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The Prevalence of CDKN2A Germ-Line Mutations and Relative Risk for Cutaneous Malignant Melanoma: An International Population-Based Study

¹ University of New Mexico, Albuquerque, New Mexico; ² Memorial Sloan-Kettering Cancer Center, New York, New York; ³ University of Sydney, Sydney, New South Wales, Australia; ⁴ Cancercare Ontario; ⁵ Women's College Hospital, Toronto, Ontario, Canada; ⁶ University of North Carolina, Chapel Hill, North Carolina; ⁷ University of Michigan, Ann Arbor, Michigan; ⁸ University of California, Irvine, California; ⁹ Centro per la Prevenzione Oncologia Torino, Piemonte, Italy; ¹⁰ British Columbia Cancer Agency, Vancouver, BC, Canada; ¹¹ Menzies Centre for Population Health, Hobart, Tasmania, Australia; ¹² University of Pennsylvania, Philadelphia, Pennsylvania; and ¹³ New Jersey Department of Health and Senior Services, Trenton, New Jersey

Requests for reprints: Marianne Berwick, University of New Mexico, Department of Internal Medicine, New Mexico Cancer Research Facility, MSC08 4630, Room 103A, 1 University of New Mexico, Albuquerque, NM 87131. Phone: 505-272-4369; Fax: 505-272-2570. E-mail: mberwick{at}salud.unm.edu

Germ-line mutations of CDKN2A have been identified as strong risk factors for melanoma in studies of multiple-case families. However, an assessment of their relative risk for melanoma in the general population has been difficult because they occur infrequently. We addressed this issue using a novel population-based case-control study design in which "cases" have incident second- or higher-order melanomas [multiple primary melanoma (MPM)] and "controls" have incident first primary melanoma [single primary melanoma (SPM)]. Participants were ascertained from nine geographic regions in Australia, Canada, Italy, and United States. In the 1,189 MPM cases and 2,424 SPM controls who were eligible and available for analysis, the relative risk of a subsequent melanoma among patients with functional mutations who have an existing diagnosis of melanoma, after adjustments for age, sex, center, and known phenotypic risk factors, is estimated to be 4.3 (95% confidence interval, 2.3-7.7). The odds ratio varied significantly depending on the type of mutation involved. The results suggest that the relative risk of mutation carriers in the population may be lower than currently believed and that different mutations on the CDKN2A gene may confer substantially different risks of melanoma. (Cancer Epidemiol Biomarkers Prev 2006;15(8)1520–5)