Role of the <i>CDKN2A</i> Locus in Patients With Multiple Primary Melanomas

Puig, Susana; Malvehy, Josep; Badenas, Cèlia; Ruiz, Anna; Jiménez, Dolores Fernández; Cuéllar, Francisco; Azón-Masoliver, Antoni; González, Urbà; Castel, Teresa; Campoy, Antoni; Herrero, Josep Eugeni; Martí, Rosa M.; Brunet, Joan; Milá, Montserrat

doi:10.1200/jco.2005.08.034

Cited by 130 publications

(129 citation statements)

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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: 95%

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: 95%

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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“…25 The finding that there was no difference in tumor proliferation between the 2 groups measured according to the mitotic rate suggests that melanomas in patients with SPM and MPM may not differ in terms of biologic , both of which function as cell-cycle inhibitors. 34 It has been estimated that germline mutations in CDKN2A occur in 8.3% to 15% of patients with MPM. 10,34,35 In a population-based, case-control study, Berwick et al reported a relative risk of 4.3 for a functionally relevant mutation in CDKN2A in patients with MPM versus patients with SPM.…”

Section: Discussionmentioning

confidence: 99%

Single versus multiple primary melanomas

Hwa

Price

Belitskaya-Lévy

et al. 2012

Cancer

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BACKGROUND:In patients with multiple primary melanomas (MPM), mean tumor thickness tends to decrease from the first melanoma to the second melanoma, and prognosis may be improved compared with the prognosis for patients who have a single primary melanoma (SPM). In this study, the authors compared the clinicopathologic features of patients with MPM and SPM to better characterize the differences between these 2 groups and to determine whether or not there is an inherent difference in tumor aggression. METHODS: In total, 788 patients with melanoma who were enrolled prospectively in the Interdisciplinary Melanoma Cooperative Group database from 2002 to 2008 were studied. Patients with SPM and with MPM were compared with regard to clinical and primary melanoma characteristics. RESULTS: Of 788 patients with melanoma, 61 patients (7.7%) had 2 or more primary melanomas. The incidence of developing a second primary melanoma 1 year and 5 years after initial melanoma diagnosis was 4.1% and 8.7%, respectively, and most of the risk accumulated within the first year. The incidence of MPM was greater in patients aged !60 years than in those aged 60 years. The absence or presence of mitosis and other tumor characteristics did not differ significantly between patients with SPM and patients with MPM (P ¼ .61). CONCLUSIONS: No difference was observed in the presence or absence of mitoses, a marker of tumor proliferation, in SPM and MPM. Because it has been demonstrated that the presence of mitosis is a powerful prognostic marker, the current findings suggested that the tumors behave similarly in patients with SPM and patients with MPM. The authors concluded that differences in tumor thickness and prognosis between SPM and MPM more likely are caused by factors other than tumor biology, such as increased surveillance. Cancer 2012;118:4184-92.

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“…Thus, in diseases such as pancreatic cancer or melanoma, loss of p16 ink4a is a relatively common event. 37 For example, in pancreatic intraepithelial neoplasia (PanIN), a well-defined precursor to invasive pancreatic carcinoma, genetic loss or epigenetic silencing of p16 ink4a follows KRAS mutations and is directly associated with progression to invasive disease. 38 It has been hypothesized that the loss of p16 ink4a is associated with a potent selection to bypass senescence that is ostensibly initiated by the oncogenic insult.…”

Section: Prognostic Features Of P16 Ink4a In Tumorsmentioning

confidence: 99%