Inactivation of p16INK4a expression in malignant mesothelioma by methylation

Wong, Long; Zhou, Joan; Anderson, Daniel G.; Kratzke, Robert A.

doi:10.1016/s0169-5002(02)00178-2

Cited by 77 publications

(47 citation statements)

References 24 publications

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“…25 This and other studies have shown that, at least in a small percentage of pleural mesotheliomas (11-21%), the CDKN2A gene is inactivated by methylation. [24][25][26] Although we did not test for aberrant methylation of the CDKN2A gene, a similar percentage of our peritoneal mesothelioma cases (19%) showed loss of p16 expression without loss of the CDKN2A gene.…”

Section: Am Krasinskas Et Almentioning

confidence: 66%

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CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

et al. 2010

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Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P ¼ 0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P ¼ 0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.

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Section: Am Krasinskas Et Almentioning

confidence: 66%

“…23 In pleural mesotheliomas, loss of p16 protein expression is typically associated with CDKN2A deletion, but a subset of cases showed loss of p16 due to inactivation of the gene by methylation. [24][25][26] The correlation between CDKN2A deletion, loss of p16 protein expression and survival has not been made in peritoneal mesotheliomas.…”

mentioning

confidence: 99%

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

et al. 2010

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“…Mesothelioma cells seem to recapitulate the epigenetic features of solid tumors since the presence of high genomic instability and a pattern of transcriptionally repressed tumor-suppressor genes, through DNA hypermethylation, has been demonstrated [7][8][9][10][11][12].…”

Section: E-mail Address: Mircofanelli@uniurbit (M Fanelli)mentioning

confidence: 99%

Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells

et al. 2009

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a b s t r a c tMalignant pleural mesothelioma (MPM) is a locally aggressive neoplasm, principally linked to asbestos fibres exposure. Strong evidences associate this pollutant with induction of DNA breaks, aberrant chromosomes segregation and important chromosomal rearrangements, considered crucial events in malignant transformation. A considerable contribution to cellular transformation in MPM is also given by the presence of high genomic instability, as well as by the increased DNA methylation, and consequent decreased expression, of tumor-suppressor genes. In this study we first demonstrated that MPM cells are characterized by a decreased methylation level of pericentromeric DNA sequences which can justify, at least in part, the genomic instability observed in this neoplasia. Concomitantly, we found a paradoxical increased expression of DNMT1, the most expressed DNA methyltransferases in MPM cells, DNMT3a and all five isoforms of DNMT3b. Thus, we compared two experimental strategies, DNMT1 silencing and usage of a demethylating agent (5-aza-2 -deoxycytidine or Decitabine), both theoretically able to revert the locally hypermethylated phenotype and considered potential future therapeutic approaches for MPM. Interestingly, both strategies substantially decrease cell survival of MPM cells but the antitumor activity of Decitabine, differently from DNMT1 silencing, is mediated, at least in part, by a p53-independent p21 upregulation, and is characterized by the arrest of MPM cells at the G2/M phase of the cell cycle. These results indicate that the two approaches act probably through different mechanisms and, thus, that DNMT1 silencing can be considered an effective alternative to Decitabine for cancer treatment.

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“…The power of DNA methylation as a marker derives not only from its ability to be detected in a wide variety of samples (from fresh specimens to bodily fluids and archival paraffin-embedded specimens) but also from the defined localization of the lesion (in promoter CpG islands of genes), allowing the design of gene-specific, targeted probes [22]. To date, findings regarding the role of DNA methylation in MM are still rather limited [23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

et al. 2007

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SummaryPatients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of noninvasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/ DNA, we also examined the methylation of these markers in lung samples (age-or environmentallyinduced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM vs. non-tumor lung samples was found for estrogen receptor 1 (ESR1; p=0.0002), solute carrier family 6 member 20 (SLC6A20; p=0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival. NIH Public Access

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Inactivation of p16INK4a expression in malignant mesothelioma by methylation

Cited by 77 publications

References 24 publications

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

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