The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma.,The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD) SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF).,We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM) and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF) method in addition to Cox proportional hazards models.,The Harrell’s C-index was used to compare the performance of model predictability.,The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM), and the hospital-based MD Anderson study consisted of 1,804 CM patients.,Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83) in the GEM study.,Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively).,The Cox model identified no significant associations after adjusting for multiplicity.,Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.
Development and validation of robust molecular biomarkers has so far been limited in melanoma research.,In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification.,We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length).,Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries).,The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3×10−4), Breslow thickness (P=5×10−10), ulceration (P=9.x10−8) and mitotic rate (P=3×10−7), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported.,Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03).,Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres.,Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.