A common variant of CDKN2A (p16) predisposes to breast cancer

Dębniak, Tadeusz; Górski, Bohdan; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Maćkiewicz, Andrzej; Gozdecka-Grodecka, S.; Gronwald, Jacek; Kowalska, E; Haus, Olga; Grzybowska, Ewa; Stawicka, Małgorzata; Swiec, M; Urbański, Krzysztof; Niepsuj, S; Waśko, Bernard; Góźdż, Stanisław; Wandzel, Piotr; Szczylik, Cezary; Surdyka, Dariusz; Rozmiarek, Andrzej; Zambrano, Obdulia Covarrubias; Posmyk, Michał; Narod, Steven A.; Lubiński, Jan

doi:10.1136/jmg.2005.031476

Cited by 72 publications

(73 citation statements)

References 23 publications

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“…The known SNP, A148T found in three tumors (5%) is reported in 6% of the global and 3% of the European population (http://www.ncbi.nlm.nih.gov/ SNP/snp_ref.cgi?rsZ3731249). It has also been reported as a predisposing alteration in connection to malignant melanoma and breast and lung cancer (Debniak et al 2005, Puig et al 2005. None of the detected sequence alterations occurred in conjunction with malignant disease.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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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“…2 Some studies have reported associations of hypermethylation of CDKN2A 6 or the A148T polymorphism in association with breast cancer risk as well. 7 Brain, head/neck and nonmelanoma skin cancer have also been reported to be more common among mutation carriers. [8][9][10] The CDKN2A gene encodes two different proteins, read from alternate reading frames of a common second exon.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

et al. 2010

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Germline mutations in CDKN2A have been reported in pancreatic cancer families, but genetic counseling for pancreatic cancer risk has been limited by lack of information on CDKN2A mutation carriers outside of selected pancreatic or melanoma kindreds. Lymphocyte DNA from consecutive, unselected white non-Hispanic patients with pancreatic adenocarcinoma was used to sequence CDKN2A. Frequencies of mutations that alter the coding of p16INK4 or p14ARF were quantified overall and in subgroups. Penetrance and likelihood of carrying mutations by family history were estimated. Among 1537 cases, 9 (0.6%) carried germline mutations in CDKN2A, including three previously unreported mutations. CDKN2A mutation carriers were more likely to have a family history of pancreatic cancer (P¼0.003) or melanoma (P¼0.03), and a personal history of melanoma (P¼0.01). Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer (95% confidence interval (CI) 8-86%), and 39% for melanoma (95% CI 0-80). Among cases who ever smoked cigarettes, the risk for pancreatic cancer was higher for carriers compared with non-carriers (HR 25.8, P¼2.1Â10 À13 ), but among nonsmokers, this comparison did not reach statistical significance. Germline mutations in CDKN2A among unselected pancreatic cancer patients are uncommon, although notably penetrant, especially among smokers. Carriers of germline mutations of CDKN2A should be counseled to avoid tobacco use to decrease risk of pancreatic cancer in addition to taking measures to decrease melanoma risk. Keywords: cyclin-dependent kinase inhibitor p16; genes; p16; pancreatic neoplasms INTRODUCTION Pancreatic cancer is associated with very poor survival rates, with long-term survivors limited to those with resected early stage tumors. However, detection of pancreatic cancer at an early stage is challenging, and this mandates identification of high-risk groups to be targeted for prevention and screening intervention.Since first observed by Lynch and Krush in 1968, 1 the incidence of pancreatic cancer has been noted to be increased in many families affected by inherited melanoma syndromes. In genetic analyses of these families, 20-40% of inherited increased melanoma susceptibility can be linked to mutations of the CDKN2A gene (p16/Ink4) located on chromosome 9p21. [2][3][4][5] As a result of the increased incidence of pancreatic cancer in melanoma families with CDKN2A mutations, it was hypothesized that mutations likely also predispose to pancreatic cancer development. 2 Mutations in CDKN2A have subsequently been described in familial pancreatic cancer kindreds, some without melanoma. 3,4 Somatic mutations of CDKN2A are present in up to 95% of pancreatic tumors. 5 These findings provide further support for the premise that CDKN2A mutations have an important role in the development of pancreatic cancer. Clinical findings in mutation carri...

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“…www.intechopen.com however, according to Debniak and co-workers (Debniak et al, 2005a) we can not exclude the possibility that it subtly affects p16 INK4a function or reduces its level of expression.…”

Section: Cdkn2a Germline Mutations In Multiple Primary Malignanciesmentioning

confidence: 87%

“…Next they studied whether the same variant exhibits breast-cancer-predisposing nature too and found that the odds ratio associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 and after the age of 50 it was 1.3. The effect was the strongest for women diagnosed at or before the age of 30 (Debniak et al, 2005a), suggesting a role of the A148T polymorphism in breast cancer predisposition. As a next step, the workgroup performed a population-based study where they compared the genotypes and the allele frequency of the A148T polymorphism in the group of 3,583 unselected cancer cases and 3,000 random controls.…”

Section: Cdkn2a Germline Mutations In Multiple Primary Malignanciesmentioning

confidence: 94%

Melanoma-Predisposing CDKN2A Mutations in Association with Breast Cancer: A Case-Study and Review of the Literature

Balogh¹,

Nemes²,

Uhercsák³

et al. 2011

Melanoma in the Clinic - Diagnosis, Management and Complications of Malignancy

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A common variant of CDKN2A (p16) predisposes to breast cancer

Cited by 72 publications

References 23 publications

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

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

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

Melanoma-Predisposing CDKN2A Mutations in Association with Breast Cancer: A Case-Study and Review of the Literature

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