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

J Natl Cancer Inst. 2005 Oct 19;97(20):1507-15. doi: 10.1093/jnci/dji312.


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 1alpha, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age Distribution
  • Aged
  • Australia / epidemiology
  • Canada / epidemiology
  • Case-Control Studies
  • Female
  • Genes, p16*
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation*
  • Humans
  • Incidence
  • Italy / epidemiology
  • Logistic Models
  • Male
  • Melanoma / epidemiology*
  • Melanoma / genetics*
  • Melanoma / mortality
  • Middle Aged
  • Penetrance
  • Risk Assessment
  • Skin Neoplasms / epidemiology*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / mortality
  • Survival Rate
  • United States / epidemiology