Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas

International audienceAbstract Background Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1,142 European UM patients and 882 healthy controls.Methods We combined two independent datasets (GSA array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were two-sided.Results We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35-1.86; P=1.98 × 10-8) and identified two additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44-2.16; P =3.55 × 10-8) and HERC locus on chromosome 15 (rs12913832: OR = 0.57, 95% CI = 0.48-0.67; P =1.88 × 10-11). The IRF4 rs12203592 SNP was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87-3.97; P =1.78 × 10-7), and the HERC2 rs12913832 SNP was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79-3.29; P =1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups.Conclusion This work identified two additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients’ genetic backgrounds