Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample

Colin B. Begg, Irene Orlow, Amanda J. Hummer, Bruce K. Armstrong, Anne Kricker, Loraine D. Marrett, Robert C. Millikan, Stephen B. Gruber, Hoda Anton-Culver, Roberto Zanetti, Richard P. Gallagher, Terence Dwyer, Timothy R. Rebbeck, Nandita Mitra, Klaus Busam, Lynn From, Marianne Berwick, Melisa Litchfield, Paul Tucker, Nicola StephensTeresa Switzer, Elizabeth Theis, Noori Chowdhury, Louise Vanasse, Mark Purdue, David Northrup, Stefano Rosso, Carlotta Sacerdote, Nancy Leighton, Maureen Gildea, Joe Bonner, Joanne Jeter, Judith Klotz, Homer Wilcox, Helen Weiss, Diane Mattingly, Jon Player, Chiu Kit Tse, Peter Kanetsky, Amy Walker, Saarene Panossian, Harvey Mohrenweiser, Richard Setlow

Research output: Contribution to journalArticlepeer-review

179 Scopus citations


Background: Germline mutations in the CDKN2A gene have been linked to melanoma incidence in many families with multiple cases of the disease. Previous studies of multiple-case families have indicated that the lifetime risk (i.e., penetrance) of melanoma in CDKN2A mutation carriers is very high, ranging from 58% in Europe to 91% in Australia by age 80 years. In this study, we examined lifetime melanoma risk among CDKN2A mutation carriers using carriers who were identified in a population-based study of melanoma. Methods: Probands for the study were incident case patients with either first or subsequent melanoma who were identified in nine geographic regions in Australia, Canada, the United States, and Italy. A total of 3626 probands (53% participation rate) with adequate DNA for analysis were recruited and genotyped for CDKN2A mutations. From the 3550 probands whose DNA could be amplified by polymerase chain reaction of CDKN2A exons 1α, 2, and 3 and surrounding regions, 65 mutation carriers were identified. Melanoma histories in first-degree relatives of these probands were used to calculate the lifetime risk in CDKN2A mutation carriers using the kin-cohort method. Results: The risk of melanoma in CDKN2A mutation carriers was approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years. Eighteen probands had three or more first-degree relatives with melanoma, but only one was a carrier of a CDKN2A mutation. Conclusions: CDKN2A mutation carriers in the general population have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. The preponderance of familial clustering of melanoma occurs in families without identifiable mutations in CDKN2A.

Original languageEnglish (US)
Pages (from-to)1507-1515
Number of pages9
JournalJournal of the National Cancer Institute
Issue number20
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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