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MiRNA-Binding Site Polymorphisms, Cancer Risk and Outcome

Since miRNAs bind to imperfect complementary sequences in the 3’UTR of target mRNAs to repress target gene expression [3, 4] [1, 2, 5-9], the 3’UTR has rightly received increased interest recently. A new insight into cancer biology has come with the finding that functional single nucleotide polymorphisms (SNPs) in miRNA binding sites in the 3’UTR of cancer genes act as biomarkers of cancer risk and outcome. We identified the first miRNA-based 3’UTR variant that predicts cancer risk and cancer outcome. This variant, in the 3’UTR of the KRAS oncogene (rs61764370), is predicted to disrupt binding of the let-7 miRNA to KRAS [10], allowing higher KRAS levels. We collaborated with a clinical oncologist, Dr. Joanne Weidhaas to show that the KRAS-variant is a genetic marker of an increased susceptibility to non-small cell lung cancer [10], ovarian cancer [11] and triple negative breast cancer [12]. We additionally found that two BRCA1 SNPs associated with breast cancer risk were indeed in miRNA-binding sites, one in the 3’UTR SNPs and one that is an exonic SNP [13]. In another study, we found that a functional SNP in a miRNA complementary site in the KIT oncogene’s 3’UTR is enriched in melanoma [14]. Despite these important contributions to the cancer literature, the cancer genome resequencing projects have largely ignored the 3’UTR of genes in the search for new lesions associated with cancer. We propose to change that by seeking more of these types of functional genetic variants to better describe the genetic causes of cancer and poor response to therapy.

 

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