Geographical variation in the penetrance of CDKN2A mutations for melanoma.
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.
Bishop
D Timothy
DT
Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, UK. tim.bishop@cancer.org.uk
Demenais
Florence
F
Goldstein
Alisa M
AM
Bergman
Wilma
W
Bishop
Julia Newton
JN
Bressac-de Paillerets
Brigitte
B
Chompret
Agnès
A
Ghiorzo
Paola
P
Gruis
Nelleke
N
Hansson
Johan
J
Harland
Mark
M
Hayward
Nicholas
N
Holland
Elizabeth A
EA
Mann
Graham J
GJ
Mantelli
Michela
M
Nancarrow
Derek
D
Platz
Anton
A
Tucker
Margaret A
MA
D001315:Australia; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005060:Europe; D005190:Family; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005843:Geography; D006801:Humans; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D012307:Risk Factors; D014481:United States
D019941:Cyclin-Dependent Kinase Inhibitor p16