Penetrance of CDKN2A mutations estimated using population-based Australian families

Background: CDKN2A gene mutations increase risk ofmelanoma (67% by age 80 when using multiple-casefamilies, and 28% by age 80 when using population-basedfamilies with unverified melanoma histories.Methods: The Australian Melanoma Family Study, apopulation-based case-control-family study, included pro-bands with incident cutaneous melanoma diagnosedbefore age 40 recruited from Brisbane, Sydney andMelbourne and their first- and second-degree relatives.We identified 12 probands with pathogenic or suspectedpathogenic CDKN2A mutations. The hazard ratio (HR) ofmelanoma incidence for carriers relative to that for thegeneral population, were estimated using a modifiedsegregation analysis that incorporates both genotypedand ungenotyped relatives and conditions on ascertain-ment to produce unbiased estimates.Results:The HR for reported melanoma was greater forfemales than males (HR 5 34.2 and 9.9, respectively;P 5 0.02). Combining males and females, the penetranceof melanoma for CDKN2A mutation carriers was 60% (95% CI: 43 to 77%) by age 80 (females 70%, males 43%). TheHRs for confirmed melanoma was 8.4 for males andfemales combined (c.f. 19.5 for reported melanoma).Conclusion: Our population-based estimates of melanomarisk which apply to the mutations identified in early-onsetcases of melanoma, appear to be higher than previouspopulation-based estimates from studying the families ofcases unselected for age at onset and were higher forfemales than males.