title: Geographical variation in the penetrance of CDKN2A mutations for melanoma.
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 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.
authors.affiliation: Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, UK. tim.bishop@cancer.org.uk
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Wilma
authors.initials: W
authors.lastname: Bergman
authors.forename: Julia Newton
authors.initials: JN
authors.lastname: Bishop
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Agnès
authors.initials: A
authors.lastname: Chompret
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.forename: Nelleke
authors.initials: N
authors.lastname: Gruis
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hayward
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holland
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Michela
authors.initials: M
authors.lastname: Mantelli
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.forename: Anton
authors.initials: A
authors.lastname: Platz
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
mesh_terms: 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
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16