPV oncogenic proteins with cellular regulatory proteins leads to up regulation of p16 INK4A , a CDK inhibitor, which is a biomarker for HPV infection. We investigated p16 expression in CIN and invasive squamous cell carcinoma (SCC which has not been reported in the Indian population previously. Materials and Methods: Retrospective analysis of 100 cases with 20 cases each of histologically normal cervical epithelium, CIN1, 2, 3 and invasive SCC for p16 expression was performed by immunohistochemistry using commercially available mouse monoclonal antibody to p16 (clone 6H12. Statistical Analysis: For differences in expression among groups, statistical analysis was carried out using ANOVA and post hoc test of Scheffe. Results: p16 immunoreactivity was found to be both nuclear and/or cytoplasmic. The normal cervical epithelium was predominantly negative for p16 (18/20. There was a progressive increase of p16 expression with the grade of CIN. In CIN 1, two cases (20% showed nuclear and nucleocytoplasmic positivity respectively. In contrast, diffuse strong nuclear or nucleocytoplasmic expression was observed in 45 and 55% cases of CIN 2 and CIN 3 respectively. All except one squamous cell carcinoma stained strongly positive for p16. The difference in expression between CIN 2/3 and SCC versus normal cervix was found highly significant (p is equal to 0.008 and p less than 0.001. Conclusions: p16 expression correlates excellently with the grade of CIN and is a sensitive marker of cervical intraepithelial neoplasia.

  19. Determination of p16 overexpression as an indicator of human papillomavirus infection in oral dysplasia and carcinoma

    Directory of Open Access Journals (Sweden)

    Adrija Pathak

    2017-01-01

    Full Text Available Context: Oral and pharyngeal cancer, grouped together, is the sixth most common cancer in the world. In the past few years, human papillomavirus (HPV infection has been suggested as a risk factor for oral cancer apart from traditional risk factors such as smoking, tobacco, and alcohol consumption. Aims: The aim of this study was to determine HPV status of the tumors using polymerase chain reaction (HPV-DNA PCR and p16 immunostaining and to correlate p16 overexpression as an indicator of HPV-associated oral dysplasia and carcinoma. Settings and Design: A prospective study was conducted in fifty cases of suspected oral cancer. Materials and Methods: PCR Amplification of extracted HPV-DNA was done for HPV-DNA status in fresh tissue of suspected oral cancer cases. Histomorphological features of the cases were analyzed, and p16 immunohistochemistry was performed on the same specimen after making paraffin blocks to study p16 overexpression. Statistical Analysis Used: Chi-square test was used to analyze the differences between discrete variables. Results: 5/6 (83.3% HPV-DNA-positive cases were positive for p16 expression, whereas 26/44 (59.09% p16-positive cases which were negative for HPV-DNA. Sensitivity and specificity of p16 as a surrogate marker for HPV-DNA were found to be 83.3% and 40%, respectively. Conclusions: p16 immunostaining is a good first-line assay for eliminating HPV-negative cases from additional analysis, but other causes of p16 overexpression in oral tumorigenesis related to tobacco consumption in keratinizing squamous cell carcinoma needs to be explored further.

  20. Expression and significance of p16 and pRb in cutaneous squamous cell carcinoma%p16和pRb在皮肤鳞癌中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    刘彦群; 魏志平; 张昕博

    2005-01-01

    目的:探讨p16、pRb蛋白在皮肤鳞癌中的表达及他们的相互关系和意义.方法:应用免疫组织化学SP法检测40例原发性皮肤鳞癌组织中p16、pRb的表达.结果:p16、pRb阳性表达率分别为37.5%和52.5%.两者在皮肤鳞癌中的表达呈显著负相关(P=0.011).结论:在原发性皮肤鳞癌中存在p16和pRb的异常表达现象,两者的表达相互抑制,呈显著负相关.

  1. Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer

    DEFF Research Database (Denmark)

    Lassen, Pernille; Primdahl, Hanne; Johansen, Jørgen

    2014-01-01

    HPV-associated p16-expression in a cohort of patients with stage III-IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin. MATERIAL AND METHODS: 1294 patients......BACKGROUND AND PURPOSE: HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed...

  2. Role of the Biomarker p16 in Downgrading -IN 2 Diagnoses and Predicting Higher-grade Lesions.

    Science.gov (United States)

    Maniar, Kruti P; Sanchez, Beatriz; Paintal, Ajit; Gursel, Demirkan B; Nayar, Ritu

    2015-12-01

    In 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology published the "LAST" recommendations for histopathology reporting of human papilloma virus-related squamous lesions of the lower anogenital tract, including the use of a 2-tier nomenclature (low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion [LSIL/HSIL]) and expanded use of the biomarker p16 to classify equivocal lesions as either precancer (HSIL) or low-grade lesions (LSIL)/non-human papilloma virus changes. We aimed to determine (1) the frequency with which the poorly reproducible diagnosis of intermediate-grade (-IN 2) lesion in the lower anogenital tract would be downgraded on the basis of p16 results, and (2) whether p16 status was predictive of subsequent higher-grade lesions. A total of 200 specimens diagnosed as an intermediate-grade (-IN 2) lesion of the cervix (168), vagina (2), vulva (2), and anus (28) were reviewed and immunostained for p16. Slides were independently reviewed by 2 pathologists, with discrepant p16 interpretations adjudicated by a third pathologist. Of the 200 cases, 32% were negative for p16. Among the 166 patients with subsequent pathology (including 131 excisions), 26.2% of p16-positive cases versus 4.4% of p16-negative cases were associated with a subsequent diagnosis of HSIL (-IN 3) or worse (P=0.002). Reproducibility of the biopsy diagnosis was fair, with no significant difference with the addition of p16 or using 2 versus 3 tiers. In 11.5% of cases, there was discordance in p16 interpretation (κ 0.735, good agreement). The results indicate that using the Lower Anogenital Squamous Terminology recommendations would result in approximately one third of equivocal (-IN 2) diagnoses being downgraded to LSIL over 1 year in a busy academic practice. The significant association of p16 expression with a higher risk for HSIL on a subsequent specimen suggests that use of p16 to adjudicate equivocal (-IN 2

  3. P16蛋白在人血管瘤不同时期的表达及意义%The expression end significance of P16 in human hemangiomas from different stages

    Institute of Scientific and Technical Information of China (English)

    王石; 郑巍; 贾占立

    2011-01-01

    目的 探讨P16蛋白在人血管瘤发生、发展及消退过程中的表达状况及其生物学意义.方法 采用免疫组织化学方法(SABC法)检测人血管瘤增生期、消退期及正常组织中P16蛋白的表达水平.结果 增生期血管瘤内皮细胞P16蛋白的表达水平低于消退期,消退期血管瘤内皮细胞P16蛋白的表达水平低于正常组织,各组之间差异均有显著性(P<0.05).结论 ①P16蛋白的表达水平与血管瘤的发生、发展及消退有关.②P16蛋白通过抑制血管瘤内皮细胞的增殖和血管生成在血管瘤的消退过程中起重要作用.%Objective To investigate the expression and significance of P16 in the occurrence, development and regression of human hemangiomaa. Methods The expression of P16 was examined in proliferating, involuting human hemangiomas and normal tissues by using immunohistochemical technique ( SABC). Results The expression of P16 was significantly lower in proliferating hemangiomas than in involuting hemangomas, and was significantly lower in the involuting hemangiomas than in normal tissues. There is significant difference between the three pathologies ( P < 0.05 ). Conclusion ①The expression of P16 is associated with the occurrence, development and regression of human hemangiomas. ②It is suggested that P16 might play an important role in the regression of human hemangiomas endothelial cells and and -angiogenesis.

  4. ALTERATIONS OF pRb/CDK4/p16INK4a PATHWAY IN GASTRIC CARCINOMAS%胃癌中p16INK4a-CDK4-pRb通路蛋白表达异常

    Institute of Scientific and Technical Information of China (English)

    赵英芳; 田新霞; 卢阳

    2005-01-01

    目的:检测胃癌组织中p16INK4a-CDK4-pRb通路p16INK4a、CDK4、pRb蛋白表达状况,探讨蛋白表达与胃癌发生发展以及临床病理指标的关系.方法:采用免疫组织化学方法检测了胃癌组织中p16INK4a、CDK4、pRb蛋白表达.结果:10例正常胃黏膜中相应蛋白表达全部阳性,而肿瘤组织中p16INK4a、pRb蛋白表达阳性率分别为54%(44/81)和90%(73/81),p16INK4a蛋白表达显著低于正常组织(P=0.005),26%(21/81)的肿瘤组织中CDK4过表达.p16INK4a、pRb、CDK4蛋白表达与肿瘤组织学类型、淋巴结转移及性别、年龄均无相关性.结论:p16INK4a、CDK4、pRb蛋白表达异常是胃癌细胞常见的分子事件,p16INK4a-CDK4-pRb细胞周期调控通路异常可能参与了胃癌的发生发展.

  5. 关于P16在大肠癌组织中表达的实验研究%Study on expression of p16 gene in colon tumors

    Institute of Scientific and Technical Information of China (English)

    商建华

    2010-01-01

    目的检测p16蛋白在大肠癌中的缺失情况及与病理分型和临床分期的关系,探索p16基因转染对大肠癌细胞各期的作用.方法应用免疫组织化学法检测p16蛋白在96例大肠癌患者中的表达.结果与结论(1)p16蛋白的缺失在大肠癌的发生发展中起重要作用,P<0.05.(2)p16蛋白表达与大肠癌分化程度和临床分期有关,随着病理分型及临床分期的变化,p16蛋白在组织中的表达也随之改变.

  6. The Study on Flow Cytometry of p16 Transfected Fibroblasts%流式细胞术分析p16转染的成纤维细胞

    Institute of Scientific and Technical Information of China (English)

    韩晓琳

    2007-01-01

    目的 研究正义p16转染的2BS(人胚肺二倍体成纤维细胞)与衰老2Bs细胞的不同,进一步探讨p16与细胞衰老的相互关系.方法 建立稳定表达的2BS/p16,2BS/asp16,和2BS/neo细胞系,并用FACS(流式细胞仪)对各种转染细胞和各阶段正常2BS细胞进行分析.结果 正义p16转染的2BS/p16细胞阻滞在G1期和G2/M期,而衰老的2BS细胞仅阻滞在G1期.结论 p16对细胞衰老的诱导,伴随着p21的表达变化.

  7. All-trans retinoic acid induces cellular senescence via upregulation of p16, p21, and p27.

    Science.gov (United States)

    Park, Sun-Hye; Lim, Joo Song; Jang, Kyung Lib

    2011-11-28

    We here present a new anti-tumor mechanism of all-trans retinoic acid (ATRA). ATRA induced several biomarkers of cellular senescence including irreversible G1 arrest, morphological changes, senescence-associated β-galactosidase, and heterochromatin foci in HepG2 cells. ATRA also upregulated levels of p16, p21, and p27 which lead to activation of Rb and subsequent inactivation of E2F1. These effects were abolished by the RNA interference-mediated silencing of p16, p21, and p27. Moreover, ATRA failed to induce cellular senescence in Huh7 and HCT116, in which p16, p21, and p27 were not upregulated by ATRA, confirming that ATRA induces cellular senescence via upregulation of p16, p21, and p27. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines

    National Research Council Canada - National Science Library

    He, J; Allen, J R; Collins, V P; Allalunis-Turner, M J; Godbout, R; Day, 3rd, R S; James, C D

    1994-01-01

    ... those established from malignant gliomas. Here we have examined 32 glioma cell lines for amplification-associated overexpression of the CDK4 gene as an alternative mechanism for abrogating the growth-regulatory effects of p16...

  9. Distribution of Human Papillomavirus 52 and 58 Genotypes, and Their Expression of p16 and p53 in Cervical Neoplasia

    National Research Council Canada - National Science Library

    Kim, Tae Eun; Kim, Hwal Woong; Lee, Kyung Eun

    2014-01-01

    This study investigates the prevalence of human papillomavirus (HPV) 52 and 58 genotypes among women residing in Busan, and the expression of p16 and p53 proteins in cervical neoplasia with HPV 52 and 58 infections...

  10. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study

    National Research Council Canada - National Science Library

    Ikenberg, Hans; Bergeron, Christine; Schmidt, Dietmar; Griesser, Henrik; Alameda, Francisco; Angeloni, Claudio; Bogers, Johannes; Dachez, Roger; Denton, Karin; Hariri, Jalil; Keller, Thomas; von Knebel Doeberitz, Magnus; Neumann, Heinrich H; Puig-Tintore, Luis M; Sideri, Mario; Rehm, Susanne; Ridder, Ruediger

    2013-01-01

    ...) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2...

  11. Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer

    DEFF Research Database (Denmark)

    Gilbert, Duncan C; Serup-Hansen, Eva; Linnemann, Dorte

    2016-01-01

    BACKGROUND: The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV- patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification...... of this group. METHODS: Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs). RESULTS: Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse......-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006). CONCLUSIONS: Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response....

  12. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia

    Science.gov (United States)

    Holst, Charles R.; Nuovo, Gerard J.; Esteller, Manel; Chew, Karen; Baylin, Stephen B.; Herman, James G.; Tlsty, Thea D.

    2003-01-01

    Cultures of human mammary epithelial cells (HMECs) contain a subpopulation of variant cells with the capacity to propagate beyond an in vitro proliferation barrier. These variant HMECs, which contain hypermethylated and silenced p16(INK4a) (p16) promoters, eventually accumulate multiple chromosomal changes, many of which are similar to those detected in premalignant and malignant lesions of breast cancer. To determine the origin of these variant HMECs in culture, we used Luria-Delbruck fluctuation analysis and found that variant HMECs exist within the population before the proliferation barrier, thereby raising the possibility that variant HMECs exist in vivo before cultivation. To test this hypothesis, we examined mammary tissue from normal women for evidence of p16 promoter hypermethylation. Here we show that epithelial cells with methylation of p16 promoter sequences occur in focal patches of histologically normal mammary tissue of a substantial fraction of healthy, cancer-free women.

  13. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens

    DEFF Research Database (Denmark)

    Lesnikova, Iana; Lidang, Marianne; Hamilton-Dutoit, Stephen

    2009-01-01

    BACKGROUND: To evaluate the usefulness of this biomarker in the diagnosis of cases of cervical neoplasia we studied the immunohistochemical expression of p16INK4a in a large series of archival cervical biopsies arranged into tissue microarray format. METHODS: TMAs were constructed with tissue cores...... from archival formalin fixed, paraffin-embedded donor tissues from 796 patients, and included cases of cervical intraepithelial neoplasia (CIN)1 (n = 249), CIN2 (n = 233), CIN3 (n = 181), and invasive cervical carcinoma (n = 133). p16INK4a expression was scored using two different protocols: 1......) positive vs negative p16INK4a staining; 2) a semi-quantitative immunohistochemical score (0 to 8 points) according to the intensity of staining and the proportion of stained cells RESULTS: p16INK4A expression was not seen in normal cervix tissue, but was found with increasing frequency in the sequence: CIN...

  14. Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters.

    Science.gov (United States)

    Dublin, E A; Patel, N K; Gillett, C E; Smith, P; Peters, G; Barnes, D M

    1998-02-20

    The cell cycle-associated retinoblastoma protein (pRb) and p16 protein were demonstrated using immuno-histochemistry on paraffin sections from 192 cases of invasive breast carcinoma. Abnormal expression of pRb was defined as negative staining and was seen in 17% of tumours. Such abnormal expression was significantly more frequent in tumours with negative oestrogen receptor (ER) status. There was also a trend for tumours which were negative for pRb to be grade III ductal carcinomas. There was no association between p16 staining and any histopathological parameter, though, surprisingly, log-rank analysis showed that strong staining was associated with a poor outcome. There was a significant inverse relationship between pRb and p16 expression and a significant positive association between pRb and cyclin D1. In a Cox multivariate analysis, which included cyclin D1, neither pRb nor p16 was an independent predictor of patient outcome.

  15. Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening.

    Science.gov (United States)

    Wentzensen, Nicolas; Fetterman, Barbara; Tokugawa, Diane; Schiffman, Mark; Castle, Philip E; Wood, Shannon N; Stiemerling, Eric; Poitras, Nancy; Lorey, Thomas; Kinney, Walter

    2014-12-01

    Dual-stain cytology for p16 and Ki-67 has been proposed as a biomarker in cervical cancer screening. The authors evaluated the reproducibility and accuracy of dual-stain cytology among 10 newly trained evaluators. In total, 480 p16/Ki-67-stained slides from human papillomavirus-positive women were evaluated in masked fashion by 10 evaluators. None of the evaluators had previous experience with p16 or p16/Ki-67 cytology. All participants underwent p16/Ki-67 training and subsequent proficiency testing. Reproducibility of dual-stain cytology was measured using the percentage agreement, individual and aggregate κ values, as well as McNemar statistics. Clinical performance for the detection of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) was evaluated for each individual evaluator and for all evaluators combined compared with the reference evaluation by a cytotechnologist who had extensive experience with dual-stain cytology. The percentage agreement of individual evaluators with the reference evaluation ranged from 83% to 91%, and the κ values ranged from 0.65 to 0.81. The combined κ value was 0.71 for all evaluators and 0.73 for cytotechnologists. The average sensitivity and specificity for the detection of CIN2+ among novice evaluators was 82% and 64%, respectively; whereas the reference evaluation had 84% sensitivity and 63% specificity, respectively. Agreement on dual-stain positivity increased with greater numbers of p16/Ki-67-positive cells on the slides. Good to excellent reproducibility of p16/Ki-67 dual-stain cytology was observed with almost identical clinical performance of novice evaluators compared with reference evaluations. The current findings suggest that p16/Ki-67 dual-stain evaluation can be implemented in routine cytology practice with limited training. © 2014 American Cancer Society.

  16. Immunolabeling for p16, WT1, and Fli-1 in the assignment of growth phase for cutaneous melanomas.

    Science.gov (United States)

    Strickler, Allen G; Schaefer, Jochen T; Slingluff, Craig L; Wick, Mark R

    2014-09-01

    Distinction between radial growth phase (RGP) and vertical growth phase (VGP) in cutaneous melanomas is prognostically significant. Despite established morphological criteria, molecular markers to separate RGP and VGP have not been well established. The goal of this study was to investigate associations of p16, WT1, and Fli-1 with RGP-to-VGP progression, by immunohistochemistry. The p16 is a tumor suppressor, whereas WT1 and Fli-1 are transcriptional activators. The authors hypothesized that entry into VGP would be associated with decreased p16 and increased WT1 and Fli-1. Paraffin sections from 18 RGP and 15 VGP melanomas were immunostained with well-characterized antibodies to p16, WT1, and Fli-1. Melanoma growth phases were determined using precodified morphological attributes. In RGP melanomas, p16 was expressed in 15 of 18 (83%), WT1 in 17 of 17 (100%), and Fli-1 at least focally in 6 of 18 (33%). The deep dermal component of VGP melanomas stained positively for Fli-1 in 9 of 14 (64%), strongly for WT1 in 10 of 14 (71%), and strongly for p16 in only 2 of 15 (13%). Observed patterns of WT1 immunopositivity did not support the authors' hypothesis; it is not likely to be a good indicator of VGP. On the other hand, Fli-1 staining trended toward more positive deep tumor compartment staining and p16 to weaker staining in the deep compartment. At present, application of histological criteria remains the best method for assignment of growth phase in melanomas; however, p16 and possibly Fli-1 immunostains may serve as useful adjuncts in morphologically indeterminate cases.

  17. P16表达与宫颈病变的相关性及临床意义%Correlation between P16 expression and cervical lesions and the clinical significance

    Institute of Scientific and Technical Information of China (English)

    金士杰; 陶秀坤; 李存肖; 谭志云

    2015-01-01

    目的:探讨P16在不同宫颈病变组织中的表达及在临床诊断中的应用价值.方法:选择慢性宫颈炎19例,各级别宫颈上皮内瘤变(CIN) 89例(CIN Ⅰ 35例,CINⅡ30例,CINⅢ24例)及宫颈鳞状细胞癌7例,采用免疫组化技术检测P16在各组患者的表达水平.结果:P16在慢性宫颈炎、CIN Ⅰ、CINⅡ、CINⅢ及宫颈鳞状细胞癌组患者的阳性表达率分别为0.00%、40.00%、66.67%、70.83%、100.00%,随宫颈病变程度的升级P16蛋白的表达率及阳性表达强度均逐渐上升,差异有统计学意义(P<0.05).结论:P16用于鉴别不同级别宫颈上皮内瘤变指异临床诊疗有重要价值.%Objective:To explore the expressions of P16 in various cervical lesions tissues and its application value in clinical diagnosis.Methods:Nineteen patients with chronic cervicitis,eighty-nine patients with cervical intraepithelial neoplasia (CIN) (35 patients with CIN Ⅰ,30 patients with CIN Ⅱ,and 24 patients with CIN Ⅲ),and seven patients with cervical squamous cell carcinoma were enrolled in the study; immunohistochemical technology was used to detect the expression levels of P16 in different groups.Results:The positive expression rates of P16 in chronic cervicitis,CIN Ⅰ,CIN Ⅱ,CIN Ⅲ,and cervical squamous cell carcinoma were 0.00%,40.00%,66.67%,70.83%,and 100.00%,respectively.The expression rate and positive expression intensity of P16 increased gradually with the aggravation of cervical lesions,there were statistically significant differences (P<0.05).Conclusion:P16 is used to identify different grades of CIN,which has an important value in guiding clinical diagnosis and treatment.

  18. 细胞周期调控因子p16和CDK4在肺癌中的表达%Expression of p16 and CDK4 in human lung carcinoma

    Institute of Scientific and Technical Information of China (English)

    路名芝; 刘勇

    2001-01-01

    Purpose:To study the expressions of p16 and CDK4 in human lung carcinoma. Methods:By using S-P immunohistochemical methods, the expressions of p16 and CDK4 in 62 cases of human lung carcnoma were studied. Results:The postive expressions for p16 and CDK4 protein were 58.1% and 48.4% respectively. A significant correlation was found between CDK4 overexpression and lymph node metastasis (P<0.01). A significant correlation between the under expression of p16 and overexpression of CDK4 was found.Conclusions:The results suggested that CDK4 overexpression plays an important role in metastasis of lung carcinoma.%目的:探讨肺癌中细胞周期调控因子p16和CDK4的表达意义。方法:应用S-P免疫组织化学方法检测62例肺癌组织中p16和CDK4的表达情况。结果:62例肺癌组织中p16和CDK4阳性率分别为58.1%和48.4%。腺癌中p16的阳性率明显高于小细胞癌(P<0.05);淋巴结转移阳性组p16的表达显著低于阴性组(P<0.05,r=0.27)。不同组织类型肺癌中CDK4的表达未见明显差异,淋巴结转移阳性组CDK4的表达高于阴性组(P<0.01,r=0.58)。p16和CDK4的表达呈明显负相关(P<0.01,r=-0.81)。结论:提示p16的表达与肺癌的组织学类型有关,CDK4高表达对肺癌细胞的淋巴结转移起重要作用。

  19. Study on p16 gene mutations in exhaled breath condensate of patients with non - small cell lung cancer%NSCLC患者呼出气冷凝液中p16基因突变的研究

    Institute of Scientific and Technical Information of China (English)

    蔡淑娟; 陈建荣; 陶国华; 周峰; 陈金亮; 陶一江

    2012-01-01

    目的 研究非小细胞肺癌患者(NSCLC)呼出气冷凝液(EBC)中p16基因突变的临床意义.方法 收集30例NSCLC患者和20例体检健康者的EBC标本,提取EBC中的DNA,对β-actin基因扩增阳性的EBC标本进行p16基因1、2、3号外显子PCR扩增,并进行DNA基因测序,用DNASTAR软件进行突变比对,结果进行统计学分析.结果 ①30例肺癌患者的EBC中,有26例β-actin基因片段扩增阳性,26例中有9例检出p16基因突变,突变率为34.6%.②9例肺癌患者发生p16基因突变的外显子,1号外显子3例,2号外显子5例,3号外显子1例.③26例肺癌患者EBC中β-actin基因片段扩增阳性中,Ⅰ期12例,p16基因突变3例,突变率25%;Ⅱ期7例,p16基因突变2例,突变率28.6%;Ⅲ期7例,p16基因突变4例,突变率57.1%.鳞癌14例,p16基因突变6例,突变率42.9%;腺癌11例,p16基因突变3例,突变率27.3%.结论 NSCLC患者EBC中可以检测到p16基因突变,特异性高,EBC中p16基因检测为肺癌研究提供新方法.

  20. Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma.

    Science.gov (United States)

    Matsuda, Yasunobu

    2008-03-21

    Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cell-cycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors. p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin D1, is frequently inactivated in HCC via CpG methylation of its promoter region. p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients. p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.

  1. Detecting of p16 Autoantibody as a Potential Early Diagnostic Serum Biomarker in Patients with Cervical Cancer.

    Science.gov (United States)

    Huangfu, Mingmei; Liu, Linlin; Xu, Shuang; Li, Siyao; Jiang, Kuo; Sun, Baosheng; Lee, Kuang-Hui; Sun, Shilong

    2016-01-01

    Over-expression of tumor-associated antigens (TAAs) may trigger secretion of their auto-antibodies. The present work was designed to test whether circulating antibody to P16 protein-derived antigens was altered in cervical cancer. 141 cases of cervical cancer patients, 133 cases of cervical benign tumor patients, and 153 healthy volunteers matched in age were recruited. The level of circulating P16 auto-antibody was tested using an ELISA developed in-house with linear peptide antigens derived from the P16 protein. The P16 auto-antibody in the malignant tumor group had a significantly higher level than the healthy control group and the benign tumor group (t = 4.016, p cervical cancer have the highest level of P16 autoantibody and the sensitivity against > 90% specificity was 20.3%. The circulating auto-antibody to P16 may be one of a series of potential biomarkers with early prognostic values for cervical cancer.

  2. P16(INK 4a) and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions.

    Science.gov (United States)

    Gültekin, Sibel Elif; Sengüven, Burcu; Klussmann, Jens Peter; Dienes, Hans Peter

    2015-03-01

    Human papilloma virus (HPV) is postulated as a risk factor in the etiology of some specific mucosal pathologies in the head and neck regions. Despite the frequent use of p16(INK4a) as a surrogate marker for HPV-infection, there is still controversy with respect to its reliability. This study has been undertaken to assess the potential role of p16(INK 4a) and Ki-67 expression in HPV-related lesions. The study was conducted on 71 specimens of oral, tonsillar and laryngeal lesions which comprised 25 dysplasia and 46 papilloma specimens. Specimens were immunohistochemically stained for p16(INK4A) and Ki-67 proteins. HPV DNA was determined by one step multiplex polymerase chain reaction. HPV DNA was detected in 33.8% of all lesions. Tonsil and larynx lesions showed significant differences with oral lesions for HPV positivity (p < 0.001). p16(INK 4a) over-expression was seen in 56.5% of papilloma and 60% of dysplasia specimens. HPV status showed a positive correlation with p16(INK 4a) expression in tonsillar dysplasias (p < 0.001). p16(INK 4a) expression may have a value as a marker in high risk HPV induced dysplasias, but not in low risk infected lesions. The proliferation index is not related to HPV-induced lesions and may be evaluated as an independent marker in head and neck premalignant lesions.

  3. p16 immunostaining as a predictor of anal and cervical dysplasia in women attending a sexually transmitted infection clinic

    Directory of Open Access Journals (Sweden)

    Deepika Pandhi

    2016-01-01

    Full Text Available Background: Carcinogenesis caused by human papillomavirus (HPV leads to over-expression of p16 protein. p16 may act as a marker of HPV integration with host genome and serve as a surrogate marker of HPV oncogenesis. Materials and Methods: A single center study of 75 women (35 HIV-positive and 40 HIV-negative women was conducted. Anal and cervical specimens were obtained for cytology and p16 immunostaining. Results: The sensitivity of p16 to diagnose anal and cervical dysplasia was 50% and 58.8%, respectively, whereas specificity was 98.6% and 100%, respectively. Positive predictive value for anal and cervical was 75% and 100%, whereas negative predictive value was 95.8% and 89.2%, respectively. A strong relationship between the grade of dysplasia and intensity of p16 immunoscore was observed (Pearson correlation r = 0.666, P< 0.0001 and r = 0.496, P< 0.0001 for anal and cervical, respectively. Conclusion: p16 immunostaining with greater specificity for high-grade lesions may improve the diagnostic accuracy, especially for high-grade lesions which have a high risk of progression to malignancy and thereby necessitate treatment.

  4. 甲状腺乳头状癌CD15s和p16表达研究

    Institute of Scientific and Technical Information of China (English)

    张金江; 尚培中; 谷化平

    2007-01-01

    目的探讨甲状腺乳头状癌(PTC)组织CD15s和p16蛋白表达与肿瘤侵袭转移的关系。方法应用免疫组织化学CSA技术检测46例PTC组织CD15s和p16蛋白的表达。结果在PTC中,CD15s和p16蛋白表达阳性率分别为69.6%和58.7%,CD15s表达阳性率与PTC的侵袭转移呈正相关(P〈0.05);P16蛋白表达阳性率与PTC的侵袭转移呈负相关(P〈0.05)。结论CD15s和p16蛋白表达与PTC侵袭转移密切相关,检测CD15s和p16可作为判断PTC预后的参考指标。

  5. P16蛋白表达一胃癌浸润转移的关系

    Institute of Scientific and Technical Information of China (English)

    白骏恒; 郭亭芳; 等

    2000-01-01

    目的:研究抑癌基因P16在胃癌中的表达,探讨P16蛋白在胃癌浸润转移中的作用。方法:采用链霉菌抗生物素蛋白过氧化物酶连接法(SP法),检测46例胃癌组织中P16蛋白的表达。结果:P16表达与性别、年龄、浸润深度无显著意义(P>0.05);伴淋巴结转移胃癌P16蛋白表达阳性率为6.9%,无淋巴结转移胃癌为35.3%,差异有显著意义(P<0.05)。结论:P16蛋白表达缺失可能与胃癌转移有关。

  6. Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand.

    Science.gov (United States)

    Kwon, H J; Brasch, H D; Benison, S; Marsh, R W; Itinteang, T; Titchener, G W; Evans, J; Tan, S T

    2016-10-01

    There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (pp16+ than in non-Europeans (67% compared with 44%, p=0.036). Patients with p16+ disease were younger (mean (SD) 56 (10) compared with 66 (9) years, pp16+ disease (65/86 (76%) compared with 15/49 (31%), p=0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (11.1) compared with 71 (11.2) years, p=0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment.

  7. DETEKSI GEN-GEN PENYANDI FAKTOR VIRULENSI PADA BAKTERI VIBRIO

    Directory of Open Access Journals (Sweden)

    Ince Ayu Khairani Kadriah

    2011-04-01

    menggunakan isolat bakteri yang diisolasi dari budidaya udang windu di berbagai daerah di Sulawesi Selatan dan Jawa. Pada penelitian ini digunakan primer spesifik untuk mendeteksi gen-gen virulen toxR gene, hemolysin (vvh gene, dan GyrB gene dengan metode PCR. Dari 35 isolat yang diisolasi, 20 isolat terdeteksi memiliki gen virulensi dan 8 di antaranya memiliki dua gen virulen. Spesies bakteri yang memiliki gen virulen adalah: V.harveyi, V. parahaemolyticus, V. mimicus, dan V. campbelli

  8. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

    Science.gov (United States)

    Kiemeney, Lambertus A; Sulem, Patrick; Besenbacher, Soren; Vermeulen, Sita H; Sigurdsson, Asgeir; Thorleifsson, Gudmar; Gudbjartsson, Daniel F; Stacey, Simon N; Gudmundsson, Julius; Zanon, Carlo; Kostic, Jelena; Masson, Gisli; Bjarnason, Hjordis; Palsson, Stefan T; Skarphedinsson, Oskar B; Gudjonsson, Sigurjon A; Witjes, J Alfred; Grotenhuis, Anne J; Verhaegh, Gerald W; Bishop, D Timothy; Sak, Sei Chung; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H; Hurst, Carolyn D; de Verdier, Petra J; Ryk, Charlotta; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Campagna, Marcello; Placidi, Donatella; Arici, Cecilia; Zeegers, Maurice P; Kellen, Eliane; Gutierrez, Berta Saez; Sanz-Velez, José I; Sanchez-Zalabardo, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D; Hengstler, Jan G; Blaszkewicz, Meinolf; Dietrich, Holger; Ophoff, Roel A; van den Berg, Leonard H; Alexiusdottir, Kristin; Kristjansson, Kristleifur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Kong, Augustine; Thorgeirsson, Thorgeir; Mungan, N Aydin; Lindblom, Annika; van Es, Michael A; Porru, Stefano; Buntinx, Frank; Golka, Klaus; Mayordomo, José I; Kumar, Rajiv; Matullo, Giuseppe; Steineck, Gunnar; Kiltie, Anne E; Aben, Katja K H; Jonsson, Eirikur; Thorsteinsdottir, Unnur; Knowles, Margaret A; Rafnar, Thorunn; Stefansson, Kari

    2010-01-01

    Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC. PMID:20348956

  9. CVH与HCC组织中Fas,PCNA,P16表达分析

    Institute of Scientific and Technical Information of China (English)

    赵相宝

    2003-01-01

    @@ 目前认为,人类肿瘤的形成与病毒的作用密切相关,至少参与了15%的人类肿瘤的形成.原发性肝细胞肝癌 (HCC)与HBV感染之间的关系更为密切,其作用机制尚未完全清楚,可能与HBV的基因插入、整合或反式激活,使原癌基因激活、抑癌基因失活有关.检测癌基因的变化在阐述肿瘤的发生机理、诊断、估计预后及防治方面具有重要意义.本研究采用LSABC免疫组化方法检测了87例慢性乙型肝炎(CVH)患者肝穿标本和30例HCC手术切除标本组织中促凋亡蛋白Fas,增殖细胞核抗原PCNA和抑癌基因P16的表达,探讨CVH不同阶段与癌变间的关系.

  10. Not all hypochondroplasia families are linked to chromosome 4p16.3

    Energy Technology Data Exchange (ETDEWEB)

    Rousseau, F.; Munnich, A.; Merrer, M.Le. [INSERM, Paris (France)] [and others

    1994-09-01

    Achondroplasia (ACH, MIM 100800) and hypochondroplasia (HCH, MIM 146000) are short limb dwarfism with enlarged head sharing some specific radiological features. Inter- and intrafamilial clinical variability and histolopathological aspects of the growth cartilage suggested that ACH and HCH are allelic disorders. Recently, the gene for achondroplasia was mapped to chromosome 4p and no recombinants were found in 9 families with hypochondroplasia between D4S111 and the telomere (Zmax=1.70, {theta}=0). By using an additional polymorphic DNA marker which detects VNTR-like polymorphism at the D4S227 locus and a new microsatellite at locus D4S? (AFM163yc1), we observed recombinant events with markers of the chromosome 4p16.3 in 3/10 hypochondroplasia families, indicating that not all hypochondroplasia families are linked to chromosome 4p. A fibroblast growth factor receptor (FGFR3) expressed in chondrocytes during endochondral ossification which is located in the 2.5 Mb candidate region for achondroplasia was regarded as a good candidate gene. No major rearrangement of the FGFR3 gene was detected by Southern blot analysis using an FGFR3 cDNA probe. Further investigations will be required to conclude as to the possible involvement of this gene in ACH.

  11. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma

    Institute of Scientific and Technical Information of China (English)

    Hong-Bing Ma; Hai-Tao Hu; Zheng-Li Di; Zuo-Ren Wang; Jing-Sen Shi; Xi-Jing Wang; Yi Li

    2005-01-01

    AIM: To investigate the role of cydin D1, p16 and retinoblastoma in cancerous process of gallbladder carcinomas and to assess the relation between cyclin D1, p16, Rb and the biological characteristics of gallbladder carcinoma.METHODS: Forty-one gallbladder carcinoma, 7 gallbladder adenoma and 14 chronic cholecystitis specimens were immunohistochemically and histopathologically investigated for the relation of cyclin D1, p16 and Rb with Nevin staging and pathologic grading.RESULTS: The expression rates of abnormal cyclin D1 in gallbladder carcinoma (68.3%)and gallbladder adenoma(57.1%) were significantly higher than those in chronic cholecystitis (7.1%) (P<0.05). No significant difference was found both among the pathological grades G1, G2 and G3and among Nevin stagings S1-S2, S3 and S4-S5 of gallbladder carcinoma. The positive rates of p16 (48.8%) and Rb(58.5%) in gallbladder carcinoma were significantly lower compared to those in adenoma (100.0%) and cholecystitis(100.0%) (P<0.05). The positive rates of p16 and Rb in Nevin stagings S1-S2 (80.0% and 90.0%) and S3 (46.2%and 61.5%) gallbladder carcinomas were significantly higher than those in S4-S5 (33.3% and 38.8%) (P<0.05),and those in pathologic grades G1 (54.5% and 81.8%) and G2 (50.0% and 62.5%) gallbladder carcinoma were significantly higher than those in G3 (28.6% and 35.7%)(P<0.05). The protein expression of p16 and Rb had a negative-correlation in gallbladder carcinoma (r = -0.2993,P<0.05), and this negative-correlation was correlated with Nevin staging (P<0.05). Moreover, the protein expression of p16 and cyclin D1 had a negative-correlation in gallbladder carcinoma (r = -0.9417, P<0.05).CONCLUSION: Cyclin D1 may play a role in the early stage of gallbladder carcinoma. Mutation of p16 and Rb genes might be correlated with progression of gallbladder carcinoma.Analysis of p16 and Rb can estimate the prognosis of gallbladder carcinoma. Expression of p16 and Rb may be correlated with Nevin

  12. p16基因甲基化检测诊断肺癌可行性分析

    Institute of Scientific and Technical Information of China (English)

    何琳琳

    2015-01-01

    目的研究分析p16基因甲基化检测诊断肺癌的可行性。方法选择2013年2月~2015年1月到本院进行诊治的42例经病理检查证实的肺癌患者,将其作为研究组,检测患者外周血血浆、肺癌组织以及癌旁正常组织p16基因甲基化;在此基础上,选择同时期到本院实施体检的40例健康人员作为对照组,检测对象血浆p16基因甲基化,对比分析两组检测结果。结果研究组中癌旁组织p16基因甲基化率为11.9%,血浆样品p16基因甲基化率为35.2%,肺癌组织p16基因甲基化率为45.2%。对照组受检对象血浆样品无p16基因甲基化,两组在血浆p16基因甲基化率比较具有统计学意义(0.05)。结论尽早且及时地检测肺癌患者血浆p16基因甲基化情况和癌组织p16基因甲基化情况,可为肺癌临床诊治提供合理且准确的参考依据。

  13. Expressions of p16, p15 and pRb in Cutaneous Squamous Cell Carcinomas%p16,p15及Rb蛋白在皮肤鳞状细胞癌中的表达

    Institute of Scientific and Technical Information of China (English)

    武钦学; 吴志华; 唐慰萍

    2004-01-01

    目的:检测p16,p15及pRb在皮肤鳞癌中的表达及相互关系,探讨它们在皮肤鳞癌发生、发展中的作用.方法:用S-P免疫组化染色法检测48例皮肤鳞癌和10例正常皮肤中p16,p15蛋白及pRb的表达.结果:p16,p15及pRb在皮肤鳞癌中均有不同程度失表达,分别为16/48(33.3%),7/48(14.6%)及8/48(16.7%).而在正常表皮均呈阳性表达:不同分化皮肤鳞癌中,p16,p15的失表达在低分化鳞癌中显著高于高中分化鳞癌(P<0.05),pRb表达无显著性差异.结论:p16,p15及/或pRb的表达异常可能与皮肤鳞癌的发生、发展有关.

  14. Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the p16 locus.

    Directory of Open Access Journals (Sweden)

    Qiang Li

    Full Text Available BACKGROUND: H3K9 trimethylation (H3K9me3 and binding of PcG repressor complex-1 (PRC1 may play crucial roles in the epigenetic silencing of the p16 gene. However, the mechanism of the initiation of this trimethylation is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that upregulating the expression of PRC1 component Cbx7 in gastric cancer cell lines MGC803 and BGC823 led to significantly suppress the expression of genes within the p16-Arf-p15 locus. H3K9me3 formation was observed at the p16 promoter and Regulatory Domain (RD. CBX7 and SUV39H2 binding to these regions were also detectable in the CBX7-stably upregulated cells. CBX7-SUV39H2 complexes were observed within nucleus in bimolecular fluorescence complementation assay (BiFC. Mutations of the chromodomain or deletion of Pc-box abolished the CBX7-binding and H3K9me3 formation, and thus partially repressed the function of CBX7. SiRNA-knockdown of Suv39h2 blocked the repressive effect of CBX7 on p16 transcription. Moreover, we found that expression of CBX7 in gastric carcinoma tissues with p16 methylation was significantly lower than that in their corresponding normal tissues, which showed a negative correlation with transcription of p16 in gastric mucosa. CONCLUSION/SIGNIFICANCE: These results demonstrated for the first time, to our knowledge, that CBX7 could initiate H3K9me3 formation at the p16 promoter.

  15. Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the p16 locus.

    Science.gov (United States)

    Li, Qiang; Wang, Xiuhong; Lu, Zheming; Zhang, Baozhen; Guan, Zhenpo; Liu, Zhaojun; Zhong, Qiming; Gu, Liankun; Zhou, Jing; Zhu, Budong; Ji, Jiafu; Deng, Dajun

    2010-10-29

    H3K9 trimethylation (H3K9me3) and binding of PcG repressor complex-1 (PRC1) may play crucial roles in the epigenetic silencing of the p16 gene. However, the mechanism of the initiation of this trimethylation is unknown. In the present study, we found that upregulating the expression of PRC1 component Cbx7 in gastric cancer cell lines MGC803 and BGC823 led to significantly suppress the expression of genes within the p16-Arf-p15 locus. H3K9me3 formation was observed at the p16 promoter and Regulatory Domain (RD). CBX7 and SUV39H2 binding to these regions were also detectable in the CBX7-stably upregulated cells. CBX7-SUV39H2 complexes were observed within nucleus in bimolecular fluorescence complementation assay (BiFC). Mutations of the chromodomain or deletion of Pc-box abolished the CBX7-binding and H3K9me3 formation, and thus partially repressed the function of CBX7. SiRNA-knockdown of Suv39h2 blocked the repressive effect of CBX7 on p16 transcription. Moreover, we found that expression of CBX7 in gastric carcinoma tissues with p16 methylation was significantly lower than that in their corresponding normal tissues, which showed a negative correlation with transcription of p16 in gastric mucosa. These results demonstrated for the first time, to our knowledge, that CBX7 could initiate H3K9me3 formation at the p16 promoter.

  16. Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.

    Science.gov (United States)

    Bhagat, Rahul; Kumar, Sandeep Sriram; Vaderhobli, Shilpa; Premalata, Chennagiri S; Pallavi, Venkateshaiah Reddihalli; Ramesh, Gawari; Krishnamoorthy, Lakshmi

    2014-09-01

    Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

  17. 抑癌基因P16INK4在sf9细胞中的表达和鉴定%EXPRESSION OF TUMOR SUPPRESSOR GENE P16INK4 IN INSECT CELL

    Institute of Scientific and Technical Information of China (English)

    张利宁; 孙汶生; 朱长军; 马春红; 曹英林; 宋静

    2001-01-01

    目的:利用杆状病毒表达系统在体外表达抑癌蛋白P16,为研究P16蛋白的结构与功能及其在肿瘤生物治疗中的应用奠定基础.方法:①利用定向克隆的方法将P16全基因序列插入转移载体pSX-IVVI+X3的EcoRI、Sall位点上,经氨苄青霉素平板初筛、菌落原位杂交、PCR扩增酶切电泳鉴定后,分离含P16的重组转移载体一pSXIVVI+X3.16;②用昆虫杆状病毒TnNPV-SVI-G感染sf9细胞扩增病毒,用PEG法沉淀病毒、酚/氟仿抽提纯化病毒DNA;③CaCl2沉淀法使重组转移载体一pSXIVVI+X3-16和病毒TnNPV-SVI-G DNA共转染sf9细胞.通过多角体观察和PCR法鉴定重组病毒;④经空斑纯化法纯化重组病毒,重组病毒感染草地夜蛾细胞(sf9)使P16大量表达,经SDS-PAGE及Western Blot鉴定所表达的P16蛋白.结果:①筛选出两株含P16全基因的重组转移载体-pSXIVVI+X3-16;②构建了含P16全基因序列的重组杆状病毒TnNPV-p16;③SDS-PAGE电泳显示重组病毒TnNPV-P16感染sf9细胞的培养上清及胞体裂解物和阳性对照Hela细胞裂解物在16kD左右均有蛋白条带,而阴性对照TnNPV-SVI-G感染的sf9细胞培养上清中无此蛋白条带,经免疫印迹染色证实此蛋白为抑癌蛋白P16.结论:利用我国自己构建的昆杆状病毒表达系统成功了表达P16蛋白,分子量大小及特异性与国外报道相同.

  18. Prognostic significance of overexpressed p16INK4a in patients with cervical cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jiaying Lin

    Full Text Available BACKGROUND: p16INK4a is a tumor suppressor protein which is induced in cells upon the interaction of high-risk HPV E7 with the retinoblastoma protein by a positive feedback loop, but cannot exert its suppressing effect. Previous reports suggested that p16INK4a immunostaining allows precise identification of even small CIN or cervical cancer lesions in biopsies. The prognostic value of overexpressed p16INK4a in cervical cancer has been evaluated for several years while the results remain controversial. We performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of overexpression of p16INK4a in cervical cancer. METHODS: Identification and review of publications assessing clinical or prognostic significance of p16INK4a overexpression in cervical cancer until March 1, 2014. A meta-analysis was performed to clarify the association between p16INK4a overexpression and clinical outcomes. RESULTS: A total of 15 publications met the criteria and comprised 1633 cases. Analysis of these data showed that p16INK4a overexpression was not significantly associated with tumor TNM staging (I+II vs. III+IV (OR = 0.75, 95% confidence interval [CI]: 0.35-1.63, P = 0.47, the tumor grade (G1+ G2 vs. G3 (OR = 0.78, 95% CI: 0.39-1.57, P = 0.49, the tumor size (< 4 vs. ≥ 4 cm (OR = 1.10, 95% CI: 0.45-2.69, P = 0.83, or vascular invasion (OR = 1.20, 95% CI: 0.69-2.08, P = 0.52. However, in the identified studies, overexpression of p16INK4a was highly correlated with no lymph node metastasis (OR = 0.51, 95% CI: 0.28-0.95, P = 0.04, increased overall survival (relative risk [RR]: 0.42, 95% CI: 0.24-0.72, P = 0.002 and increased disease free survival (RR: 0.60, 95% CI: 0.44-0.82, P = 0.001. CONCLUSIONS: This meta-analysis shows overexpression of p16INK4a in cervical cancer is connected with increased overall and disease free survival and thus marks a better prognosis.

  19. Association between P(16INK4a promoter methylation and non-small cell lung cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jundong Gu

    Full Text Available BACKGROUND: Aberrant methylation of CpG islands acquired in tumor cells in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates P(16INK4a gene promoter hypermethylation is involved in non-small cell lung carcinoma (NSCLC, indicating it may be a potential biomarker for this disease. The aim of this study is to evaluate the frequency of P(16INK4a gene promoter methylation between cancer tissue and autologous controls by summarizing published studies. METHODS: By searching Medline, EMBSE and CNKI databases, the open published studies about P(16INK4a gene promoter methylation and NSCLC were identified using a systematic search strategy. The pooled odds of P(16INK4A promoter methylation in lung cancer tissue versus autologous controls were calculated by meta-analysis method. RESULTS: Thirty-four studies, including 2 652 NSCLC patients with 5 175 samples were included in this meta-analysis. Generally, the frequency of P(16INK4A promoter methylation ranged from 17% to 80% (median 44% in the lung cancer tissue and 0 to 80% (median 15% in the autologous controls, which indicated the methylation frequency in cancer tissue was much higher than that in autologous samples. We also find a strong and significant correlation between tumor tissue and autologous controls of P(16INK4A promoter methylation frequency across studies (Correlation coefficient 0.71, 95% CI:0.51-0.83, P<0.0001. And the pooled odds ratio of P(16INK4A promoter methylation in cancer tissue was 3.45 (95% CI: 2.63-4.54 compared to controls under random-effect model. CONCLUSION: Frequency of P(16INK4a promoter methylation in cancer tissue was much higher than that in autologous controls, indicating promoter methylation plays an important role in carcinogenesis of the NSCLC. Strong and significant correlation between tumor tissue and autologous samples of P(16INK4A promoter methylation demonstrated a promising biomarker for NSCLC.

  20. P53,P16,PRb的表达与宫颈上皮病理改变的关系%Expression and significiation of P16,P53 and PRb in cervical intraepithilial neoplasia and cervical carcinoma

    Institute of Scientific and Technical Information of China (English)

    喻珊; 王鹤林; 宋增武; 易蓉

    2011-01-01

    目的 探讨P16,P53和PRb在宫颈上皮内瘤变和宫颈癌中的表达及意义.方法 用免疫组化的方法检测44例宫颈上皮内瘤变,12例宫颈鳞癌和10例宫颈炎标本中P16,P53和PRb的表达情况.结果 P16在宫颈炎、CIN和宫颈癌的阳性表达率为0%,90.9%,100%,其表达有统计学意义(P<0.01);P53 在宫颈炎、CIN和宫颈癌的阳性表达率为10%,36.1%,41.7%,表达无统计学意义(P=1.00);PRb的表达率为0%,95.5%,100%.(P<0.01)具有统计学意义.从宫颈炎-CIN-宫颈癌的演变过程中,P16和PRb的表达成递增趋势,具有高度相关性(r=0.807, 0.668),而P53的表达与疾病演变过程呈低度相关性(r=0.331).结论 P16和PRb的表达强度在宫颈CIN到宫颈癌的演变过程中逐步升高,P53表达则主要出现在病变的早期阶段.P16,PRb和P53结合应用有助于宫颈CIN分级和宫颈癌的诊断及鉴别诊断.

  1. PCAF acts as a gastric cancer suppressor through a novel PCAF-p16-CDK4 axis.

    Science.gov (United States)

    Fei, Hong-Jun; Zu, Li-Dong; Wu, Jun; Jiang, Xiao-Shu; Wang, Jing-Long; Chin, Y Eugene; Fu, Guo-Hui

    2016-01-01

    Gastric cancer (GC) is a leading cause of cancer-related death worldwide and the pathogenesis of GC remains largely unknown. Here, we demonstrate a novel mechanism by which P300/CBP associating factor (PCAF) acts as a tumor suppressor in GC cells. We showed that both PCAF mRNA and protein were downregulated in GC cells, and that this downregulation correlated with poor survival. Meanwhile, the interaction between human anion exchanger 1 (AE1) and p16 is a key event in GC development. We found that PCAF inhibited GC growth by interacting with AE1 and p16 to promote ubiquitin-mediated degradation of AE1 and p16 upregulation and translocation into the nucleus. Binding of nuclear p16 to CDK4 prevented the CDK4-Cyclin D1 interaction to inhibit GC proliferation. Furthermore, reduced PCAF levels in GC cells were associated with intracellular alkalinization and decreased immunity. Together these results suggest that PCAF acts as a GC suppressor through a novel PCAF-p16-CDK4 axis. The downregulation of PCAF expression in GC cells that follows intracellular alkalinization and decreased immune response, indicates that GC therapies should focus on restoring PCAF levels.

  2. Predicting malignant potential of gastrointestinal stromal tumors: Role of p16 and E2F1 expression.

    Science.gov (United States)

    Tetikkurt, Umit Seza; Ozaydin, Ipek Yildiz; Ceylan, Sule; Gurbuz, Yesim; Erdogan, Nusret; Oz, Feriha

    2010-07-01

    Altered expression of cell cycle regulatory proteins in GISTs (gastrointestinal stromal tumors) may be the mechanism for their diversity in clinical behavior. The use of these tumorigenetic and cell proliferative proteins may provide an alternative route for follow-up and treatment. The aim of this study was to determine the prognostic relevance of the E2F1 and p16 expression in GISTs. Tissues from 21 cases with GIST were collected retrospectively. Tumor grade was designated according to the consensus system. Immunohistochemistry was done with antibodies against Ki-67, p16, E2F1. For statistical analysis, Ki-67 proliferation index was evaluated in 2 categories: 10%, whereas p16 expression was scored as negative or positive. E2F1 expression cutoff values were tested for risk group variables as >5% and >10%. Correlation between the presence of necrosis, Ki-67 proliferation index, p16, E2F1 expression and the risk grade was determined by Spearman correlation test. Sensitivity and specificity were determined by Fisher exact test with P p16 expression. Our results suggest that in addition to high Ki-67 proliferation index, high E2F1 expression may also be a useful predictive marker for malignant potential of GISTs.

  3. The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence.

    Science.gov (United States)

    Feng, Yunpeng; Wang, Xiuli; Xu, Liang; Pan, Hong; Zhu, Shan; Liang, Qian; Huang, Baiqu; Lu, Jun

    2009-08-01

    The transcription factor ZBP-89 has been implicated in the induction of growth arrest and apoptosis. In this article, we demonstrate that ZBP-89 was able to restrain senescence in NCI-H460 human lung cancer cells, through epigenetically regulating p(16INK4a) expression. Specifically, our results indicate that knockdown of ZBP-89 by RNA interference stimulated cellular senescence in NCI-H460 cells, as judged by the senescence-associated beta-galactosidase activity assay and senescence-associated heterochromatin foci assay, and this process could be reversed by RNA interference-mediated p16(INK4a) silencing. We also show that histone deacetylase (HDAC) 3 and HDAC4 inhibited p16(INK4a) promoter activity in a dose-dependent manner. Furthermore, chromatin immunoprecipitation assays verified that HDAC3 was recruited to the p16(INK4a) promoter by ZBP-89 through an epigenetic mechanism involving histone acetylation modification. Moreover, immunofluorescence and coimmunoprecipitation assays revealed that ZBP-89 and HDAC3 formed a complex. These data suggest that ZBP-89 and HDAC3, but not HDAC4, can work coordinately to restrain cell senescence by downregulating p16(INK4a) expression through an epigenetic modification of histones.

  4. Status of p16(INK4a) and E-cadherin gene promoter methylation in Moroccan patients with cervical carcinoma.

    Science.gov (United States)

    Attaleb, Mohammed; El hamadani, Wail; Khyatti, Meriem; Benbacer, Laila; Benchekroun, Nadia; Benider, Abdellatif; Amrani, Mariam; El Mzibri, Mohammed

    2009-01-01

    Aberrant methylation of tumor suppressor gene promoters has been extensively investigated in cervical cancer. Transcriptional silencing, as a main consequence of hypermethylation of CpG islands, is the predominant mechanism of p16(INK4a) and E-cadherin gene inactivation in malignant epithelial tumors. This study was conducted to evaluate the promoter methylation status of p16(INK4a) and E-cadherin genes in 22 specimens of cervical carcinomas, four cervical cancer cell lines (HeLa, SiHa, Caski, C33A), and 20 human papillomavirus negative specimens, obtained from normal cervical swabs, using the methylation-specific PCR approach. Hypermethylation of the 5' CpG island of the p16(INK4a) and E-cadherin genes were found in 13 (59.1%) and 10 (45.5%) of 22 cervical cancer samples, respectively. Furthermore, our findings did not show any correlation between promoter methylation of p16(INK4a) and E-cadherin genes and clinicopathological parameters, including HPV infection, phenotypic distribution, and stage of the disease. However, hypermethylation of E-cadherin gene promoter appears to be age related in cervical cancer, whereas the frequency of aberrant methylation of p16(INK4a) gene promoter is unchanged according to the age of patients. Thus, caution must be made to use these markers in the diagnosis of cervical cancer. However, dietary or pharmaceutical agents that can inhibit these epigenetic events may prevent or delay the development of cervical cancer.

  5. Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas.

    Science.gov (United States)

    Bezerra, Stephania M; Chaux, Alcides; Ball, Mark W; Faraj, Sheila F; Munari, Enrico; Gonzalez-Roibon, Nilda; Sharma, Rajni; Bivalacqua, Trinity J; Burnett, Arthur L; Netto, George J

    2015-04-01

    Approximately 50% of penile squamous cell carcinomas (SCC) are associated with high-risk human papillomavirus (HR-HPV) infection. We evaluated the correlation of p16(INK4a) expression and HR-HPV with clinicopathological features and outcome in a cohort of patients with penile SCC. Two tissue microarrays were constructed from 53 invasive penile SCC at our hospital. p16(INK4a) expression was assessed by immunohistochemistry (CINtec Kit). High-risk human papillomavirus status was assessed by in situ hybridization (INFORM HPV III family 16 probe B cocktail). High-risk human papillomavirus was detected in 8 cases (15%), and p16(INK4a) overexpression was found in 23 cases (44%). Both markers showed a significant association with histologic subtype (P = .017 and P = .01, respectively) and lymphovascular invasion (P = .015 and P = .015, respectively). Regarding outcome analyses, neither HPV infection nor p16(INK4a) overexpression significantly predicted overall survival or cancer-specific survival using Cox proportional hazards regression model. High-risk human papillomavirus positivity and p16(INK4a) overexpression were significantly associated with histologic subtype and presence of lymphovascular invasion. Human papillomavirus status was not predictive of outcome in our cohort.

  6. p16及pRb在宫颈癌中的表达及意义%Immunochemical analysis of p16 and pRb in uterine cervical lesions

    Institute of Scientific and Technical Information of China (English)

    武海英; 魏利; 史惠蓉

    2011-01-01

    Objective To detect the expression of pi6 and pRb in cervical intraepithelial neoplasia and their association with cervical cancers. Methods Human papilloma virus was detected with surface plasmon resonance technique, and the expressions of P16 and pRb were examined with immunohistochemistry technique in 108 cases of CIN I , 50 cases of CIN H ? 35 cases of CINIH and 52 cases of cervical carcinomas. Results The positive rate of human papilloma virus and PI6 showed increasing tendency, and the positive rate of pRb showed decreasing tendency in CIN I , CINFJ ? CIN UI , cervical squamous carcinoma and cervical adenocarcinoma. The expression of PI6 and human papilloma virus were negatively correlated with the expression of pRb(r= -0. 537,PP16(r=0. 815, P<0. 05). Conclusion Human papilloma virus infection is an essential factor of cervical cancer. The expression of pi6 would be an early indicator for cervical cancer.%目的 探讨人乳头瘤病毒、p16及pRb在宫颈癌的表达及其相关性.方法 宫颈上皮内瘤样变(cervical intraepithelial neoplasia,CIN)I型患者108例,CINⅡ型患者50例,CINⅢ型患者35例及宫颈癌患者52例,应用表面等离子体谐振技术、免疫组织化学方法检测人乳头瘤病毒P16及pRb的表达情况.结果 从CIN到宫颈癌患者人乳头瘤病毒、P16阳性率呈逐渐增高趋势,pRb阳性率呈逐渐下降趋势;P16表达与pRb表达呈负相关(r=-0.537,P<0.01),人乳头瘤病毒与pRb表达呈负相关(r=-0.513,P<0.05),人乳头瘤病毒与P16表达呈正相关(r=0.815,P<0.05).结论 人乳头瘤病毒感染是宫颈癌发生的主要原因,p16可作为宫颈癌的早期预测指标.

  7. Hepatitis C virus Core protein stimulates cell growth by down-regulating p16 expression via DNA methylation.

    Science.gov (United States)

    Park, Sun-Hye; Lim, Joo Song; Lim, Su-Yeon; Tiwari, Indira; Jang, Kyung Lib

    2011-11-01

    Hepatitis C virus Core plays a vital role in the development of hepatocellular carcinoma; however, its action mechanism is still controversial. Here, we showed that Core down-regulated levels of p16, resulting in inactivation of Rb and subsequent activation of E2F1, which lead to growth stimulation of hepatocytes. For this effect, Core inhibited p16 expression by inducing promoter hypermethylation via up-regulation of DNA methyltransferase 1 (DNMT1) and DNMT3b. The growth stimulatory effect of Core was abolished when levels of p16 were restored by either exogenous complementation or treatment with 5-Aza-2'dC, indicating that the effect is critical for the stimulation of cell growth by Core. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population.

    Science.gov (United States)

    Wentzensen, Nicolas; Schwartz, Lauren; Zuna, Rosemary E; Smith, Katie; Mathews, Cara; Gold, Michael A; Allen, R Andy; Zhang, Roy; Dunn, S Terence; Walker, Joan L; Schiffman, Mark

    2012-08-01

    Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches. Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap. p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV-positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively. p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies.

  9. Evaluation of Ki67, p16 and CK17 Markers in Differentiating Cervical Intraepithelial Neoplasia and Benign Lesions

    Directory of Open Access Journals (Sweden)

    Fatemeh Sari Aslani

    2013-03-01

    Full Text Available Background: Cervical intraepithelial neoplasia (CIN is a premalignant lesion capable of progressing to cervical cancer. Despite the existing well-defined criteria, the histomorphologic diagnosis is subject to high rates of discordance among pathologists. The aim of this study was to evaluate Ki-67 (MIB-1, CK17 and p16 INK4a (p16 markers by immunohistochemical methods in differentiating CIN from benign cervical lesions. Methods: The present study reviewed and re-classified 77 cervical biopsies, originally diagnosed as 31 non-CIN, and 46 CIN, as 54 non-CIN, and 23 CIN based on at least two similar diagnoses. Immunostaining by Ki67, p16 and CK17 markers was performed on all cases and the results were compared with pervious and consensus diagnosis.Results: The overall agreement between pervious and consensus diagnosis was 67.5% (Kappa=0.39, P<0.001. The sensitivity and specificity of Ki67 immunostaining were 95.6% and 85.1% respectively, while for p16 the corresponding values were 91.3% and 98.1%. The overall agreement, for both p16 and Ki67, with consensus diagnosis were significant (P<0.001. The sensitivity and specificity of CK17 negative staining in CIN detection were 39.1% and 40.7% respectively.Conclusion: Ki67 and p16 markers are recommended as complementary tests for differentiating between dysplastic and non-dysplastic lesions. CK17 does not discriminate between immature metaplasia with and without dysplasia.

  10. A systematic review of p16/Ki-67 immuno-testing for triage of low grade cervical cytology.

    Science.gov (United States)

    Kisser, A; Zechmeister-Koss, I

    2015-01-01

    Screening for cervical cancer precursors by Papanicolaou cytology is a public health success story; however, its low sensitivity entails unnecessary referrals to colposcopy of healthy women with equivocal (ASCUS) or mild dysplasia (LSIL) cytology. We assessed the accuracy of p16/Ki-67 immuno-testing for triage of low grade cervical cytology. We systematically searched Medline, Embase, CRD and Cochrane databases, and handsearched key references. Eligible studies included women with ASCUS or LSIL cervical cytology who had undergone p16/Ki-67 testing and subsequent verification by colposcopy-directed biopsies and histologic analysis. We extracted data on patient characteristics and test conduct, diagnostic accuracy measures and assessed the methodological quality of the studies. R software was used to perform a bivariate analysis of test performance data. Five eligible studies were identified. Four of the studies had high risk of bias. In the LSIL subgroup, the sensitivity of p16/Ki-67 testing ranged from 0.86 to 0.98, compared with 0.92-0.96 of high-risk HPV testing (hrHPV); specificity ranged from 0.43 to 0.68 versus 0.19 to 0.37, respectively. In the ASCUS subgroup, sensitivity ranged from 0.64 to 0.92 (p16/Ki67 test) versus 0.91 to 0.97 (hrHPV); specificity ranged from 0.53 to 0.81 versus 0.26 to 0.44, respectively. p16/Ki-67 testing cannot be recommended for triage women with ASCUS or LSIL cytology due to insufficient high-quality evidence. Further studies on test performance and the impact of p16/Ki-67-based triage on health outcomes are needed for a definitive evaluation of its clinical utility. © 2014 Royal College of Obstetricians and Gynaecologists.

  11. 4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: New insights into mechanisms and critical regions.

    Science.gov (United States)

    Bi, Weimin; Cheung, Sau-Wai; Breman, Amy M; Bacino, Carlos A

    2016-10-01

    Deletions in the 4p16.3 region cause Wolf-Hirschhorn syndrome, a well known contiguous microdeletion syndrome with the critical region for common phenotype mapped in WHSCR2. Recently, duplications in 4p16.3 were reported in three patients with developmental delay and dysmorphic features. Through chromosomal microarray analysis, we identified 156 patients with a deletion (n = 109) or duplication (n = 47) in 4p16.3 out of approximately 60,000 patients analyzed by Baylor Miraca Genetics Laboratories. Seventy-five of the postnatally detected deletions encompassed the entire critical region, 32 (43%) of which were associated with other chromosome rearrangements, including six patients (8%) that had a duplication adjacent to the terminal deletion. Our data indicate that Wolf-Hirschhorn syndrome deletions with an adjacent duplication occur at a higher frequency than previously appreciated. Pure deletions (n = 14) or duplications (n = 15) without other copy number changes distal to or inside the WHSCR2 were identified for mapping of critical regions. Our data suggest that deletion of the segment from 0.6 to 0.9 Mb from the terminus of 4p causes a seizure phenotype and duplications of a region distal to the previously defined smallest region of overlap for 4p16.3 microduplication syndrome are associated with neurodevelopmental problems. We detected seven Wolf-Hirschhorn syndrome deletions and one 4p16.3 duplication prenatally; all of the seven are either >8 Mb in size and/or associated with large duplications. In conclusion, our study provides deeper insight into the molecular mechanisms, the critical regions and effective prenatal diagnosis for 4p16.3 deletions/ duplications. © 2016 Wiley Periodicals, Inc.

  12. THE EXPRESSIONS AND SIGNIFICANCES OF p15,p16 AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IN GASTRIC CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    王天宝; 高鹏; 曲延刚; 陈咸增; 李兆亭

    2000-01-01

    Objective:To investigate the relationships between the expressions of p15,p16 and vascular endothelial growth factor (VEGF) and gastric carcinoma(GC).Methods: Using immunohistochemical staining to examine the expressions of p15, p16and VEGF in archival wax-embedded specimens of 80 GC and 20 gastric benign disease(GBD). Results: The positive expression rate (PER) of p15 was significantly lower in GC than in GBD (43.75% VS. 69.23%, P<0.05). No relationship was found between PER of p15 and clinicopathologic factors. PER of p16 was 20% in GC, 55% in GBD (P<0.01).PER of p16 wasn't significantly different in gross types, histological types, with or without distant metastasis and pTNM stages. PER of p16 was 71.43% in invasive mucosa or suomucosa group, 17. 24% in invasive muscle group and 13. 64% in invoive serosa group (P<0.01); 12.96% in GC with lymph nodes metastasis, 34.62% in GC without lymph node metastasis (P<0.05). PER of VEGF in GC was 75. 00%, in GBD 7.69% (P<0. 001), in ulcerative type of GC and infiltrating type of GC were 81.97% and 40. 00%, respectively (P <0.05), in GC of invasive serosa was 95.45%, in GC of invasive muscle 51.72%(P<0.001), in GC of invasive mucosa or sulomucosa 42.86% (P<0.001). PER of VEGF in GC with lymph node metastasis was 82. 8%, without lymph node metastasis 54. 6%(P<0.05), in GC accompanied with distant metastasis was 100%, in GC without distant metastasis71.1% (P<0.05). PER of VEGF in pTNM Ⅰ and Ⅱ was 53.13%, in Ⅲ and IV 89.56% (P<0. 001). The expression of p15 correlated significantly With that of VEGF (P<0.001) and with that of p16 (P<0.01) in GC. Conclusion: p15 expression down-regulation has relationship with GC, but on relationship with the progress. p16 expression downregulation and VEGF expression up-regulation show significant relationships with clinicopathologic factors. There are significant relations between p15 and p16 negative expressionsand between p15 expression down-regulation and VEGF expression up-regulation.

  13. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis

    OpenAIRE

    Nuovo,Gerard J; Plaia, Todd W.; Steven A Belinsky; Baylin, Stephen B.; Herman, James G.

    1999-01-01

    We have developed a technique, methylation-specific PCR in situ hybridization (MSP-ISH), which allows for the methylation status of specific DNA sequences to be visualized in individual cells. We use MSP-ISH to monitor the timing and consequences of aberrant hypermethylation of the p16 tumor suppresser gene during the progression of cancers of the lung and cervix. Hypermethylation of p16 was localized only to the neoplastic cells in both in situ lesions and invasive cancers, and was associate...

  14. The Utility of p16INK4a and Ki-67 as a Conjunctive Tool in Uterine Cervical Lesions

    OpenAIRE

    Lee, Sangho; Kim, Hyunchul; Kim, Hyesun; Kim, Chulhwan; Kim, Insun

    2012-01-01

    Background Immunohistochemical staining for p16INK4a and Ki-67 has been used to improve the accuracy in making a diagnosis of the uterine cervix cancer on biopsy. This study was conducted to examine the usefulness of these markers in the pathological diagnosis based on cervical biopsy. Methods We selected a consecutive series of 111 colposcopically directed cervical punch biopsies. Using these biopsy samples, we performed an immunohistochemical staining for p16INK4a and Ki-67 to establish a d...

  15. Expressions of P16, P53 and MDM2 protein in retinoblastoma%视网膜母细胞瘤中MDM2、P16和P53的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    雷晓华; 朱润庆; 胡学斌

    2006-01-01

    目的 研究P16、P53和癌基因MDM2在视网膜母细胞瘤的表达作用.方法 对已明确诊断的42例视网膜母细胞瘤标本采用免疫组织化学方法检测P16、P53和MDM2表达.结果 42例标本中P16、P53和MDM2阳性检出率分别是35.7%、69.1%和38.1%,P53和MDM2的共表达率为23.8%.结论 P16、P53和MDM2在视网膜母细胞瘤的产生和发展过程中起重要作用.

  16. 鼻内翻性乳头状瘤与PTEN及P16蛋白表达的关系%The expression of PTEN and P16 protein in nasal inverted papilloma

    Institute of Scientific and Technical Information of China (English)

    赵建东; 王彦君; 孔维佳

    2009-01-01

    目的:探讨PTEN和P16蛋白在鼻内翻性乳头状瘤(NIP)中的表达及与肿瘤发生、发展、预后的关系.方法:采用免疫组织化学SP法和计算机图像分析系统,检测27例NIP和10例正常蝶窦黏膜中PTEN、P16蛋白的表达,并对两者在不同NIP预后分组中的表达进行对比分析.结果:PTEN和P16蛋白在NIP组织中的表达与正常蝶寞黏膜相比,均差异有统计学意义(均P0.05).结论:PTEN蛋白减少或缺失是NIP发生、发展及不良预后的重要指标,P16蛋白亦与NIP的发生、发展相关,两者具有重要的临床意义.

  17. Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions.

    NARCIS (Netherlands)

    Breuer, R.H.J.; Snijders, P.J.F.; Sutedja, T.G.; Sewalt, R.G.A.B.; Otte, A.P.; Postmus, P.E.; Meijer, C.J.L.M.; Raaphorst, F.M.; Smit, E.F.

    2005-01-01

    It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region ca

  18. EXPRESSION OF THE p16 AND Rb GENES mRNA AND PROTEIN LEVELS IN LUNG CANCER%肺癌p16、Rb基因mRNA和蛋白水平表达的定位观察

    Institute of Scientific and Technical Information of China (English)

    苏长青; 叶玉坤; 汪栋; 曹祥荣; 单祥年

    2001-01-01

    The authors used immunohistochemistry and in situ hybridization to observe the expression of the p16 and Rb mRNA and protein levels in 89 cases of lung cancer. The results showed that the loss of p16 gene expression took place mainly in non-small cell lung cancer, and loss of Rb gene expression mainly in small cell lung cancer. The expression of these genes on protein level fundamentally corresponded with mRNA level. It is suggested that the expression of these two genes are related to the histological type of lung cancer, and the p16 and Rb genes can be considered as one of molecular biological targets for gene classification diagnosis. There may exist a mechanism at gene translation level which leads to the inactivation of the p16 and Rb genes.%为研究p16和Rb基因在蛋白水平和mRNA水平的表达及其与肺癌发生发展的关系,采用免疫组化和原位杂交的方法,对89例肺癌手术标本进行了p16和Rb基因表达的定位观察。发现p16基因蛋白的丢失主要发生于非小细胞肺癌,Rb基因蛋白的丢失主要发生于小细胞肺癌。两种基因各自在蛋白水平和mRNA水平的表达基本相符。提示p16和Rb基因的表达与肺癌的组织学类型密切相关,有可能作为非小细胞肺癌与小细胞肺癌基因分型诊断的分子生物学指标之一;在翻译水平上也存在着引起基因失活的可能机制。

  19. p53和p16及VEGF 蛋白表达与胆囊癌预后的关系%Association of p53, p16 and VEGF Protein Expression with the Prognosis of Gallbladder Cancer

    Institute of Scientific and Technical Information of China (English)

    全志伟; 王建军; 施伟斌; 李济宇; 张忠德

    2001-01-01

    目的分析抑癌基因p53和p16以及VEGF的表达在胆囊良恶性疾病中的差异,探讨其与胆囊癌病理分期及预后的关系.方法用免疫组化方法定性检测p53、p16及VEGF在24例胆囊癌、20例胆囊腺瘤、18例慢性胆囊炎标本中的表达,并对胆囊癌进行组织病理分期.结果胆囊癌中p53、p16及VEGF表达阳性率均明显高于胆囊腺瘤和(或)慢性胆囊炎(P<0.05).按照临床Nevin分期,p53在Nevin S1~S3期胆囊癌中的阳性率明显高于S4~S5期(P<0 05),VEGF的表达阳性率则以S4~S5期胆囊癌中为高(P<0.05);而p16的表达在NevinS1~S3期和Nevin S4~S5期之间无差异.按照病理分期,p16在病理Ⅲ期胆囊癌中的表达高于病理I、Ⅱ期(P<0.05),而p53和VEGF的表达在病理I、Ⅱ期和病理Ⅲ期间无差异.结论p53和p16基因突变在胆囊癌的发生中起重要作用,而VEGF在肿瘤进展和转移中发挥重要作用.胆囊癌中p53的表达出现减低趋势及p16、VEGF的表达增强提示远处转移及预后不良.

  20. 细胞块上检测P16蛋白对诊断ASCUS的意义%The clinical significance of detecting P16 protein in cervical cell block of ASCUS

    Institute of Scientific and Technical Information of China (English)

    胡波; 于晶功; 孙静阳; 裴笑月; 李晓慧; 孙海姣; 王炜智

    2013-01-01

    Objective Through the cell block technique to detect the expression of P16 protein in the liquid-based cytology with atypical squamous cells of undetermined significance (ASCUS) and high degree of cervical intraepithelial lesions (HSIL),to explore the significance of P16 protein in ASCUS re-evaluate.Methods Collected in our hospital in 2012 cervix liquid based cytology specimens of 45 patients,including of 15 ASCUS,11 HSIL cases,low in 11 cases of epithelial lesions (LSIL) and 2 cases of squamous cell carcinoma,2 cases of atypical glandular cells,4 cases of normal cells as a control.Immunocytochemical analysis of P16 protein control analysis,cytology and histology results.Results The expressing of P16 protein in normal cells,ASCUS,LSIL,HSIL,squamous cell carcinoma,atypical glandular cells in the positive expression rates were 0,20%,27.2%,63.6%,100%,100%.Cytology and biopsy results,cytologic diagnosis of ASCUS 15 cases,biopsy:12 cases of cervicitis,CIN Ⅱ-Ⅲ in 3 cases; cytology the in LSIL11,biopsy:5 cases of cervicitis,CIN Ⅰ 6 cases ; the cytological diagnosis HSIL11 cases,biopsy:cervical four cases of intlammation,CIN Ⅱ-Ⅲ ; cytologic diagnosis of atypical glandular cells in 2 cases,biopsy:adenocarcinoma; cytologic diagnosis of squamous cell carcinoma in 2 cases,biopsy:squamous cell carcinoma.Conclusion Detection of P16 protein on the cell block can be used for ASCUS classification ASCUS reassessment.%目的 通过细胞块技术,检测P16蛋白在液基细胞学不典型鳞状上皮细胞(ASCUS)和宫颈上皮内高度病变(HSIL)中的表达,探讨P16蛋白在ASCUS重新评估中的意义.方法 收集本院2012年宫颈液基细胞学标本45例,其中15例细胞学诊断为ASCUS的病例,11例HSIL、11例宫颈上皮内低度病变(LSIL)和2例鳞癌、2例非典型腺细胞、4例正常细胞作为对照.细胞免疫化学染色,分析P16蛋白表达,将细胞学与组织学结果对照分析.结果 薄层液基细胞学涂片45例,P16