Methylation and Messenger RNA Expression of <i>p15INK4b</i> but Not <i>p16INK4a</i> Are Independent Risk Factors for Ovarian Cancer

Liu, Zhensheng; Wang, Li E.; Luo, Wei; Lu, Karen H.; Mills, Gordon B.; Bondy, Melissa L.; Wei, Qingyi

doi:10.1158/1078-0432.ccr-04-2293

Cited by 21 publications

(13 citation statements)

References 37 publications

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“…Although most of authors hold the traditional viewpoint that detectable P16 methylation necessarily link to the inactivation of P16 protein, or transcriptional silencing of P16 gene [20,21], coexistence of P16 methylation and P16 expression in tumors has been frequently described [22,23]. Our findings support coexistence of P16 methylation and P16 expression in tumors.…”

Section: Discussionsupporting

confidence: 71%

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Çavuşoğlu¹,

Sevinç²,

Saydam³

et al. 2010

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We studied the promoter methylation status and expression levels of P16 and CDH1 genes in breast cancer and their adjacent normal tissues with normal control breast tissues, to correlate with their histopathological parameters. Hundred twenty four samples (tumor and adjacent nonmalignant tissues) from 62 breast cancer patients and 4 normal control breast tissues were included in the study. We used methylation specific PCR to evaluate methylation status and quantitative RT-PCR to measure the gene expression levels. Methylation incidence of P16 gene and CDH1 gene in tumor tissues were 24.2 % and 33.9 %, respectively. CDH1 and P16 gene were not methylated in normal control tissues. CDH1 underexpression is found to be significant in correlation with advanced stage, histologic type, high tumor grade and lymph node involvement. P16 expression is found not to be significantly related with any histopathological parameters. But 60% of cases which overexpresses P16 were estrogen negative, and 40% of them were histologic grade 3. Both P16 and CDH1 had different expression levels in tumor tissues compared to the adjacent normal tissues and in adjacent normal tissues compared to the normal non-tumor tissues. Key words: Breast cancer, P16, CDH1, methylationhomophilic cell-cell adhesion in epithelial tissues. CDH1 (E Cadherin), a Ca++ dependent transmembrane glycoprotein functioning in cell to cell adhesion placed in 16q22.1, is one of the cardinal regulators of morphogenesis [7]. Decreased levels of CDH1 expression related with the advanced stage and poorly differentiated cancers [8].We aimed to find out any possible relationship and concordance between promoter methylation status and expression levels of CDH1 and P16 genes, two critical genes in the carcinogenesis, with the histopathological parameters in sporadic breast cancer and adjacent normal breast tissue. Materials and methodsBreast cancer primary tissues. Breast tumors and adjacent nonmalignant tissues from resection margin are obtained from the Dokuz Eylül Breast Tumor Biobank (DEBTB) under permission of local clinical and laboratory research ethical council for analysis of patient samples. All the breast tissue samples were collected from patients, who had neither chemotherapy nor radiotherapy before operation. Tissue samples were constituted of tumor cells at average of 60% of the whole specimens Changes in the status of DNA methylation represent one of the most common molecular alterations in human neoplasia [1], including breast cancer [2]. Methylation in breast cancer has been related to clinical and pathologic characteristics evident at presentation and clinical outcomes. A higher prevalence of HIN-1 and RAR β2 methylation was found in the lymph nodes, bone, brain, and lung metastases than the primary tumor [3]. Widschwendter and colleagues [4] reported that the methylation of certain genes was associated with hormone receptor status, in addition to the response to treatment with tamoxifen.An uncontrolled cell division requires further progression through G1 p...

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Section: Discussionsupporting

confidence: 71%

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Çavuşoğlu¹,

Sevinç²,

Saydam³

et al. 2010

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“…INK4A promoter methylation status and mRNA expression have been reported previously (Hardie et al 2005, Liu et al 2005. p16 INK4A sequence variations were detected in four tumors, which all caused amino acid changes.…”

Section: Discussionsupporting

confidence: 66%

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Kiss¹,

Geli²,

Lundberg³

et al. 2008

Endocrine Related Cancer

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Pheochromocytomas and abdominal extra-adrenal paragangliomas are related to endocrine tumors of the sympathetic nervous system. Studies in animal models have shown that inactivation of the products of the cyclin dependent kinase inhibitor 2A (CDKN2A) gene locus, p16INK4A and p14 ARF , promotes the development of pheochromocytoma, especially in malignant form. The present study evaluated the involvement of CDKN2A in human pheochromocytomas and abdominal extra-adrenal paragangliomas from 55 patients. Promoter methylation was assessed using quantitative Pyrosequencing and methylation-specific PCR, and mRNA expression was measured by quantitative real-time PCR. For p16, western blot analysis and sequencing were also performed. succinate dehydrogenase complex subunit B (SDHB) sequencing analysis included extra-adrenal paragangliomas, all tumors classified as malignant, and cases diagnosed at 30 years or younger. The p16INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P!0.0043) and SDHB mutation (P!0.002). p16INK4A mRNA expression showed moderate suppression in malignant cases (P!0.05). In contrast, very little p14 ARF promoter methylation was seen and there was no significant difference in p14 ARF expression between tumors and normal samples. The p16 protein expression was reduced in 16 tumors, and sequence variations were observed in four tumors including the missense mutation A57V and the single nucleotide polymorphism (SNP) A148T. The results suggest that p16 INK4A, and not p14 ARF , is a subject of frequent involvement in these tumors. Importantly, hypermethylation of the p16 INK4A promoter was significantly associated with malignancy and metastasis, and SDHB gene mutations. This finding suggests an etiological link and could provide a clinical utility for diagnostic purposes.

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“…The inactivation of the CDK inhibitors p16 [94,[113][114][115][116][117][118][119][120] or p15 [113,115,118,121], due to gene deletion or promoter hypermethylation, has been sometimes observed in ovarian carcinomatous tissues. The loss of p16 function is more common in serous than in nonserous tumours [119,122].…”

Section: Ink Family Membersmentioning

confidence: 99%

Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer

Gadducci

Cosio

Tana

et al. 2009

Critical Reviews in Oncology/Hematology

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Methylation and Messenger RNA Expression of p15INK4b but Not p16INK4a Are Independent Risk Factors for Ovarian Cancer

Cited by 21 publications

References 37 publications

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer

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