Single-Nucleotide Polymorphisms Inside MicroRNA Target Sites Influence Tumor Susceptibility

Abstract

Single-nucleotide polymorphisms (SNP) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy, or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPs is a widespread mechanism relevant to cancer susceptibility. To test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted ∼64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by >90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1 significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs, allelic variants, and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following overexpression of the two interacting miRNAs (miR-638 and miR-628-5p). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and, consequently, protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation. Cancer Res; 70(7); 2789-98. ©2010 AACR.

Lack of Association of BRCA1 and BRCA2 Variants with Breast Cancer in an Ethnic Population of Saudi Arabia, an Emerging High-Risk Area

“…Recently in a Chinese study, BRCA1 (rs799917) was found to be associated with breast cancer risk (Huo et al, 2009). Nicoloso et al (2010) found that a codon SNP (rs799917) in BRCA1 gene, which is predicted to be a binding site for miR-638, was associated with increased risk of breast cancer and germline occurrence of BRCA1 (rs799917) significantly varies among populations with different risks of developing breast cancer. Cox et al (2005a) also have reported the association of BRCA1 (rs799917) with breast cancer, but Sehl et al (2009) showed a lack of association between the BRCA1 (rs799917) and breast cancer.…”

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

“…As the majority of these miRNAs binds to the 3'UTR region of the genes (Sehl et al, 2009), variations in the 3'UTR regions of BRCA1/2 may also affect the regulation of related proteins and thus response to the applied therapy (Nilsen, 2007). In addition, the importance of miRNA-binding site single-nucleotide polymorphisms (SNPs) of the BRCA1/2 genes in breast and ovarian cancer has been emphasized in recent studies of certain individual populations (Barroso et al, 2009;Pongsavee et al, 2009;Sehl et al, 2009;Kontorovich et al, 2010;Nicoloso et al, 2010;Joseph et al, 2011). However, knowledge about the effect of 3'UTR site variations of BRCA1/2 remains elusive.…”

rs12904 Polymorphism in the 3'UTR of EFNA1 is Associated with Colorectal Cancer Susceptibility in a Chinese Population

“…The majority of miRNAs bind to target sequences located in the 3'UTR of mRNAs by base pairing, resulting in the cleavage of target mRNA or repression of their translation. When SNPs occur in the 3'UTR, they may modulate gene expression by altering miRNA target binding capacity, ultimately leading to DOI:http://dx.doi.org/10.7314/APJCP.2013.14.9.5037 Associations Between EFNA1 and Colorectal Cancer in Chinese differences in the disease susceptibility (Nicoloso et al, 2010). As predicted by TargetScan (http://www.targetscan.…”