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High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL

¹ Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda Maryland; ² Inherited Disease Research Branch, National Human Genome Research Institute, NIH, Department of Health and Human Services, Baltimore, Maryland; ³ Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds, United Kingdom; ⁴ Department of Medical Genetics, University of Glasgow, Glasgow, United Kingdom; ⁵ Queensland Institute of Medical Research, Brisbane, Queensland, Australia; ⁶ Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia; ⁷ Service de Génétique and ⁸ Service de Dermatologie, Institut Gustave Roussy, Villejuif, France; ⁹ Institut National de la Sante et de la Recherche Medicale-U794, Université d'Evry, Evry, France; ¹⁰ Department of Dermatology and ¹¹ Molecular Cell Biology Laboratory, Department of Internal Medicine C, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; ¹² Department of Oncology, Biology, and Genetics, University of Genova, Genova, Italy; ¹³ Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy; ¹⁴ Department of Medical Informatics and ¹⁵ Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; ¹⁶ Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics and ¹⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ¹⁸ Department of Dermatology and ¹⁹ Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; ²⁰ Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden; ²¹ Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden (see Appendix B); ²² Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; ²³ Wellman Center for Photomedicine, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; and ²⁴ Dermatology Department and ²⁵ Genetics Service, Melanoma Unit, Hospital Clínic, Institut de Investigació Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain; ²⁶ See Appendix A

Requests for reprints: Alisa M. Goldstein, Genetic Epidemiology Branch/National Cancer Institute/NIH/Department of Health and Human Services, Executive Plaza South, Room 7004, 6120 Executive Boulevard, MSC 7236, Bethesda, MD 20892-7236. Phone: 301-496-4375; Fax: 301-402-4489; E-mail: goldstea{at}exchange.nih.gov.

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. (Cancer Res 2006; 66(20): 9818-28)

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