Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case-Control Studies

Jiang DK (2013) Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case- Control Studies. PLoS ONE 8(11): e79584. doi:10.1371/journal.pone.0079584 Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case-Control Studies Xiao Pin Ma 0 Ting Zhang 0 Bo Peng 0 Long Yu 0 De Ke Jiang 0 Georgina L. Hold, University of Aberdeen, United Kingdom 0 1 State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University , Shanghai , China , 2 Institute of Biomedical Science, Fudan University , Shanghai , China , 3 Fudan-VARI Center for Genetic Epidemiology, Fudan University , Shanghai, China, 4 Central Laboratory , The Affiliated Jiangyin Hospital of Southeast University Medical College , Jiangyin, Jiangsu , China MicroRNAs (miRNAs) are small non-coding RNA molecules, which participate in diverse biological processes and may regulate tumor suppressor genes or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNA may contribute to diverse functional consequences, including cancer development, by altering miRNA expression. Numerous studies have shown the association between miRNA SNPs and cancer risk; however, the results are generally debatable and inconclusive, mainly due to limited statistical power. To assess the relationship between the five most common SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832, and miR-27a rs895919) and the risk cancer development, we performed a meta-analysis of 66 published case-control studies. Crude odds ratios at 95% confidence intervals were used to investigate the strength of the association. No association was observed between rs2910164 and cancer risk in the overall group. However, in stratified analysis, we found that either the rs2910164 C allele or the CC genotype was protective against bladder cancer, prostate cancer, cervical cancer, and colorectal cancer, whereas it was a risk factor for papillary thyroid carcinoma and squamous cell carcinoma of the head and neck (SCCHN). Further, rs11614913 was found to be significantly associated with decreased cancer risk, in particular, for bladder cancer, gastric cancer, and SCCHN. For miR-499, a significant association was found between the rs3746444 polymorphism and cancer risk in pooled analysis. In subgroup analysis, similar results were mainly observed for breast cancer. Finally, no association was found between rs2292832 and rs895919 polymorphisms and cancer risk in the overall group and in stratified analysis. In summary, miR-196a2 rs11614913, miR-146a rs2910164, and miR-499 rs3746444 are risk factors for cancer development, whereas mir149 rs2292832 and miR-27a rs895919 are not associated with cancer risk. - Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Cancer is an outcome of unregulated expression of genes involved in development, cell growth, and differentiation. Many studies have shown that cancer is not only related to environmental factors, but also to individuals genetic susceptibility (predisposition). Recently, a new mechanism of microRNA (miRNA)-mediated transcriptional regulation was elucidated [1]. MiRNAs are a class of single-stranded short (21,25 nt) RNAs, which are evolutionarily well conserved but are nonproteincoding. These RNAs regulate a broad range of biologic and pathologic process, including apoptosis, proliferation, differentiation, angiogenesis, and immune response, which are known to play critical roles in carcinogenesis [13]. MiRNAs bind to the 39untranslated region of the target mRNAs, leading to their degradation or translational suppression, thereby regulating the expression of target genes at the post-transcriptional level [2]. Estimates suggest that a single miRNA can target hundreds of mRNAs, and approximately 50% miRNA genes are located in cancer-related chromosomal regions [47]. Studies have shown that mature miRNAs regulate the expression of roughly 1030% of all human genes [8]. Moreover, recent studies have suggested that miRNAs may participate in the carcinogenesis, progression (proliferation, migration, and invasion), and prognosis of multiple human malignancies by regulating the expression of tumor suppressor genes or proto-oncogenes [912]. Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome, affecting sequence coding and splicing, which can influence the population diversity, disease susceptibility, and individual response to medicine [13]. SNPs can alter miRNA expression and/or maturation to affect function in three ways: through the transcription of the primary transcript, through pri-miRNA and pre-miRNA processing, and by affecting miRNAmRNA interactions [14]. Many epidemiological studies have demonstrated the association of SNPs in miRNAs with the development and progression of cancer [14,15]. MiR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832, and miR-27a rs895919 are well-established miRNA polymorphisms [1628] that have been reported to be associated with cancer risk [14]. However, conclusions of these studies remain inconsistent due to heterogeneity of the cancer subtype, limited sample size, and differences in the ethnicity of patients. To better assess the association of miR146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832, and miR-27a rs895919 in the miRNA genes with cancer risk, we conducted a meta-analysis of all eligible published case-control studies and evaluated the effect of the five SNPs on overall cancer risk. The effects of tumor type, ethnicity, source of controls, and sample size were also evaluated. Materials and Methods Publication Search To identify all potentially eligible studies on miRNA polymorphisms and cancer risk, we carried out a systematic search on PubMed, Web of Science, Science Direct, and Embase, covering all papers published up to June 30, 2013, by using the search terms: microRNA 146a/196a2/499/149/27a, mir-146a/ 196a2/499/27a, polymorphism, and cancer. References of the retrieved articles and review articles were also screened. Eligible studies had to meet all of the following criteria: (a) full-text study, (b) evaluation of the association between miRNA polymorphisms and cancer risk, (c) unrelated case-control design, and (d) sufficient data for estimating the odds ratio (OR) with 95% confidence interval (CI) and a P-value. Studies containing two or more case-control groups were considered as two or more independent studies. Data Extraction Two investigators independently reviewed and extracted information from all publications that met the inclusion criteria. In the case of a conflict, an agreement was reached by discussion between the two reviewers. The following information was sought from each publication: first authors surname, year of publication, country of o (...truncated)