The melanoma risk loci as determinants of melanoma prognosis.

Abstract

8557Background: Genetic risk factors of human cancer emerge as promising markers of clinical outcome. The recent melanoma genome-wide scans (GWAS) have identified loci associated with the disease risk, nevi or UV/pigmentation, but the prognostic potential of these variants is yet to be determined. In this study, we performed the first-to-date systematic evaluation of the association between established melanoma risk loci and melanoma progression. Methods: 891 melanoma patients prospectively accrued and followed up at NYU Medical Center were studied. We examined the association of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent GWASs on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and overall survival (OS). The genotyping was performed using Sequenom I-plex. Cox PH model was used to test the association between each SNP and RFS and OS adjusted by age at diagnosis, gender, tumor stage and histological subtype. ROC curves were used to measure predictive utility of SNPs in predicting 3-year recurrence. Results: The strong association was observed for rs7538876 (RCC2) with RFS (HR=2.445, 95% CI 1.57 – 3.8, p=0.0006) and rs9960018 (DLGAP1) with both RFS and OS (HR=4.7, 95% CI=2.11-10.43, p=0.0061, HR=1.55, 95% CI=1.11-2.17, p=0.0094, respectively) using adjusted multivariate analysis. In addition, we identified the classifier with rs7538876 and rs9960018, stage and histological type at primary tumor diagnosis, achieving a higher area under the ROC curve (AUC=84%) compared to the baseline (AUC=78%) in predicting 3-year recurrence. Univariate survival analyses have identified associations of several SNPs with ulceration and/or tumor thickness. Conclusions: Our data revealed an association between specific melanoma susceptibility variants and worse clinicopathological variables at the time of diagnosis as well as worse disease outcome. The strength of associations observed for rs7538876 and rs9960018 suggest biological implication of these loci in melanoma recurrence. The observed predictive patterns of associated variants with clinical outcome provide for the first time evidence for the potential utilization of genetic markers in melanoma prognostication.