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

Goldstein, Alisa M.; Chan, May; Harland, Mark; Gillanders, Elizabeth M.; Hayward, Nicholas K.; Avril, Marie-Francoise; Azizi, Esther; Bianchi-Scarra, Giovanna; Bishop, D. Timothy and Bressac-de Paillerets, Brigitte, et al. (2006) In Cancer Research 66(20). p.9818-9828
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... (More)
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, cdVS2-105A > 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. (Less)
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Cancer Research
volume
66
issue
20
pages
9818 - 9828
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000241392700007
  • scopus:33750567811
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-06-0494
language
English
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yes
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c4c101d4-cd49-4146-9519-6c1038f1ec67 (old id 388145)
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2007-10-03 09:36:34
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@article{c4c101d4-cd49-4146-9519-6c1038f1ec67,
  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, cdVS2-105A &gt; G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P &lt; 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.},
  author       = {Goldstein, Alisa M. and Chan, May and Harland, Mark and Gillanders, Elizabeth M. and Hayward, Nicholas K. and Avril, Marie-Francoise and Azizi, Esther and Bianchi-Scarra, Giovanna and Bishop, D. Timothy and Bressac-de Paillerets, Brigitte and Bruno, William and Calista, Donato and Cannon Albright, Lisa A. and Demenais, Florence and Elder, David E. and Ghiorzo, Paola and Gruis, Nelleke A. and Hansson, Johan and Hogg, David and Holland, Elizabeth A. and Kanetsky, Peter A. and Kefford, Richard F. and Landi, Maria Teresa and Lang, Julie and Leachman, Sancy A. and MacKie, Rona M. and Magnusson, Veronica and Mann, Graham J. and Niendorf, Kristin and Newton Bishop, Julia and Palmer, Jane M. and Puig, Susana and Puig-Butille, Joan A. and de Snoo, Femke A. and Stark, Mitchell and Tsao, Hensin and Tucker, Margaret A. and Whitaker, Linda and Yakobson, Emanuel and Borg, Åke and Olsson, Håkan},
  issn         = {1538-7445},
  language     = {eng},
  number       = {20},
  pages        = {9818--9828},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-06-0494},
  volume       = {66},
  year         = {2006},
}