title: New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment.
abstract: Germline mutations in the CDKN2A gene have been shown to predispose individuals to cutaneous malignant melanoma. Here, we describe three melanoma-prone families and one isolated patient affected by multiple melanoma who carried a tandem germline mutation of CDKN2A at the nucleotide level, [c.339G>C;c.340C>T], [p.Leu113Leu;p.Pro114Ser]. We also describe three other melanoma-prone families that carried a missense germline CDKN2A mutation, c.167G>T, p.Ser56Ile. All these families and patients resided in southeast France. We analyzed six 9p21 markers where the CDKN2A gene is located and found that carrier haplotypes for both mutations were consistent with two respective common founder ancestors. In one family, we identified two fourth-degree relatives homozygous for the Ser56Ile mutation, indicating a possible consanguinity. Furthermore, we observed that a carrier of the founder CDKN2A [p.Leu113Leu;p.Pro114Ser] mutation as well as two MC1R moderate-risk variants, [p.Arg151Cys(+)p.Arg163Gln] developed 22 primary melanomas in the three years that followed initiation of levodopa therapy for Parkinson's disease. This observation suggests that there is a need for reconsideration of the hypothesis that levodopa may play a role in melanoma development, at least when in the context of a high-risk genetic background.
authors.affiliation: Service de Génétique, Institut Gustave Roussy, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dalle
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Leccia
authors.forename: Marie Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Valerie
authors.initials: V
authors.lastname: Bonadona
authors.forename: Agnès
authors.initials: A
authors.lastname: Chompret
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lenoir
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
mesh_terms: D004252:DNA Mutational Analysis; D005190:Family; D005192:Family Health; D018703:Founder Effect; D005602:France; D005787:Gene Frequency; D019942:Genes, p16; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008545:Melanoma / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D010375:Pedigree
chemical_list: D007980:Levodopa