Functional SNP in stem of mir-146a affects Her2 status and breast cancer survival

Abstract

In-silico investigation suggested a common variant within stem of miR-146a-5p precursor (rs2910164, n.60C>G) associated with breast cancer (BC) phenotypes. Our aim was computationally predicting possible targets of miR-146a-5p and probable rs2910164 mechanism of action in expression of phenotypes in BC. Additionally, a case-control study was designated to examine experimentally the correlation of mir-146a rs2910164 variant and BC phenotypes. In this study, 152 BC subjects and healthy controls were genotyped using RFLP-PCR. Allelic and genotypic association and Armitage's trend tests were run to investigate the correlation between the alleles and genotypes and expressed phenotypes of BC. Bioinformatics analyses introduce regulatory function of miR-146a-5p in numerous signaling pathways and impact of allele substitution upon mir-146a stem-loop stability. Logistic regression data represented the C allele of rs2910164 (OR = 4.00, p= 0.0037) as the risk allele and associated with Her2-positive phenotype. In a similar vein, data revealed the correlation of the C allele and cancer death less than two years in BC patients (OR = 2.65, p= 0.0217). Ultimately, unconditional logistical regression models suggested log-additive model for inheritance manner of rs2910164 in either Her2 status or BC survival (OR = 5.64, p= 0.0025 and OR = 3.13, p= 0.019, respectively). Using bioinformatics connected association of Her2 status to altered function of miR-146a-5p in regulation of focal adhesion and Ras pathway. Furthermore, computations inferred the association between death phenotype and studied SNP upon specific target genes of miR-146a-5p involved in focal adhesion, EGF receptor, Ras, ErbB, interleukin, Toll-like receptor, NGF, angiogenesis, and p53 feedback loops 2 signaling pathways. These verdicts may enhance our perceptions of how mir-146a rs2910164 affect expressed phenotypes in BC, and might have potential implications to develop BC treatment in future.

Down‐regulation of microRNA‐19b in hormone receptor‐positive/HER2‐negative breast cancer

“…MiRNAs are chief regulators of the cell and their deregulation has been recognized in many cancer kinds with high clinical consequence . During tumorigenesis and progression of various types of cancer, dysregulated miRNAs play either tumor‐suppressor or oncogenic roles, depending on their target genes.…”

Investigating the association of rs2910164 with cancer predisposition in an Irish cohort

“…It has been postulated that ethnicity may significantly modify the association between miRNA polymorphisms and cancer risk ( 38 ). An association between genotype and sporadic BC risk and phenotype has been investigated in variably powered studies from China ( 37 ), Italy ( 35 , 39 ), Germany ( 39 ), Spain ( 40 ), Australia ( 41 ), Saudi Arabia ( 42 ), India ( 43 ) and Iran ( 44 , 45 , 46 ); and in numerous meta-analyses with conflicting results ( 26 , 47 , 48 , 49 ). To date, no Irish samples have been included in such analyses.…”

Meta-analysis of the association between three microRNA polymorphisms and breast cancer susceptibility

“…After screening the title and abstract, 192 articles uncorrelated with BC risk and miR-146a/-196a2/-499 SNPs were excluded. 25 articles were then evaluated in detail, and 8 articles were further excluded, among which 3 were meeting reports [ 16 – 18 ], 2 had inadequate information to calculate ORs [ 19 , 20 ], and the other 3 were not case-control studies [ 21 – 23 ]. Finally, 17 eligible articles were included in our meta-analysis [ 12 – 15 , 24 – 36 ] (Figure 1 ).…”