Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom

Mark Harland, Anne E Cust, Celia Badenas, Yu-Mei Chang, Elizabeth A Holland, Paula Aguilera, Joanne F Aitken, Bruce K Armstrong, Jennifer H Barrett, Cristina Carrera, May Chan, Joanne Gascoyne, Graham G Giles, Chantelle Agha-Hamilton, John L Hopper, Mark A Jenkins, Peter A Kanetsky, Richard F Kefford, Isabel Kolm, Johanna Lowery, Josep Malvehy, Zighereda Ogbah, Joan-Anton Puig-Butille, Jordi Orihuela-Segalés, Juliette A Randerson-Moor, Helen Schmid, Claire F Taylor, Linda Whitaker, D Timothy Bishop, Graham J Mann, Julia A Newton-Bishop, Susana Puig

Mutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence. Population-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4. The prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations. There is a low probability (<2%) of detecting a germline CDKN2A mutation in people with melanoma except for those with a strong family history of melanoma (≥2 affected relatives, 25%), three or more primary melanomas (29%), or more than one primary melanoma who also have other affected relatives (27%).