Abstract 4510: KIT melanomas are developmentally racially biased

Abstract

Abstract KIT is a critical pathway for melanocytic homeostasis and it is often down-regulated in cutaneous melanoma. However, KIT activation plays a critical role in a subpopulation of melanomas especially those in acral locations and melanomas on chronically sun damaged skin. We analyzed exome and RNAseq data from The Cancer Genome Atlas (TCGA) Network (321 cutaneous melanomas in the data set) to identify patterns unique to KIT activation. The melanomas were divided based on known mutually exclusive mutations (BRAF, NRAS and KIT) vs those without (WT). We compared RNA data between each group. KIT group had significantly higher expression of KIT than BRAF, NRAS and WT (p<0.01, FDR<0.01) and isoform 2 expression was higher than 1. KIT melanomas were found to overexpress Wnt pathway, pigmentation and genes involved epithelial-mesenchymal transition. From the exome data, germline SNPs with incidence in ethnic groups (Caucasian, Asian and African) and more likely to be present in a specific melanoma groups were selected. Comparing the 3 ethnicity groups across the 4 tumor groups Asian SNPs were significantly enhanced in KIT tumors, African in WT and Caucasian in BRAF and NRAS melanomas. We evaluated the tumors for the primary type of genetic damage. The three signatures that appeared most divergent were CC>TT for UV, (G/A)C(G)>(G/A)T(G) for deamination, and G>T for oxidative damage. UV and deamination appeared inversely proportional, while oxidative damage appeared to be independent of those other two features. KIT and WT had a greater% of non UV high deamination tumoral environments. A fraction of these tumors also had very high oxidative signatures. We then compared 2 KIT subgroups UV vs non UV (absence of CC>TT mutations) for germline ethnicity differences. Asian SNPs were highly increased in non UV subgroup whereas Caucasian SNPs were in UV subgroup. Further, we divided KIT non UV subgroup into deamination and oxidative damage subgroups and compared ethnicity differences. Deamination was significantly higher in Asians whereas oxidative damage was higher in Caucasians. A similar analysis was done to the WT group, where African SNPs were significantly increased in the non UV subgroup and were primarily associated with oxidative damage. This data implies that KIT mutant melanomas develop in a unique genetic and mutational environments and makes this an ideal system to in which study racial disparities at the molecular level. Citation Format: Margaret I. Sanchez, James M. Grichnik. KIT melanomas are developmentally racially biased. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4510.