Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival

Cutaneous melanoma (CM) is considered as a steroid hormone-related malignancy. However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR-related genes) in CM-specific survival (CMSS). Here, we performed a pathway-based analysis to evaluate genetic variants of 191 SHR-related genes in 858 CMSS patients using a dataset from a genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS. Using multivariate Cox proportional hazards regression analysis, we identified three-independent SNPs (RORA rs782917 G > A, RORA rs17204952 C > T and DNMT1 rs7253062 G > A) as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25-2.09), 1.60 (1.20-2.13) and 1.52 (1.20-1.94), respectively. Combined analysis of risk genotypes of these three SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (p_trend  < 0.001); however, no improvement in the prediction model was observed (area under the curve [AUC] = 79.6-80.8%, p = 0.656), when these risk genotypes were added to the model containing clinical variables. Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies.