Association between miR-146a rs2910164 polymorphism and specific cancer susceptibility: an updated meta-analysis

The rapidly increasing of cancer risk nationwide and worldwide has threatened human health and caused the changes of disease and death spectrum. MicroRNA (MiRNA) as cancer biomarker on susceptibility has enjoyed a high level of concern. This article will discuss the association between miR-146 rs2910164 polymorphism and cancer susceptibility in 38 independent case-control studies from 34905 individuals. The 38 case-control studies which were searched from PubMed were used for conducting a meta-analysis. There were 14670 cases and 20235 controls. ORs and 95% CIs were used for reflecting the strength of association between miR-146a rs2910164 polymorphism and cancer susceptibility. Subgroup analysis based on the cancer type, ethnicity and study designs. All analysis were performed by using the Stata 11.0 software. MiR-146a rs2910164 polymorphism and overall cancer susceptibility were significantly uncorrelated in all genetic models. In the subgroup analysis for cancer types, miR-146a rs2910164 polymorphism was associated with the susceptibility of lung cancer (CC vs. GG: OR 1.275, 95% CI 1.117–1.455 (P?=?0.000); CC?+?CG vs. GG: OR 1.166, 95% CI 1.052–1.293 (P?=?0.003); CC vs. CG?+?GG: OR 1.239, 95% CI 1.116–1.375 (P?=?0.000); C vs. G OR 1.151, 95% CI 1.080–1.227 (P?=?0.000)) and nasopharyngeal carcinoma (CC vs. GG: OR 1.713, 95% CI 1.183–2.479 (P?=?0.004); CC vs. CG?+?GG: OR 1.672, 95% CI 1.330–2.103 (P?=?0.000); C vs. G: OR 1.400, 95% CI 1.181–1.659 (P?=?0.000)), but it was not associated with hepatocellular carcinoma and gastric cancer. However, in the other subgroup analysis by ethnicity and study designs, no significant associations were found. MiR-146a rs2910164 polymorphism might be associated with the susceptibility to lung cancer and nasopharyngeal carcinoma.     

A functional polymorphism in the miR-146a gene is associated with the risk of childhood acute lymphoblastic leukemia: a preliminary report

Growing evidence showed that microRNAs (miRs) are involved in normal hematopoiesis and the pathogenesis of several hematological malignancies. Genetic variations or mutations occurring in the miR gene region may affect the property of miRs through altering miR expression and/or maturation. The aim of the present study was to evaluate the possible relationship between two miRs polymorphisms, hsa-miR-146a (rs2910164 G>C) and hsa-miR-499 (rs3746444 T>C), and the susceptibility to childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. This case–control study was performed on 75 children diagnosed with ALL and 115 age- and sex-matched children with no history of cancer of any type (as the control group). Tetra-primer amplification refractory mutation system-polymerase chain reaction was applied for genotyping the variants. We found that the rs2910164 G>C variant of hsa-miR-146a significantly increased the risk of ALL (CC vs. GG, OR?=?4.24, 95 %CI?=?1.52–11.87, P?=?0.006; GC vs. GG, OR?=?3.55, 95 % CI?=?1.41–8.93, P?=?0.007; C vs. T, OR?=?1.73, 95 % CI?=?1.13–2.67, P?=?0.012). With respect to hsa-miR-499 rs3746444 T/C, no significant difference in allele and genotype frequencies of the rs3746444 variant between ALL patients and controls was observed. Our results for the first time demonstrated that the miR-146a rs2910164, but not miR-499 rs3746444 variant, was associated with increased risk for developing pediatrics ALL in an Iranian population.     

Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma

MicroRNAs (miRNAs) function as gene regulator and they participate in diverse biological pathways. Common single nucleotide polymorphisms (SNPs) in pre‐microRNAs may change their property through altering miRNAs expression and/or maturation. We conducted a pilot study to test whether SNPs in pre‐microRNAs were associated with cervical squamous cell carcinoma (CSCC). Genotypes of three SNPs in pre‐miRNAs (hsa‐miR‐196a2 rs11614913 C/T, hsa‐miR‐499 rs3746444 A/G, and hsa‐miR‐146a rs2910164 G/C) in 226 CSCC patients and 309 control subjects were determined with the use of PCR‐restriction fragment length polymorphism (RFLP) assay. Significantly increased CSCC risks were found to be associated with G allele of rs3746444 and G allele of rs2910164 (P = 0.017, OR = 1.454, and P = 0.016, OR = 1.355, respectively). Increased CSCC risks were associated with them in different genetic model (P = 0.0004, OR = 1.98 for rs3746444 in an overdominant model, and P = 0.024, OR = 2.10 for rs2910164 in a codominant model, respectively). Results of stratified analyses revealed that rs2910164 is associated with tumor differentiation and lymph node status (P = 0.043, OR = 2.08, and a borderline P = 0.057, OR = 0.41, respectively). No association between rs11614913 and CSCC risk was observed. The present study provides evidence that rs3746444 and rs2910164 are associated with CSCC, indicating that common genetic polymorphisms in pre‐microRNAs contribute to the pathogenesis of CSCC. Mol. Carcinog. © 2011 Wiley‐Liss, Inc.     

A functional varient in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han

MicroRNAs are a new class of non-proteincoding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. A G>C polymorphism (rs2910164), which is located in the sequence of miR-146a precursor, results in a change from G:U to C:U in its stem region. However, it remains largely unknown whether this single nucleotide polymorphism (SNP) may alter esophageal squamous cell carcinoma (ESCC) susceptibility. In the current study, we evaluated association between rs2910164 and ESCC susceptibility in a case–control study of 444 sporadic ESCC patients and 468 matched cancer-free controls in a Chinese Han population. Compared with rs2910164 variant genotype CC, genotype GG was associated with increased risk of ESCC (Odds Ratio, 2.39, 95% Confidence Interval, 1.36–4.20). In the smokers, the risk of rs2910164 GG genotype was more notable (Odds Ratio, 3.17, 95% Confidence Interval, 1.71–4.46). In the stratification analyses, we also found there was a strong correlation between rs2910164 C/G variant and the clinical TNM stage (P < 0.01). These findings suggest that this functional SNP in pre-miR-146a could contribute to ESCC susceptibility and clinical outcome.     

miR-146a G > C polymorphisms and risk of hepatocellular carcinoma in a Chinese population

MicroRNAs (miRNAs) are thought to have a role in cancer development. We investigated the association among miR-146a G?>?C genetic variations, hepatitis B (HBV), and C (HCV) infection, and risk of hepatocellular carcinoma (HCC). Unconditional logistical regression analysis suggested that the miR-146a GG genotype and G allele carried a 2.10- (95 % confidence interval (CI)?=?1.03–4.37) and 1.42-fold (95 % CI?=?1.07–1.92) increased HCC risk, respectively. HBV-positive subjects carrying the miR-146a GG genotype (odds ratio (OR)?=?2.95, 95 % CI?=?1.31–6.81) and G allele (OR?=?1.65, 95 % CI?=?1.15–2.58) had an increased risk of HCC. However, the miR-146a GG genotype and G allele did not carry a significantly enhanced risk of HCC in either hepatitis-negative or HCV-infected subjects. miR-146a G?>?C polymorphisms appear to influence susceptibility to HCC, especially in HBV-infected patients.     

Pre-microRNA variants predict HPV16-positive tumors and survival in patients with squamous cell carcinoma of the oropharynx

To identify non-tumor biomarkers for prediction of tumor HPV status and prognosis of patients with squamous cell carcinoma of the oropharynx (SCCOP), we evaluated the association of single nucleotide polymorphisms (SNPs) in pre-miRNAs with HPV16 status and survival for SCCOP patients. We analyzed HPV16 status in tumor specimens and genotyped four SNPs in pre-miRNAs (hsa-mir-146a rs2910164 G > C, hsa-mir-149 rs2292832 G > T, hsa-mir-196a2 rs11614913 C > T, and hsa-mir-499 rs3746444 A > G) in 309 SCCOP patients. Unconditional logistic regression models were used for calculation of odds ratio (OR) and 95% confidence intervals (CIs), and Kaplan–Meier analysis and Cox proportional hazards regression were used to evaluate associations. We found that statistically significant associations with HPV16-positive SCCOP and survival were found for hsa-mir-146a rs2910164 and hsa-mir-196a2 rs11614913, while such similar associations were not observed for hsa-mir-149 rs2292832 and hsa-mir499 rs3746444. Compared with those with corresponding hsa-mir-146a CG/CC and has-mir-196a2 CC genotypes, the hsa-mir-146a GG and hsa-mir-196a2 CT/TT wild-type genotypes were significantly associated with HPV16-positive tumor status (adjusted OR, 2.4; 95% CI, 1.4–4.1 and adjusted OR, 2.1, 95% CI, 1.2–3.6), respectively. Patients having hsa-mir-146a rs2910164 GG and hsa-mir196a2 rs11614913 CT/TT genotypes had significantly better overall, disease-specific, and disease-free survival compared with those having the corresponding CG/CC and CC genotypes, respectively. Furthermore, these genotypes were significantly associated with reduced risk of overall death, death owing to disease, and recurrence after adjustment for important prognostic confounders including HPV status, smoking, and stage. Our findings indicate pre-miRNA polymorphisms may predict tumor HPV16-positive SCCOP cases and may be prognostic biomarkers for SCCOP.     

Association ofmicroRNA polymorphisms withthe risk ofhead andneck squamous cell carcinoma ina Chinese population:a case-control study

Background:MicroRNA (miRNA) polymorphisms may alter miRNA-related processes, and they likely contribute to cancer susceptibility. Various studies have investigated the associations between genetic variants in several key miR-NAs and the risk of human cancers; however, few studies have focused on head and neck squamous cell carcinoma (HNSCC) risk. This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population. Methods:In this study, we genotyped ifve common single-nucleotide polymorphisms (SNPs) in several key miRNAs (miR-149 rs2292832,miR-146a rs2910164,miR-605 rs2043556,miR-608 rs4919510, andmiR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case–control study including 576 cases and 1552 controls, which were matched by age and sex in a Chinese population. Results:The results revealed thatmiR-605 rs2043556 [dominant model: adjusted odds ratio (OR) 0.71, 95% conif-dence interval (CI) 0.58–0.88; additive model: adjusted OR 0.74, 95% CI 0.62–0.89] andmiR-196a2 rs11614913 (domi-nant model: adjusted OR 1.36, 95% CI 1.08–1.72; additive model: adjusted OR 1.28, 95% CI 1.10–1.48) were signiifcantly associated with the risk of oral squamous cell carcinoma (OSCC). Furthermore, when these two loci were evaluated together based on the number of putative risk alleles (rs2043556 A and rs11614913 G), a signiifcant locus-dosage effect was noted on the risk of OSCC (Ptrend<0.001). However, no signiifcant association was detected between the other three SNPs (miR-149 rs2292832,miR-146a rs2910164, andmiR-608 rs4919510) and HNSCC risk. Conclusion:Our study provided the evidence thatmiR-605 rs2043556 andmiR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.     

Effects of common polymorphisms rs2910164 in miR-146a and rs11614913 in miR-196a2 on susceptibility to colorectal cancer: a systematic review meta-analysis

Purpose

Emerging evidence has shown that single nucleotide polymorphisms occurred in microRNAs may contribute to the development of colorectal cancer (CRC). rs2910164 in miR-146a and rs11614913 in miR-196a2 are suggested to be associated with the susceptibility to CRC, but individually published studies revealed inconclusive results. To systematically summarize the possible correlationship between these polymorphisms and CRC risk, we performed this meta-analysis.

Methods

We retrieved the relevant articles of the associations between these two microRNA polymorphisms and susceptibility to CRC for the period up to July 1, 2013. A total of seven articles were identified with 2,143 cases and 2,457 controls for miR-146a rs2910164, 1,594 cases and 2,252 controls for miR-196a2 rs11614913. Odds ratio and 95 % confidence interval were calculated to investigate the strength of the association.

Results

The pooled analysis showed that miR-146a rs2910164 did not reveal any correlation with CRC susceptibility. However, a decreased risk was observed between miR-196a2 rs11614913 and CRC in all genetic models.

Conclusion

Our current meta-analysis demonstrates that miR-196a2 rs11614913 most likely contributes to decreased risk of CRC, whereas miR-146a rs2910164 may not be associated with the susceptibility to CRC.     

Interactions of miR-34b/c and TP-53 polymorphisms on the risk of nasopharyngeal carcinoma

Growing evidence indicates that tumor suppressor gene TP-53 and non-coding RNA miR-34b/c independently and/or jointly play crucial roles in carcinogenesis. We hypothesized that the polymorphisms of rs4938723 in the promoter region of pri-miR-34b/c and TP-53 Arg72-Pro may be related to the risk of nasopharyngeal carcinoma (NPC). We performed a case–control study between 217 patients with NPC and 360 healthy controls in a Chinese population using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. A significantly increased risk of NPC was observed in the miR-34b/c rs4938723 CT/CC genotypes compared with the TT genotype (adjusted OR?=?1.44, 95 % CI 1.02–2.03, p?=?0.04), and also the C allele (adjusted OR?=?1.33, 95 % CI 1.04–1.70, p?=?0.03). The gene–gene interaction of miR-34b/c rs4938723 and TP-53 Arg72-Pro showed that the combined genotypes of rs4938723CT/CC and TP-53CG/CC increased the risk of NPC (rs4938723CT/CC?+?TP-53CG/CC vs. rs4938723 TT?+?TP-53 CG/CC: OR?=?1.58, 95 % CI 1.04–2.42, p?=?0.03). These findings suggest that miR-34b/c rs4938723 and TP-53 Arg72Pro polymorphisms may singly or collaboratively contribute to the risk of NPC.     

Role of genetic variants of deleted in colorectal carcinoma (DCC) polymorphisms and esophageal and gastric cancers risk in Kashmir Valley and meta-analysis

Genetic alterations in the deleted in colorectal carcinoma (DCC) gene have been a priori reported to associate with metastasis in variety of human cancers. We investigated the association between potentially functional SNPs in DCC and susceptibility to esophageal (EC) and gastric (GC) cancers in Kashmir Valley. We genotyped two SNPs DCC rs714 (A>G) and DCC rs2229080 (C>G) of DCC in 135 EC patients, 108 GC patients, and 195 controls matched by age and sex in Kashmir Valley by polymerase chain reaction–RFLP method. Risk for developing EC and GC was estimated by binary logistic regression by using SPSS. We also performed a meta-analysis on DCC rs714 (A>G) and evaluated the association between the DCC rs714 (A>G) polymorphisms and cancer risk. A significant difference in DCC rs714 (A>G) genotype distribution between EC and GC cases and corresponding control groups was observed (odds ratio (OR)?=?1.92; P?=?0.03; P-trend?=?0.04; false discovery rate (FDR) Pcorr?=?0.03: OR?=?2.15; P?=?0.02; P-trend?=?0.01; FDR Pcorr?=?0.03). But no such association was observed in DCC rs2229080 (C>G). Further, DCC rs714 (A>G) AA genotype showed significantly increased risk for both gastric squamous cell carcinoma (OR?=?5.63; P?=?0.02; FDR Pcorr?=?0.01) and gastric adenocarcinoma (OR?=?2.15; P?=?0.02; FDR Pcorr?=?0.01). Smoking and salted tea are independently associated with both EC and GC, but gene–environment interaction did not further modulate the risk. Meta-analysis also suggested both independent and overall association of DCC rs714 (A>G) polymorphism with cancer (P?=?0.000). In conclusion, genetic variations in DCC rs714 (A>G) modulate risk of EC and GC in high-risk Kashmir population.     

A Genetic Variant in MiR-146a Modifies Digestive System Cancer Risk: a Meta-analysis

MicroRNAs (miRNAs) negatively regulate gene expression and act as tumor suppressors or oncogenes inoncogenesis. The association between a single nucleotide polymorphism (SNP) in miR-146a rs2910164 andsusceptibility to digestive system cancers was inconsistent in previous studies. In this study, we conducted aliterature search of PubMed to identify all relevant studies published before August 31, 2013. A total of 21independent case-control studies were included in this updated meta-analysis with 9,558 cases and 10,614controls. We found that the miR-146a rs2910164 polymorphism was significantly associated with decreased riskof digestive system cancers in an allele model (OR=0.90, 95%CI 0.87-0.94), homozygote model (OR=0.84, 95%CI0.77-0.91), dominant model (OR=0.90, 95%CI 0.84-0.96), and recessive model (OR=0.85, 95%CI 0.79-0.91), whilein a heterozygous model (OR = 0.99, 95% CI 0.89-1.11) the association showed marginal significance. Subgroupanalysis by cancer site revealed decreased risk in colorectal cancer above allele model (OR=0.90, 95%CI 0.83-0.97) and homozygote model (OR=0.85, 95%CI 0.72-1.00). Similarly, decreased cancer risk was observed whencompared with allele model (OR=0.87, 95%CI 0.81-0.93) and recessive model (OR=0.81, 95%CI 0.72-0.90) ingastric cancer. When stratified by ethnicity, genotyping methods and quality score, decreased cancer risks werealso observed. This current meta-analysis indicated that miR-146a rs2910164 polymorphism may decrease thesusceptibility to digestive system cancers, especially in Asian populations.     

miR-146a 多态性与非小细胞肺癌易感性的研究

目的：研究汉族人群miR-146a rs2910164 G/C基因多态性与非小细胞肺癌易感性的关系。方法：通过病例-对照研究,应用PCR-限制性片段长度多态性（PCR-RFLP）检测技术对198例非小细胞肺癌患者与218例对照组人群进行rs2910164基因型的检测,并随机抽取10%的样本进行DNA测序,进行遗传平衡检测。进一步采用Logistic回归分析该位点与非小细胞肺癌的相关性。结果：rs2910164被酶切成GG、GC、CC基因型,GG、GC、CC分型在对照组分别为103例（47.25%）、85例（38.99%）、30例（13.76%）;在病例组分别为31例（15.66%）、99例（50.00%）、68例（34.34%）。随机抽取10%的样本进行DNA测序,其结果与PCRRFLP分型结果一致,基因分型频率满足Hardy-Weinberg遗传平衡（P>0.05）。与对照组相比,Logistic回归分析发现携带C等位基因的基因型可明显增加非小细胞肺癌的发病风险[显性模型OR=5.04,95%CI为（4.72,5.39）,P<0.01;隐性模型OR=2.75,95%CI为（2.57,2.94）,P<0.01];而rs2910164基因多态性与非小细胞肺癌的临床病理特征（分级、分期、转移）之间无明显相关关系（P>0.05）,rs2910164基因多态性与吸烟之间无交互作用（P>0.05）。结论：携带miR-146a rs2910164 C等位基因的基因型可能与非小细胞肺癌的遗传易感性相关。     

Associations of Single Nucleotide Polymorphisms in miR-146a,miR-196a,miR-149 and miR-499 with Colorectal Cancer Susceptibility

Background: MicroRNAs (miRNAs) are an abundant class of endogenous small non-coding RNAs of 20-25nucleotides in length that function as negative gene regulators. MiRNAs play roles in most biological processes,as well as diverse human diseases including cancer. Recently, many studies investigated the association betweenSNPs in miR-146a rs2910164, miR-196a2 rs11614913, miR-149 rs229283, miR-499 rs3746444 and colorectalcancer (CRC), which results have been inconclusive. Methodology/Principal Findings: PubMed, EMBASE,CNKI databases were searched with the last search updated on November 5, 2013. For miR-196a2 rs11614913,a significantly decreased risk of CRC development was observed under three genetic models (dominant model:OR = 0.848, 95%CI: 0.735–0.979, P = 0.025; recessive model: OR = 0.838, 95%CI: 0.721–0.974, P = 0.021;homozygous model: OR = 0.754, 95%CI: 0.627–0.907, P = 0.003). In the subgroup analyses, miR-196a2*Tvariant was associated with a significantly decreased susceptibility of CRC (allele model: OR = 0.839, 95%CI:0.749–0.940, P = 0.000; dominant model: OR = 0.770, 95%CI: 0.653–0.980, P = 0.002; recessive model: OR =0.802, 95%CI: 0.685–0.939, P = 0.006; homozygous model: OR = 0.695, 95%CI: 0.570–0.847, P = 0.000). Asfor miR-149 rs2292832, the two genetic models (recessive model: OR = 1.199, 95% CI 1.028-1.398, P = 0.021;heterozygous model: OR = 1.226, 95% CI 1.039-1.447, P = 0.013) demonstrated increased susceptibility to CRC.On subgroup analysis, significantly increased susceptibility of CRC was found in the genetic models (recessivemodel: OR = 1.180, 95% CI 1.008-1.382, P = 0.040; heterozygous model: OR = 1.202, 95% CI 1.013-1.425, P =0.013) in the Asian group. Conclusions: These findings supported that the miR-196a2 rs11614913 and miR-149rs2292832 polymorphisms may contribute to susceptibility to CRC.     

A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis

A G to C polymorphism (rs2910164) is located within the sequence of miR-146a precursor, which leads to a change from a G:U pair to a C:U mismatch in its stem region. The predicted miR-146a target genes include BRCA1 and BRCA2, which are key breast and ovarian cancer genes. To examine whether rs2910164 plays any role in breast and/or ovarian cancer, we studied associations between this polymorphism and age of diagnosis in 42 patients with familial breast cancer and 82 patients with familial ovarian cancer. Breast cancer patients who had at least one miR-146a variant allele were diagnosed at an earlier age than with no variant alleles (median age 45 versus 56, P = 0.029) and ovarian cancer patients who had at least one miR-146a variant allele were diagnosed younger than women without any variant allele (median age 45 versus 50, P = 0.014). In further functional analysis, we found that the variant allele displayed increased production of mature miR-146a from the precursor microRNA compared with the common allele. Consistent with the target prediction, in a target in vitro assay, we observed that miR-146a could bind to the 3' untranslated regions (UTRs) of BRCA1 and BRCA2 messenger RNAs (mRNAs) and potentially modulate their mRNA expression. Intriguingly, the binding capacity between the 3' UTR of BRCA1 and miR-146a was statistically significantly stronger in variant C allele than those in common G allele (P = 0.046). Taken together, our data suggest that breast/ovarian cancer patients with variant C allele miR-146a may have high levels of mature miR-146 and that these variants predispose them to an earlier age of onset of familial breast and ovarian cancers.     

The miR-146a rs2910164 G > C Polymorphism and Susceptibility to Digestive Cancer in Chinese

Background: Several studies have reported the role of the miR-146a rs2910164 G > C polymorphism as asusceptibility factor for several digestive cancers. However, the results have been controversial. Therefore, weconducted the present meta-analysis to obtain the most reliable estimate of the association. Methods: PubMed,Embase and Web of Science databases were searched. Crude odds ratios (ORs) with 95% confidence intervals(CIs) were extracted and pooled to assess the strength of the association between miR-146a rs2910164 G > Cpolymorphism and digestive cancer risk. A total of four eligible studies including 3,447 cases and 5,041 controlsbased on the search criteria were included. Results: We observed that miR-146a rs2910164 G > C polymorphismwas not significantly correlated with digestive cancer risks when all studies were pooled into the meta-analysis.While we found that miR-146a rs2910164 polymorphism was not associated with gastric cancer, it was significantlylinked with hepatocellular cancer risk (the homozygote codominant model: OR = 1.40, 95% CI = 1.04-1.87). Inthe stratified analysis by ethnicity, significant associations were observed in Chinese population for the allelecontrast model (OR = 1.25; 95% CI = 1.12-1.38), for the homozygote codominant model (OR = 1.62; 95% CI= 1.28-2.04), and for the recessive model (OR = 1.38; 95% CI = 1.16-1.64). However, studies with Asian groupspresented no significant association for all genetic models. Conclusions: This meta-analysis suggests that themiR-146a rs2910164 G > C polymorphism is a low-penetrant risk factor for digestive cancers in Chinese.