Genetic variations in miR-27a gene decrease mature miR-27a level and reduce gastric cancer susceptibility

Abstract

MicroRNAs (miRNAs) are noncoding RNAs that function as post-transcriptional regulators of tumor oncogenes and suppressors. Single-nucleotide polymorphisms (SNPs) in miRNA genes are a novel class of genetic variations in the human genome that are currently being identified and investigated in human cancers. In this study, we aimed to investigate whether SNPs in the miR-27a gene affect miR-27a expression and alter susceptibility to gastric cancer. Therefore, we conducted a case-control population study and the allele and genotype frequencies for polymorphism rs11671784 in miR-27a gene were examined in the study population. As a result, we found that the G/A polymorphism in the miR-27a gene exhibited a significant effect on gastric cancer risk. Compared with GG homozygotes, subjects who were GA heterozygotes or AA homozygotes exhibited a decreased risk of gastric cancer. The G/A polymorphism impaired the processing of pre-miR-27a to mature miR-27a, resulting in significantly reduced expression of mature miR-27a and an increased level of its target HOXA10. Furthermore, we confirmed these findings in in vitro studies by overexpressing pre-miR-27a carrying G or A allele. It provided further evidence demonstrating that allelic difference of rs11671784 is linked to gastric tumorigenesis. In summary, our results indicate that the G/A polymorphism in miR-27a gene (rs11671784) decreases miR-27a expression, reduces gastric cancer risk and plays a role in gastric tumorigenesis. This is the first study to address the role and function of miR-27a polymorphism rs11671784 in gastric cancer. These results could be useful to assess individual susceptibility of gastric cancer and will improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis.

Association between five common polymorphisms in microRNA genes and the risk of gastric cancer: a meta-analysis

“…Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used by ten studies; real-time PCR (qPCR) was conducted by six studies; PCR with confronting two-pair primers (PCR-CTPP) was adopted by one study; and a single study applied locus-specific PCR (LS-PCR) for genotyping. Genotype distributions in the control groups were consistent with HWE, except for those in three studies (Okubo et al, 2010;Yang et al, 2014;Pu et al, 2014). The NOS scores of the selected studies ranged from six to nine stars, which were moderately high.…”

“…According to the inclusion criteria, 49 articles were excluded. Eventually, 19 case-control studies from 16 articles (Okubo et al, 2010;Peng et al, 2010;Sun et al, 2010;Zeng et al, 2010;Hishida et al, 2011;Ahn et al, 2012;Ma and Zheng, 2012;Zhang et al, 2012b;Zhou et al, 2012a,b;Wang et al, 2013b;Wu et al, 2013b;Yang et al, 2014;Dikeakos et al, 2014;Kupcinskas et al, 2014;Pu et al, 2014) were included in our meta-analysis, with 8285 patients and 10,716 controls in total. The details of the selection process are presented in Figure 1.…”

Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity

“…However, great caution should be used in interpreting the findings from the three preclinical studies investigating the effect of rs11671784 on miR-27a expression. 20,22,23 The allele frequency of rs11671784 in this study, in the previous study by Amstutz et al and according to the 1000 genomes project, is around 0.010-0.020 in European and American populations, and was reported to be 0.000 in Chinese populations. 21,26 Remarkably, the allele frequencies reported in the three preclinical investigations, all performed in China, were much higher, between 0.30 and 0.50.…”

“…Three preclinical investigations have shown that the rs11671784 T allele is associated with reduced miR-27a expression, as opposed to the increase in expression caused by rs895819. 20,22,23 This appears to contradict an increased risk of toxicity in carriers of this variant, as a reduction in miR27a expression is expected to lead to higher DPD activity. However, great caution should be used in interpreting the findings from the three preclinical studies investigating the effect of rs11671784 on miR-27a expression.…”

“…19 Polymorphisms in MIR27A, the gene encoding miR-27a, have been shown to influence miR-27a expression. 19,20 A common A>G polymorphism in MIR27A, rs895819, was found to increase miR-27a expression in lymphoblastoid cell lines, and was associated with reduced DPD activity in peripheral blood mononuclear cells (PBMCs) of human volunteers. 19 The latter suggests that rs895819 may have a relevant effect on 5-FU metabolism.…”