A genetic variant in microRNA-146a is associated with sporadic breast cancer in a Southern Brazilian Population

Abstract

MicroRNAs (miRNAs) play an essential role in gene expression and affect the development of tumours, including breast cancer (BC). Polymorphisms in miRNA genes can affect the interaction of miRNAs with their target messenger RNA by interfering, creating or disrupting target sites. The single nucleotide polymorphism (SNP) rs2910164, located in the seed region of miR146a, was shown to be associated with BC among different populations. In the present study, we investigated whether rs2910164 is associated with BC in 326 patients and 411 controls from a Brazilian population of predominantly European ancestry. The presence of the allele rs2910164*C was associated with an increased risk of BC (OR=1.4, 95% CI=1.03-1.85, p = 0.03). We also analysed publicly available RNA-seq data to evaluate if miR146a is differentially expressed in different subtypes of BC. Genotyping was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP). By leveraging public data from TCGA database, we analysed 461 patients and found that miR146a is significantly more expressed in BC than in non-tumor tissue (1.47 fold, p = 0.02) and is expressed to a greater degree in aggressive BC subtypes.

SNPs in miRNAs and Target Sequences: Role in Cancer and Diabetes

“…miR-146a polymorphism, rs2910164, involves a G>C nucleotide alteration on the seed region of miR146a-3p, resulting in G:U pair to a C:U mismatch pairing in the stem of the miR-146a affecting the specificity of mature miR-146a binding to its targets and results in elevated expression of miR-146a ( Brincas et al, 2020 ). Previous studies have established the association of rs2910164 in pre-miR-146a with strong association with breast cancer (BC), hepatocellular carcinoma (HCC), papillary thyroid carcinoma (PTC), esophageal squamous cell carcinoma (ESCC), primary liver cancer, and colorectal cancer ( Hu et al, 2009 ; Vitale et al, 2011 ; Xiang et al, 2012 ; Zhou et al, 2012 ).…”

“…The allele C is associated with BC risk in the European population but did not show any association with BC in the Asian population. This discrepancy might be on account of ethnicity, different exposure to carcinogens, or linkage disequilibrium with different causal variants ( Brincas et al, 2020 ).…”

“…Molecular targets of miR-146a include BRCA1, TRAF6, IRAK1, and NUMB genes ( Brincas et al, 2020 ). The variant allele of rs2910164 leads to increased levels of mature miR-146a that binds with greater affinity to the BRCA1 gene.…”

“…Alternatively, rs2910146 might disrupt the well-documented role of miR-146a as a mediator of the pro-apoptotic transcriptional factor NF-κB. Also, the expression levels of miR146a-5p were observed three times higher in triple negative tumors compared to other subgroups of mammary tumors ( Brincas et al, 2020 ). Two other significant targets of miR-146a, TRAF6, and IRAK1 are important adapter molecules downstream of the toll-like and cytokine receptors that have a vital role in signaling cell growth and immune recognition ( Omrani et al, 2014 ).…”

“…Both the genes have been associated with progression and metastasis. The reduced TRAF6 and IRAK1 levels reduce the activity of NF-kB, a potential inducer of proliferation, survival, angiogenesis, and metastasis ( Brincas et al, 2020 ).…”