Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

Objective: To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression of microRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers. Methods: FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNP rs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) were used to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. Results: Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs (miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739 genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping and microRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes (P < 0.05) in the risk group (A allele). Conclusions: We present two novel methods to analyze SNPs within 3' UTRs that use: (i) a single miRNA marker expression and (ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these two methods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.