Abstract
The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Highlights
1234567890():,; The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk
Since number of cutaneous nevus is strongly correlated with melanoma risk, and known nevus loci were associated with cutaneous malignant melanoma (CM), it seemed likely that this would be a fruitful approach
Among those novel pleiotropic loci implicated in nevus count, CYP1B1 and PPARGC1B both appear in a recent skin pigmentation meta-analysis[30] as harboring variants lightening skin color
Summary
1234567890():,; The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. The strongest CM epidemiological risk factor acting within populations of European descent is the number of cutaneous acquired melanocytic nevi, with risk increasing by 2–4% per additional nevus counted[2]. Nevi are benign melanocytic tumors usually characterized by a signature somatic BRAF mutation Their association with CM can be direct, in that a proportion of melanomas arise within a preexisting nevus (due to a “second hit” mutation), or indirect, where genetic or environmental risk factors for both traits are shared. We present a new large nevus genome-wide association meta-analysis, and combine these results with those of a previously published meta-analysis of melanoma[10]
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