TY - JOUR
T1 - High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL
AU - Goldstein, Alisa M.
AU - Chan, May
AU - Harland, Mark
AU - Gillanders, Elizabeth M.
AU - Hayward, Nicholas K.
AU - Avril, Marie Francoise
AU - Azizi, Esther
AU - Bianchi-Scarra, Giovanna
AU - Bishop, D. Timothy
AU - Bressac-De Paillerets, Brigitte
AU - Bruno, William
AU - Calista, Donato
AU - Albright, Lisa A.Cannon
AU - Demenais, Florence
AU - Elder, David E.
AU - Ghiorzo, Paola
AU - Gruis, Nelleke A.
AU - Hansson, Johan
AU - Hogg, David
AU - Holland, Elizabeth A.
AU - Kanetsky, Peter A.
AU - Kefford, Richard F.
AU - Landi, Maria Teresa
AU - Lang, Julie
AU - Leachman, Sancy A.
AU - MacKie, Rona M.
AU - Magnusson, Veronica
AU - Mann, Graham J.
AU - Niendorf, Kristin
AU - Bishop, Julia Newton
AU - Palmer, Jane M.
AU - Puig, Susana
AU - Puig-Butille, Joan A.
AU - De Snoo, Femke A.
AU - Stark, Mitchell
AU - Tsao, Hensin
AU - Tucker, Margaret A.
AU - Whitaker, Linda
AU - Yakobson, Emanuel
AU - Malvehy, J.
AU - Badenas, C.
AU - Cervera, R.
AU - Cuellar, Francisco
AU - Martí, Rosa
AU - Brunet-Vidal, Joan
AU - Yang, Guang
AU - Martin, Nicholas
AU - Whiteman, David
AU - Green, Adele
AU - Aitken, Joanne
PY - 2006/10/15
Y1 - 2006/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33750567811&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33750567811&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-0494
DO - 10.1158/0008-5472.CAN-06-0494
M3 - Article
C2 - 17047042
AN - SCOPUS:33750567811
SN - 0008-5472
VL - 66
SP - 9818
EP - 9828
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -