title: Genetic variation at KIT locus may predispose to melanoma.
abstract: As loss of KIT frequently occurs in melanoma progression, we hypothesized that KIT is implicated in predisposition to melanoma (MM). Thus, we sequenced the KIT coding region in 112 familial MM cases and 143 matched controls and genotyped tag single-nucleotide polymorphisms (SNPs) in two cohorts of melanoma patients and matched controls. Five rare KIT substitutions, all predicted possibly or probably deleterious, were identified in five patients, but none in controls [RR = 2.26 (1.26-2.26)]. Expressed in melanocyte lines, three substitutions inhibited KIT signaling. Comparison with exomes database (7020 alleles) confirmed a significant excess of rare deleterious KIT substitutions in patients. Additionally, a common SNP, rs2237028, was associated with MM risk, and 6 KIT variants were associated with nevus count. Our data strongly suggest that rare KIT substitutions predispose to melanoma and that common variants at KIT locus may also impact nevus count and melanoma risk.
authors.affiliation: Département de Génétique, Hôpital Bichat-Claude Bernard, APHP, Paris, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bourillon
authors.forename: Hui-Han
authors.initials: HH
authors.lastname: Hu
authors.forename: Gilles
authors.initials: G
authors.lastname: Hetet
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lacapere
authors.forename: Jocelyne
authors.initials: J
authors.lastname: André
authors.forename: Vincent
authors.initials: V
authors.lastname: Descamps
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.forename: Zighereda
authors.initials: Z
authors.lastname: Ogbah
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.forename: Philippe
authors.initials: P
authors.lastname: Saiag
authors.forename: Martine
authors.initials: M
authors.lastname: Bagot
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.forename: Nadem
authors.initials: N
authors.lastname: Soufir
mesh_terms: D016022:Case-Control Studies; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D010766:Phosphorylation; D010858:Pigmentation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D019009:Proto-Oncogene Proteins c-kit