edited and revised the manuscript. Tomas Kirchhoff led the project. All authors have read and approved the final version of the manuscript. Ethical approval and ethical standards Written informed consents for the use of the blood specimens and clinical information were obtained at the time of enrollment from all participants and the study was approved by the Institutional Review Board (IRB) at all institutions
Purpose The identification of personalized germline markers with biological relevance for the prediction of cutaneous melanoma (CM) prognosis is highly demanded but to date it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating CM outcomes. Experimental Design Using whole genome eQTL data from a healthy population, we identified 385 variants -significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 CM patients for their association with overall (OS) and recurrence-free survival using Cox regression models. Results We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR 0.56, 95%CI 0.41–0.77; P=0.0002) and rs6695772, controlling the expression of BATF3 (HR 1.64, 95%CI 1.19–2.24; P=0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR 1.92, 95%CI 1.43–2.60; P=2.38e–5). Conclusions Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of CM prognosis that are independent of current histopathological markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers.
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.
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