A Variant in a MicroRNA Complementary Site in the 3′UTR of the KIT Oncogene Increases Risk of Acral Melanoma

MicroRNAs are small ~22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3′UTRs of target gene mRNAs. Recently, mutations have been identified in both microRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be up-regulated in some melanomas, and is also a target of the microRNA miR-221. Here we describe a genetic variant in the 3′UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma.