Journal
ONCOGENE
Volume 30, Issue 13, Pages 1542-1550Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.536
Keywords
melanoma; acral; microRNA; cancer risk; miR-221; KIT
Funding
- National Cancer Institute [1 P50 CA121974]
- National Center for Research Resources (NCRR), National Institutes of Health (NIH) [UL1 RR024139]
- NIH roadmap for Medical Research
- [K08 CA124484]
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MicroRNAs (miRNAs) are small similar to 22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs 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 upregulated in some melanomas, and is also a target of the miRNA 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. Oncogene (2011) 30, 1542-1550; doi: 10.1038/onc.2010.536; published online 29 November 2010
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