Cutaneous melanoma mutation pathways and driver mutations as racially biased.

Abstract

e22066 Background: Cutaneous melanoma (CM) demonstrates differences in its clinical prevalence in different racial groups. CM generally exhibits a high tumor mutational burden (TMB) and mutually exclusive driving mutations in NRAS, BRAF or KIT. TMB may be driven by different pathways including ultraviolet radiation (UVR), oxidation and deamination. UVR is the most common mutational signature found in CMs, but deamination and oxidation are also present. Methods: We analyzed 321 CMs exome data from The Cancer Genome Atlas network. BRAF, NRAS, KIT and those without (WT) were used to divide the melanomas. Germline SNPs with racial information (Caucasian, African and Asian) that were enriched in melanomas with a particular driving mutation were identified. Results: We compared the 3 racial groups across the 4 driving mutation types, Asian SNPs were significantly higher in KIT, African in WT and Caucasian in BRAF and NRAS. The melanomas were also evaluated by the type of substitution mutations including CC > TT for UV, G > T for oxidative damage and (G/A)C (G) > (G/A)T(G) for deamination. UV and deamination appeared inversely proportional, while oxidative damage appeared to be independent. UV signal was more prominent in BRAF and NRAS groups. KIT had a greater percentage of deamination while WT revealed more oxidative damage. We further compared UV and non-UV (CC > TT absence) KIT subgroups for racial differences. Asian SNPs were greatly increased in non-UV subgroup whereas Caucasian SNPs were in UV subgroup. Further, the non-UV KIT subgroup was divided into deamination and oxidative damage subgroups to compare racial differences. Deamination was significantly increased in Asians whereas oxidative damage was higher in Caucasians. In the case of the WT group, African SNPs were significantly higher in the non UV subgroup and were primarily correlated with oxidative damage. Conclusions: This study suggests that racial genetic background may predispose the distinctive mutational and genetic environments of melanoma development.