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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.
AuthorsF Lesueur, M de Lichy, M Barrois, G Durand, J Bombled, M-F Avril, A Chompret, F Boitier, G M Lenoir, , B Bressac-de Paillerets, Monique Baccard, Bertrand Bachollet, Pascaline Berthet, Valérie Bonadona, Jean-Marie Bonnetblanc, Olivier Caron, Jacqueline Chevrant-Breton, Jean-François Cuny, Stéphane Dalle, Michèle Delaunay, Liliane Demange, Julie De Quatrebarbes, Jean-François Doré, Marc Frénay, Jean-Pierre Fricker, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, Philippe Gorry, Florent Grange, Andrew Green, Laetitia Huiart, Nicolas Janin, Pascal Joly, Delphine Kérob, Christine Lasset, Dominique Leroux, Jean-Marc Limacher, Michel Longy, Sandrine Mansard, Karine Marrou, Tanguy Martin-Denavit, Christine Mateus, Eve Maubec, Laurence Olivier-Faivre, Vincent Orlandini, Pascal Pujol, Bruno Sassolas, Dominique Stoppa-Lyonnet, Luc Thomas, Pierre Vabres, Laurence Venat, Ewa Wierzbicka, Hélène Zattara
JournalBritish journal of cancer (Br J Cancer) Vol. 99 Issue 2 Pg. 364-70 (Jul 22 2008) ISSN: 1532-1827 [Electronic] England
PMID18612309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • KLHL6 protein, human
  • Tumor Suppressor Protein p14ARF
Topics
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Carrier Proteins (genetics)
  • Chromosomes, Human, Pair 9
  • Cyclin-Dependent Kinase Inhibitor p16 (genetics)
  • Exons
  • Female
  • Gene Deletion
  • Genes, p16
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Melanoma (genetics)
  • Middle Aged
  • Molecular Sequence Data
  • Pedigree
  • Point Mutation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p14ARF (genetics)

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