title: CDKN2A germline mutations in individuals with cutaneous malignant melanoma.
abstract: Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1alpha and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position -34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk.
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. orlowi@mskcc.org
authors.forename: Irene
authors.initials: I
authors.lastname: Orlow
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.forename: Javier
authors.initials: J
authors.lastname: Cotignola
authors.forename: Pampa
authors.initials: P
authors.lastname: Roy
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hummer
authors.forename: Brian A
authors.initials: BA
authors.lastname: Clas
authors.forename: Urvi
authors.initials: U
authors.lastname: Mujumdar
authors.forename: Rebecca
authors.initials: R
authors.lastname: Canchola
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.forename: Anne
authors.initials: A
authors.lastname: Kricker
authors.forename: Loraine D
authors.initials: LD
authors.lastname: Marrett
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Roberto
authors.initials: R
authors.lastname: Zanetti
authors.forename: Richard P
authors.initials: RP
authors.lastname: Gallagher
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Homer
authors.initials: H
authors.lastname: Wilcox
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Lynn
authors.initials: L
authors.lastname: From
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
mesh_terms: D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000503:physiopathology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm