Does polygenic risk influence associations between sun exposure and melanoma?: a prospective cohort analysis

Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on these interactions from prospective studies are scant however. We aimed to quantify the association between ambient and personal ultraviolet (UV) exposure and incident melanoma in a large population‐based prospective study of men and women residing in a high ambient UV setting, and to examine potential gene‐environment interactions. Among participants with genetic data (n=15,373), 420 (2.7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow‐up time of 4.4 years. Country of birth, age at migration, having greater than 50 sunburns in childhood/adolescence and a history of keratinocyte cancer/actinic lesions were significantly associated with melanoma risk. An interaction with polygenic risk was suggested; among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high‐level early life ambient exposure (as measured by place of birth) were associated with melanoma (HR for born in Australia vs. overseas 3.16, 95% CI 1.39‐7.22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development.