High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.
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.
Goldstein
Alisa M
AM
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. goldstea@exchange.nih.gov
Chan
May
M
Harland
Mark
M
Gillanders
Elizabeth M
EM
Hayward
Nicholas K
NK
Avril
Marie-Francoise
MF
Azizi
Esther
E
Bianchi-Scarra
Giovanna
G
Bishop
D Timothy
DT
Bressac-de Paillerets
Brigitte
B
Bruno
William
W
Calista
Donato
D
Cannon Albright
Lisa A
LA
Demenais
Florence
F
Elder
David E
DE
Ghiorzo
Paola
P
Gruis
Nelleke A
NA
Hansson
Johan
J
Hogg
David
D
Holland
Elizabeth A
EA
Kanetsky
Peter A
PA
Kefford
Richard F
RF
Landi
Maria Teresa
MT
Lang
Julie
J
Leachman
Sancy A
SA
Mackie
Rona M
RM
Magnusson
Veronica
V
Mann
Graham J
GJ
Niendorf
Kristin
K
Newton Bishop
Julia
J
Palmer
Jane M
JM
Puig
Susana
S
Puig-Butille
Joan A
JA
de Snoo
Femke A
FA
Stark
Mitchell
M
Tsao
Hensin
H
Tucker
Margaret A
MA
Whitaker
Linda
L
Yakobson
Emanuel
E
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*