Evidences from a Systematic Review and Meta-Analysis Unveil the Role of MiRNA Polymorphisms in the Predisposition to Female Neoplasms

Abstract

Breast (BCa) and gynecological (GCa) cancers constitute a group of female neoplasms that has a worldwide significant contribution to cancer morbidity and mortality. Evidence suggests that polymorphisms influencing miRNA function can provide useful information towards predicting the risk of female neoplasms. Inconsistent findings in the literature should be detected and resolved to facilitate the genetic screening of miRNA polymorphisms, even during childhood or adolescence, and their use as predictors of future malignancies. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and the risk of female neoplasms. Meta-analysis was performed by pooling odds-ratios (ORs) and generalized ORs while using a random-effects model for 15 miRNA polymorphisms. The results suggest that miR-146a rs2910164 is implicated in the susceptibility to GCa. Moreover, miR-196a2 rs11614913-T had a moderate protective effect against female neoplasms, especially GCa, in Asians but not in Caucasians. MiR-27a rs895819-G might pose a protective effect against BCa among Caucasians. MiR-499 rs3746444-C may slightly increase the risk of female neoplasms, especially BCa. MiR-124 rs531564-G may be associated with a lower risk of female neoplasms. The current evidences do not support the association of the remaining polymorphisms and the risk of female neoplasms.

Keywords: breast neoplasm; cancer; female neoplasm; microRNA; polymorphism; susceptibility.

Figure 1

The process of study selection.

Figure 2

Forest plots of the meta-analysis between miR-146a rs2910164 (top-left), miR-196a2 rs11614913 (top-right), miR-27a rs895819 (bottom-left), and miR-499 rs3746444 (bottom-right) and risk of female neoplasms. The x-axes represent Generalized Odds Ratio (ORG).

Figure 3

Funnel plots for the meta-analysis between miRNA polymorphisms and female neoplasms. Top-left: miR-146a rs2910164, top-right: miR-196a2 rs11614913, bottom-left: miR-27a rs895819, bottom-right: miR-499 rs3746444. The x-axes represent logarithm of generalized odds ratio and y-axes represent standard error.

Figure 4

Influential diagnostics for miR-196a2 rs11614913. Each number in the x axes refers to one of the 31 studies included in the meta-analysis. For the 31 studies evaluating the association of miR-196a2 rs11614913 and the risk of female neoplasms, following plots are shown (Please refer to [108,109] for details about each measure): plot of the externally standardized residuals (rstudent), the DFFITS statistic (which is a scaled measure of the change in the predicted value for the ith observation and is calculated by deleting the ith observation), Cook′s distances (which is an estimate of the influence of a data point), covariance ratios, estimates of τ² and test statistics for (residual) heterogeneity when each study is removed in turn, hat values, and weights. A red point indicates the influential study.

Figure 5

Forest plots for meta-analyses between miR-423 rs6505162 (top-left), miR-149 rs2292832 (top-right), miR-605 rs2043556 (bottom-left), and miR-608 rs4919510 (bottom-right) and risk of female neoplasms.

Figure 6

Forest plots for meta-analyses between miR-100 rs1834306 (top-left), miR-124 rs531564 (top-right), miR-218 rs11134527 (bottom-left), and miR-34b/c rs4938723 (bottom-right) and risk of female neoplasms.

Figure 7

Forest plots for meta-analyses between miR-26a-1 rs7372209 (top), miR-373 rs12983273 (middle), and miR-618 rs2682818 (bottom) and risk of female neoplasms.