title: Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect.
abstract: Multiple primary cancers are one of the hallmarks of inherited predisposition. Outside the familial context, multiple primary tumors could be related either to germline de novo mutations or to low-penetrance mutations, in predisposing genes. We selected 100 patients who displayed multiple primary melanoma (MPM) without any known melanoma cases recorded within their families and looked for germline mutations in the two melanoma-predisposing genes identified to date, CDKN2A and CDK4 exon 2. Nine patients (9%) had germline mutations in CDKN2A, whereas none carried germline mutations in exon 2 of CDK4. Seven cases displayed a recurrent missense mutation, G101W, already described in more than 20 melanoma-prone families; one case carried a missense mutation never reported to date (P114S), and the last case was a carrier of a 6 bp insertion at nucleotide 57 resulting in a duplication of codons 18 and 19. To ascertain whether the G101W was a mutational hot spot for de novo mutations or a common founder mutation, we genotyped eight microsatellite markers flanking the CDKN2A gene. After allowing for recombination over time, haplotype sharing provided evidence for an original G101W mutation common to 6 out of 7 sporadic MPM cases. Therefore, it can be concluded that de novo germline CDKN2A mutations associated with MPM are rare.
authors.affiliation: Service de Génétique, Institut Gustave Roussy, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Auroy
authors.forename: M F
authors.initials: MF
authors.lastname: Avril
authors.forename: A
authors.initials: A
authors.lastname: Chompret
authors.forename: D
authors.initials: D
authors.lastname: Pham
authors.forename: A M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: G
authors.initials: G
authors.lastname: Bianchi-Scarrà
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.forename: P
authors.initials: P
authors.lastname: Joly
authors.forename: A
authors.initials: A
authors.lastname: Spatz
authors.forename: C
authors.initials: C
authors.lastname: Rubino
authors.forename: F
authors.initials: F
authors.lastname: Demenais
authors.forename: B
authors.initials: B
authors.lastname: Bressac-de Paillerets
mesh_terms: D000328:Adult; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D018703:Founder Effect; D019942:Genes, p16; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010375:Pedigree; D011518:Proto-Oncogene Proteins; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases