High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

Alisa M. Goldstein, May Chan, Mark Harland, Elizabeth M. Gillanders, Nicholas K. Hayward, Marie Francoise Avril, Esther Azizi, Giovanna Bianchi-Scarra, D. Timothy Bishop, Brigitte Bressac-De Paillerets, William Bruno, Donato Calista, Lisa A.Cannon Albright, Florence Demenais, David E. Elder, Paola Ghiorzo, Nelleke A. Gruis, Johan Hansson, David Hogg, Elizabeth A. HollandPeter A. Kanetsky, Richard F. Kefford, Maria Teresa Landi, Julie Lang, Sancy A. Leachman, Rona M. MacKie, Veronica Magnusson, Graham J. Mann, Kristin Niendorf, Julia Newton Bishop, Jane M. Palmer, Susana Puig, Joan A. Puig-Butille, Femke A. De Snoo, Mitchell Stark, Hensin Tsao, Margaret A. Tucker, Linda Whitaker, Emanuel Yakobson, J. Malvehy, C. Badenas, R. Cervera, Francisco Cuellar, Rosa Martí, Joan Brunet-Vidal, Guang Yang, Nicholas Martin, David Whiteman, Adele Green, Joanne Aitken

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350 Scopus citations


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.M531, 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.

Original languageEnglish (US)
Pages (from-to)9818-9828
Number of pages11
JournalCancer Research
Issue number20
StatePublished - Oct 15 2006


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