title: High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.
abstract: GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. goldstea@exchange.nih.gov
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: May
authors.initials: M
authors.lastname: Chan
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gillanders
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Esther
authors.initials: E
authors.lastname: Azizi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi-Scarra
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: William
authors.initials: W
authors.lastname: Bruno
authors.forename: Donato
authors.initials: D
authors.lastname: Calista
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cannon Albright
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.forename: David E
authors.initials: DE
authors.lastname: Elder
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holland
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Julie
authors.initials: J
authors.lastname: Lang
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
authors.forename: Rona M
authors.initials: RM
authors.lastname: Mackie
authors.forename: Veronica
authors.initials: V
authors.lastname: Magnusson
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Kristin
authors.initials: K
authors.lastname: Niendorf
authors.forename: Julia
authors.initials: J
authors.lastname: Newton Bishop
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.forename: Joan A
authors.initials: JA
authors.lastname: Puig-Butille
authors.forename: Femke A
authors.initials: FA
authors.lastname: de Snoo
authors.forename: Mitchell
authors.initials: M
authors.lastname: Stark
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Linda
authors.initials: L
authors.lastname: Whitaker
authors.forename: Emanuel
authors.initials: E
authors.lastname: Yakobson
mesh_terms: D000328:Adult; D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009380:Neoplasms, Nerve Tissue / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics*