Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

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, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. 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 via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

Body site‐specific genetic effects influence naevus count distribution in women

“…We hypothesise that we were not able to replicate the association with IRF4 because the effect of these variants on the H&N plus trunk and the lower limbs, which include 26% and 31% of the total naevus count, has an opposite direction, therefore nullifying the effect on the whole body. On the other hand, it is likely that DOCK8 and KITLG exert a small effect on naevus count, detectable only by a large sample, as that reached in the recent meta‐analysis study of 52,506 individuals that lead to their identification (Duffy et al, ).…”

“…Genome‐wide association studies have shown that melanoma and naevus count share a common genetic background (Duffy et al, ). According to Whiteman's “divergent pathway hypothesis”, subjects with high melanocyte proliferation are more likely to develop melanoma at those body sites showing high naevus count (Whiteman et al, ).…”

“…Genotyping was performed in 2,864 females from the TwinsUK cohort with a combination of Illumina arrays (HumanHap300, HumanHap610, 1M‐Duo and 1.2M‐Duo 1M), and imputation was carried out using the Michigan Imputation Server and the Haplotype Reference Consortium (HRC version r1.1) panel (the Haplotype Reference Consortium, ). We selected ten SNPs at the IRF4, DOCK8, MTAP , 9q31.2, KITLG and PLA2G6 loci which were previously associated with naevus count (Duffy et al, , ; Falchi et al, ) and extended this set with 2,435 SNPs in high linkage disequilibrium with them ( r 2 > .8, distance limit 500 kb; EUR populations), as detected using LDLink (Machiela & Chanock, ) . We then used for the association testing 1,836 out of the 2,435 SNPs, which were available in our panel and met the following conditions: call rate ≥95%, minor allele frequency (MAF) ≥1% and Hardy–Weinberg equilibrium test with p ≥ 1 × 10 −9 (Table ).…”

“…Then, we estimated the genetic and environmental contributions influencing naevus count variation at the different body sites. Finally, we studied the site‐specific association of naevus count distribution with common DNA variants at five loci previously associated, in genome‐wide association studies, with both naevus count and melanoma susceptibility, that is IRF4 , DOCK8 , MTAP , 9q31.2, KITLG and PLA2G6 (Duffy et al, , ; Falchi et al, ).…”

Iris pigmented lesions as a marker of cutaneous melanoma risk: an Australian case-control study

“…Our study highlighted two genes, OCA2 and IRF4 , that were associated with iris colour and iris pigmented lesions. OCA2 does not have a large effect on skin freckling and naevus count, whereas IRF4 is a major gene for skin freckling and naevi and has a growth regulatory effect on cutaneous melanocytes . We found that other known melanocytic naevus genes, MTAP (rs7023329) and PLA2G6 (rs132972), are not associated with iris pigmented lesions .…”