Person:

Zhang, Mingfeng

Single genetic variants discovered so far have been only weakly associated with melanoma. This study aims to use multiple single nucleotide polymorphisms (SNPs) jointly to obtain a larger genetic effect and to improve the predictive value of a conventional phenotypic model. We analyzed 11 SNPs that were associated with melanoma risk in previous studies and were genotyped in MD Anderson Cancer Center (MDACC) and Harvard Medical School investigations. Participants with ≥15 risk alleles were 5-fold more likely to have melanoma compared to those carrying ≤6. Compared to a model using the most significant single variant rs12913832, the increase in predictive value for the model using a polygenic risk score (PRS) comprised of 11 SNPs was 0.07(95% CI, 0.05-0.07). The overall predictive value of the PRS together with conventional phenotypic factors in the MDACC population was 0.69 (95% CI, 0.64-0.69). PRS significantly improved the risk prediction and reclassification in melanoma as compared with the conventional model. Our study suggests that a polygenic profile can improve the predictive value of an individual gene polymorphism and may be able to significantly improve the predictive value beyond conventional phenotypic melanoma risk factors.

Background: Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) are 3 types of skin cancer that have distinct biologic characteristics and prognoses. We evaluated phenotypic differences in the risk of these cancers in US women. Methods: We conducted a prospective study of 113 139 female nurses from 1984 to 2002. Over the 18 years of follow-up, there were 375 cases of melanoma, 495 cases of SCC, and 9423 cases of BCC. Results: Women with melanoma were more likely to have a family history of melanoma (melanoma: RR 1.94, 95% confidence interval [CI] 1.36–2.76; SCC: RR 0.82, 95% CI 0.58–1.37; BCC: RR 1.49, 95% CI 1.38–1.62) and 6 or more moles on the left arm (melanoma: RR 3.66, 95% CI 2.15–6.24; SCC: RR 1.53, 95% CI 0.83–2.79; BCC: RR 1.48, 95% CI 1.28–1.72). Polytomous logistic regression analysis showed that age at diagnosis (P < 0.0001), family history of melanoma (P = 0.016), and number of moles on the left arm (P = 0.007) were significantly different across the 3 cancers. Conclusions: This prospective observational study demonstrated that known phenotypic factors for skin cancer have a differential impact on the risk of melanoma, SCC, and BCC.