Geographical variation in the penetrance of CDKN2A mutations for melanoma

Bishop, D. T., Demenais, F., Goldstein, A. M., Bergman, W., Newton Bishop, J., Bressac-de Paillerets, B., Chompret, A., Ghiorzo, P., Gruis, N., Hansson, J., Harland, M., Hayward, N., Holland, E. A., Mann, G. J. and Mantelli, M. (2002) Geographical variation in the penetrance of CDKN2A mutations for melanoma. Journal of the National Cancer Institute, 94 12: 894-903.

Author Bishop, D. T.
Demenais, F.
Goldstein, A. M.
Bergman, W.
Newton Bishop, J.
Bressac-de Paillerets, B.
Chompret, A.
Ghiorzo, P.
Gruis, N.
Hansson, J.
Harland, M.
Hayward, N.
Holland, E. A.
Mann, G. J.
Mantelli, M.
Title Geographical variation in the penetrance of CDKN2A mutations for melanoma
Journal name Journal of the National Cancer Institute   Check publisher's open access policy
ISSN 0027-8874
Publication date 2002-01-01
Sub-type Article (original research)
Open Access Status Not yet assessed
Volume 94
Issue 12
Start page 894
End page 903
Total pages 10
Editor B. S. Kramer
S. B. Green et al.
Place of publication Cary, U.S.A.
Publisher Oxford University Press
Language eng
Subject C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
Abstract 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 p14APF 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.
Keyword Oncology
Cutaneous Malignant-melanoma
Dysplastic Nevus Syndrome
Familial Melanoma
Germline Mutations
Prone Families
Anatomic Site
Segregation Analysis
P16 Gene
Q-Index Code C1
Additional Notes Authors of this document: Bishop, DT; Demenais, F; Goldstein, AM; Bergman, W; Bishop, JN; Bressac-de Paillerets, B; Chompret, A; Ghiorzo, P; Gruis, N; Hansson, J; Harland, M; Hayward, N; Holland, EA; Mann, GJ; Mantelli, M; Nancarrow, D; Platz, A; Tucker, MA; Melanoma Genetics Consortium.

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Created: Wed, 15 Aug 2007, 03:13:57 EST