Abstract
While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415–0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419–0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339–0.637; p = 3.04E-07) are correlated (r2 > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.
Highlights
Uveal melanoma (UM) is the most common primary adult intraocular cancer[1,2] with relatively unclear etiology, some specific risk factors, such as ethnicity or eye/skin pigmentation traits, have been suggested[3]
We analyzed 28 SNPs established in recent genome-wide association study (GWAS) for association with cutaneous melanoma (CM) or related host phenotypes (Supplementary Table 1), in a population of 272 uveal melanoma (UM) patients and 760 controls that were of European ancestry (Supplementary Table 2)
Logistic regression analysis adjusted by age and gender revealed a novel association with reduced UM risk in the locus of HERC2/OCA2 at 15q13 for 3 correlated SNPs (r2 > 0.5), which were still significant following adjustment for multiple testing (Table 1, full results in Supplementary Table 3): rs12913832 (OR = 0.529, 95% confidence intervals (95% CI) 0.415–0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419–0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339–0.637; p = 3.04E-07)
Summary
We analyzed 28 SNPs (one SNP did not pass genotype filtering) established in recent GWASs for association with CM or related host phenotypes (including skin and eye pigmentation) (Supplementary Table 1), in a population of 272 UM patients and 760 controls that were of European ancestry (Supplementary Table 2). To provide a true estimate of potential risk effect with smaller size for remaining subset of variants in our selection, a larger study will be needed as part of national or international consortia As part of such collaborative efforts, the consideration of additional covariates such as pigmentation phenotypes in studied populations would be essential, as in the current study, while important, this data was not available. The molecular effect of pigmentation on different UM subtypes has recently been suggested, as different GNAQ mutation signatures were observed in posterior (choroid) versus anterior UM tumors (ciliary body, iris), likely reflecting divergent UM pathways related to toxic pheomelanin synthesis[17] This molecular support for a role of melanin in UM histologies and the association of germline variants of eye color with UM risk found in this study suggest interplay between both somatic and inherited factors of pigmentation pathways in UM development. Complementing our findings with other high-risk loci (e.g. BAP1) will further expand the clinical implications for both UM risk-prediction and biological understanding of pigmentation in UM etiology
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