title: 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.
authors.affiliation: Groupe Mélanome, Institut Gustave Roussy, FRE2939 CNRS-Université Paris-Sud, Villejuif, France.
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authors.lastname: Lesueur
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authors.lastname: de Lichy
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authors.lastname: Barrois
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authors.lastname: Gorry
authors.forename: Florent
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authors.lastname: Green
authors.forename: Laetitia
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authors.lastname: Huiart
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authors.lastname: Janin
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authors.forename: Delphine
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authors.lastname: Kérob
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authors.forename: Dominique
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authors.lastname: Leroux
authors.forename: Jean-Marc
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authors.lastname: Limacher
authors.forename: Michel
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authors.lastname: Longy
authors.forename: Sandrine
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authors.lastname: Mansard
authors.forename: Karine
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authors.lastname: Marrou
authors.forename: Tanguy
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authors.lastname: Martin-Denavit
authors.forename: Christine
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authors.lastname: Mateus
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authors.lastname: Maubec
authors.forename: Laurence
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authors.lastname: Olivier-Faivre
authors.forename: Vincent
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authors.lastname: Orlandini
authors.forename: Pascal
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authors.lastname: Pujol
authors.forename: Bruno
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authors.lastname: Sassolas
authors.forename: Dominique
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authors.lastname: Stoppa-Lyonnet
authors.forename: Luc
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authors.lastname: Thomas
authors.forename: Pierre
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authors.lastname: Vabres
authors.forename: Laurence
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authors.lastname: Venat
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authors.lastname: Wierzbicka
authors.forename: Hélène
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authors.lastname: Zattara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C473356:KLHL6 protein, human; D025803:Tumor Suppressor Protein p14ARF