Single Nucleotide Polymorphisms of microRNA Machinery Genes Modify the Risk of Renal Cell Carcinoma

Abstract

Purpose: MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of basic cellular functions through posttranscriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA machinery genes could be associated with the risk of renal cell carcinoma. Experimental Design: We genotyped 40 single nucleotide polymorphisms (SNP) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with renal cell carcinoma and 278 matched controls. Results: We found that two SNPs in the GEMIN4 gene were significantly associated with altered renal cell carcinoma risks. The variant-containing genotypes of Asn929Asp and Cys1033Arg exhibited significantly reduced risks, with odds ratios (OR) of 0.67 [95% confidence interval (95% CI), 0.47-0.96] and 0.68 (95% CI, 0.47-0.98), respectively. Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR, 0.66; 95% CI, 0.45-0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group with one unfavorable genotype, the median-risk and high-risk groups exhibited a 1.55-fold (95% CI, 0.96-2.50) and a 2.49-fold (95% CI, 1.58-3.91) increased risk of renal cell carcinoma, respectively (P for trend < 0.001). Conclusions:Our results suggested that genetic polymorphisms of the miRNA-machinery genes may affect renal cell carcinoma susceptibility individually and jointly.Renal cell carcinoma accounts for f3% of all human malignancies and is the 10th leading cause of male cancer death in the United States (1). Genetic aberrations have been associated with the etiology of sporadic renal cell carcinoma. For example, loss of chromosome 3p and VHL gene mutations were frequently identified in conventional renal cell carcinomas, and MET mutations were observed in papillary type renal cell carcinomas (2). However, renal cell carcinoma is recognized as a heterogeneous disease, in terms of its presentation, pathology, and clinical course. Moreover, the underlying molecular and genetic mechanisms for renal cell carcinoma initiation and development have largely remained unclear.MicroRNAs (miRNA) are a class of small noncoding RNA molecules f20 nucleotides (nt) in length. MiRNAs regulate gene expression in animals and plants through binding to the 3 ¶ untranslated region (UTR) of the mRNAs of their target genes and leading to mRNA cleavage or translation repression (3). It is estimated that f30% of human genes are regulated by miRNAs. Aberrant expression of miRNAs contributes to the etiology of many common human diseases including cancer (3). Numerous recent studies have shown that alteration of miRNAs plays a critical r...

An miR-502–Binding Site Single-Nucleotide Polymorphism in the 3′-Untranslated Region of the SET8 Gene Is Associated with Early Age of Breast Cancer Onset

“…This class of polymorphisms within microRNA binding sites, as well as in microRNAs or their precursors, is emerging as a key risk factor for disease phenotypes (32,33). Shen et al (34) recently reported that a G→C single-nucleotide polymorphism (rs2910164) located within the miR-146a precursor leads to a change from a G:U pair to a C:U mismatch in its stem region and that breast cancer patients who had at least one miR-146a variant C allele were diagnosed with the disease at an earlier age than those without this variant allele (median age, 45 versus 56 years; P = 0.029).…”

miR-196a2 polymorphisms and susceptibility to cancer: A meta-analysis involving 24,697 subjects

“…Thirty studies were excluded by article review, including 17 studies repeated or overlapped in the PubMed and Embase databases; 6 studies were not concerned with cancer risk research, 1 study was an animal study, 1 study was a cell study, and 5 studies were meta-analysis. During the reading of the 25 full-text manuscripts, 4 studies were excluded due to incomplete rs11614913 polymorphism distribution data required for OR calculation (10)(11)(12)(13). For the remaining 21 records, baseline characteristics of the patients and control subjects were summarized, the study quality was assessed, HWE in particular was assessed by Chi-square test; two records involving Indian populations published in 2011 were excluded for disagreement with HWE (P<0.05) (14,15), thus leaving 19 articles identified with criteria for inclusion and exclusion (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Association between a functional variant in microRNA-27a and susceptibility to colorectal cancer in a Chinese Han population

“…As a class of 22-nucleotide noncoding RNAs, miRNAs are thought to function as negative regulators of gene expression. Various single nucleotide polymorphisms (SNPs) exist in miRNA genes that can lead to variations in the quantity of miRNAs, resulting in diverse functional consequences that include cancer development (Horikawa et al, 2008). For example, a study by Zhang et al (2010) provided evidence that an miR-196a2 polymorphism might contribute to CRC susceptibility in Chinese populations through modulating mature miR-196a expression.…”