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The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

ABSTRACT: Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

SUBMITTER: Lesueur F

PROVIDER: S-EPMC2480975 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

Lesueur F F de Lichy M M Barrois M M Durand G G Bombled J J Avril M-F MF Chompret A A Boitier F F Lenoir G M GM Bressac-de Paillerets B B Baccard Monique M Bachollet Bertrand B Berthet Pascaline P Bonadona Valérie V Bonnetblanc Jean-Marie JM Caron Olivier O Chevrant-Breton Jacqueline J Cuny Jean-François JF Dalle Stéphane S Delaunay Michèle M Demange Liliane L De Quatrebarbes Julie J Doré Jean-François JF Frénay Marc M Fricker Jean-Pierre JP Gauthier-Villars Marion M Gesta Paul P Giraud Sophie S Gorry Philippe P Grange Florent F Green Andrew A Huiart Laetitia L Janin Nicolas N Joly Pascal P Kérob Delphine D Lasset Christine C Leroux Dominique D Limacher Jean-Marc JM Longy Michel M Mansard Sandrine S Marrou Karine K Martin-Denavit Tanguy T Mateus Christine C Maubec Eve E Olivier-Faivre Laurence L Orlandini Vincent V Pujol Pascal P Sassolas Bruno B Stoppa-Lyonnet Dominique D Thomas Luc L Vabres Pierre P Venat Laurence L Wierzbicka Ewa E Zattara Hélène H

British journal of cancer 20080708 2

Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9 ...[more]

PMID: 18612309

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Project description:BackgroundInherited mutations in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Further, previous studies have reported inferior melanoma-specific survival in CDKN2A mutation carriers.ObjectivesHere, the melanoma-specific survival was studied, depending on CDKN2A carrier status and if the melanomas had been diagnosed before or after families were included in a surveillance program.MethodsMelanoma-prone families participating in this study were identified through a nationwide preventive program starting in 1987. Information on melanoma tumours and deaths was obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan-Meier and Cox proportional hazards regression models were used to assess melanoma-specific survival in four defined cohorts, CDKN2A mutation (MUT) carriers with first invasive melanoma before or after inclusion [MUT-pre (n = 53) and MUT-post (n = 43)] and likewise in CDKN2A wild type (WT) cases [WT-pre (n = 255) and WT-post (n = 122)].ResultsThe MUT-pre and MUT-post cases were diagnosed with their first invasive melanoma at a significantly younger ages (38 and 42 years, respectively) than the WT-pre and WT-post cases (48 and 57 years, respectively). The melanomas in the MUT-pre had significantly higher T stage compared with MUT-post (p = 0.006), whereas no such difference was seen comparing WT-pre with WT-post (p = 0.849). MUT-pre had compared with WT-pre, significantly worse melanoma-specific survival, unadjusted (HR 2.33, 95% CI 1.33-4.08, p = 0.003) adjusted (HR 2.70, 95% CI 1.46-5.00, p = 0.001). However, the MUT-post cases had compared with the WT-post cases, no significant survival differences.ConclusionThis study is the first to address the impact on survival from introducing a dermatologic surveillance program to familial melanoma cases with or without CDKN2A mutations. The CDKN2A-mut carriers appeared to have a clear benefit with less advanced melanomas diagnosed and better melanoma-specific survival after inclusion. Among the CDKN2A-wt cases, the effect of the inclusion on the studied outcomes was less evident.

Dataset Information

The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

Publications

The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

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