© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 12, 894-903,
June 19, 2002
© 2002 Oxford University Press
ARTICLE |
Geographical Variation in the Penetrance of CDKN2A Mutations for Melanoma
The Melanoma Genetics Consortium
Affiliations of authors: D. T. Bishop, J. Newton Bishop, M. Harland, Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds, U.K.; F. Demenais, Institut National de la Santé et de la Recherche Médicale EMI 00–06, Evry, France; A. M. Goldstein, M. A. Tucker, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; W. Bergman, N. Gruis, Department of Dermatology and Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; B. Bressac-de Paillerets, A. Chompret, Institut Gustave Rousy, Villejuif, France; P. Ghiorzo, M. Mantelli, Department of Oncology, Biology, and Genetics, University of Genova, Genova, Italy; J. Hansson, A. Platz, Department of Oncology–Pathology, Karolinska Hospital, Stockholm, Sweden; N. Hayward, D. Nancarrow, Queensland Cancer Fund Research Unit, Brisbane, Australia; E. A. Holland, G. J. Mann, Westmead Institute for Cancer Research, Sydney, Australia.
Correspondence to: D. Timothy Bishop, Ph.D., Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Cancer Genetics Building, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, U.K. (e-mail: tim.bishop{at}cancer.org.uk).
Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium. Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.
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