Zeng Y, Sun QM, Liu NN, Dong GH, Chen J, Yang L, Wang B. Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol 2010; 16(28): 3578-3583 [PMID: 20653068 DOI: 10.3748/wjg.v16.i28.3578]
Corresponding Author of This Article
Bin Wang, Professor, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu Province, China. binwangnjmu@gmail.com
Article-Type of This Article
Brief Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ying Zeng, Nan-Nan Liu, Guang-Hui Dong, Jie Chen, Bin Wang, Key Laboratory of Reproductive Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Qing-Min Sun, The Affiliated Wuxi Hospital for Maternal and Child Health Care of Nanjing Medical University, Wuxi 214002, Jiangsu Province, China
Li Yang, Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
ORCID number: $[AuthorORCIDs]
Author contributions: Zeng Y participated in the study design, conducted polymerase chain reaction-restriction fragment length polymorphism, analyzed the data, wrote the manuscript; Sun QM and Liu NN participated in the study design, extracted genetic DNA from all blood samples; Dong GH, Yang L and Chen J collected blood samples from the Affiliated Hospital of Nanjing Medical University; Wang B designed and coordinated the study and revised the manuscript.
Supported by National Natural Science Foundation of China, No. 30873099; Natural Science Foundation of Jiangsu Province, No. BK2006525; No. 08KJB320004, “333 Project” and “Qinglan Project” Funds for the Young Academic Leader of Jiangsu Province to Wang B
Correspondence to: Bin Wang, Professor, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu Province, China. binwangnjmu@gmail.com
Telephone: +86-25-86862884 Fax: +86-25-86862884
Received: March 17, 2010 Revised: May 20, 2010 Accepted: May 27, 2010 Published online: July 28, 2010
Abstract
AIM: To investigate the association between pre-miR-146a C/G polymorphism and gastric cancer risk.
METHODS: We performed a hospital-based, case-control study using polymerase chain reaction-restriction fragment length polymorphism method in 608 individuals (304 gastric cancer patients and 304 age and sex matched cancer-free controls).
RESULTS: The frequencies of pre-miR-146a C/G genotypes in the case group were significantly different from those in the control groups (P = 0.037). Compared with CC genotype carriers, subjects with the variant genotypes (GC + GG) had a 58% increased risk of gastric cancer (adjusted OR = 1.58, 95% CI: 1.11-2.20, P = 0.009). Moreover, a higher gastric cancer risk was especially evident in younger individuals aged ≤ 58 years, nonsmokers, and males (adjusted OR = 1.76, 95% CI: 1.08-2.87, P = 0.024; adjusted OR = 1.55, 95% CI: 1.06-2.28, P = 0.025; adjusted OR = 1.53, 95% CI: 1.04-2.27, P = 0.033; respectively).
CONCLUSION: Pre-miR-146a C/G polymorphism might be associated with an elevated risk of gastric cancer in Chinese population.
Citation: Zeng Y, Sun QM, Liu NN, Dong GH, Chen J, Yang L, Wang B. Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol 2010; 16(28): 3578-3583
MicroRNAs (miRNAs) are endogenous 19- to 25-nt noncoding RNAs, which could negatively regulate gene expression through suppressing translation or degrading mRNA[1]. Bioinformatic data identified that a single miRNA could bind to a large number of mRNA targets, which could be implicated in disease development[2-8]. Interestingly, recent evidences indicated that miR-146a can play a role of mediator in a wide spectrum of biological processes, such as cell proliferation, differentiation, apoptosis, immune response and tumorigenesis[9-15]. Aberrant expression of miR-146a has been reported as a signature in breast cancer, pancreatic cancer, prostate cancer, and cervical cancer [16-18].
Single nucleotide polymorphism (SNP) is the most common type of genetic variation in the human genome. Polymorphisms in human pre-miRNA genome lesion modify the processing and/or target selection of human miRNAs, which are implicated in cell cycle regulation, and thereby play critical roles in carcinogenesis[19,20]. Calin et al[21] found that the pre-miR-206 precursor mutation was associated with the risk of chronic lymphocytic leukemias (CLL). They also found a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of miRNA expression in vivo and in vitro[21].
Pre-miR-146a C/G polymorphism designated rs2910164 is located on chromosome 5, in the stem region opposite to the mature miR-146a sequence[22]. Several epidemiological studies have examined the role of the pre-miR-146a polymorphism in many human cancers, such as hepatocellular carcinoma (HCC), prostate cancer, breast cancer and papillary thyroid carcinoma (PTC)[22-26]. However, the results of these studies were inconsistent. Furthermore, no data are available concerning the association between pre-miR-146a C/G polymorphism and the risk of gastric cancer. Therefore, we have conducted a hospital-based case-control study to investigate the potential link between this polymorphism and gastric cancer in Chinese population.
MATERIALS AND METHODS
Subjects
This is a hospital-based case-control study, which comprised 304 gastric cancer patients and 304 cancer-free controls, consecutively recruited at the Affiliated Hospital of Nanjing Medical University. All the participants were genetically unrelated Han Chinese and were from Jiangsu Province or its surrounding regions. The diagnoses of gastric cancer were all confirmed by endoscopic biopsy or surgical specimens. Patients with secondary or recurrent tumors were excluded. Control subjects matched to gastric cancer cases by gender and age (within 5 years), were selected from patients hospitalized because of a variety of nonmalignant diseases during the time of case collection. Patients with previous histories of cancer or severe clinical symptoms and genetic disease were excluded. A structured questionnaire was administered by interviewers to collect information on demographic information and personal medical history. Those who formerly or currently smoked ≥ 10 cigarettes per day on average were defined as smokers. Pathologic variables were obtained after histopathological investigation. Depth of tumor invasion and local lymph node status were classified according to the tumor-node-metastasis (TNM) classification system of the International Union Against Cancer (UICC)[27]. Differentiation grade was classified according to WHO classification. The study was approved by the Ethics Committee of the First Affiliated Hospital, Nanjing Medical University and informed consent was obtained from each participant.
Genotyping
The protocol for genomic DNA extraction was described in our previous study[28]. The polymorphism was genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. To control the quality of genotyping, the RFLP assay was performed without knowing the status of the cases or controls. The 372-bp DNA fragment containing the polymorphic site was amplified using two primers 5'-CATGGGTTGTGTCAGTGTTAGA-3' and 5'-CCAAGAGTCTCGTATAACAGCA-3'. PCR was done in 20 reaction mixtures containing 2 μL of 10 × PCR buffer (MBI Fermentas), 1.375 mmol/L MaCl2, 0.1 mmol/L dNTPs, 1 unit Taq polymerase (MBI Fermentas), 200 ng genomic DNA, and 0.25 μmol/L of each primer. The PCR conditions were 95°C for 8 min, followed by 35 cycles of 30 s at 95°C, 30 s at 54°C, and 30 s at 72°C, with a final elongation at 72°C for 10 min. PCR product was digested with HPY188I (New England BioLabs), 5 units for 12 h at 37°C, followed by electrophoresis on a 3% agarose gel. The CC genotype yielded three bands at 211, 134 and 27 bp, and GG had two bands at 211 and 161 bp, while the GC produced four bands at 211, 161, 134, and 27 bp. Two research assistants independently examined the gel pictures and performed the repeated assays until they reached a consensus on the tested genotype.
In addition, 10% of the samples were randomly selected for retest, and the results were 100% concordant.
Statistical analysis
All the statistical analyses were performed using Stata Version 8.0 (STATA Corporation, College Station, TX). The Shapiro-Wilk statistics were used to estimate the normality of distribution. Quantitative variables departing from the normal distribution were summarized as median and estimated by the Mann-Whitney rank sum test. Pearson χ2 test was used to investigate the difference in the distribution of categorical variables and genotype frequencies between the cases and controls. Hardy-Weinberg equilibrium of the pre-miR-146a genotypes was analyzed by the goodness-of-fit χ2 test. Odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the association between the polymorphism and the risk of gastric cancer. CC homozygotes were used as the reference. Crude OR was assessed by the Woolf approximation method, and the adjusted OR was computed using unconditional logistic regression with adjustment for age, gender, smoking status, residence, hypertension and diabetes. All statistical tests were two-tailed and considered statistically significant at a value of P < 0.05.
RESULTS
Demographic information
The demographic characteristics of the study participants are listed in Table 1. Cases and controls were well matched in terms of gender and age (within 5 years). Moreover, the two groups were similar with regard to smoking status, residence, history of hypertension, and diabetes. The number of patients with cancer of the gastric cardia and noncardia was 85 and 219, respectively. Most of the cases were adenocarcinoma (96.05%). Among those 304 gastric cancers with available clinicopathologic data, 52, 36, 142 and 67 were T1, T2, T3, and T4, respectively and 41, 165, and 91 were reported to be well, moderately, and poorly differentiated. Positive lymph nodes were identified in 190 cases.
Table 1 The characteristics of cases and controls n (%).
Distributions of pre-miR-146a C/G genotype in cases and controls
Table 2 presents the genotype frequency and the association between pre-miR-146a C/G polymorphism and the risk of gastric cancer. The genotype distributions complied well with Hardy-Weinberg equilibrium in cases and controls (P = 0.7993 and P = 0.1223, respectively), indicating that there was no genetic drift or any selective advantage for particular pre-miR-146a alleles. A significantly different distribution of the pre-miR-146a genotypes was demonstrated between the cases and controls (χ2 = 6.5768, P = 0.037). Furthermore, a higher frequency of G allele frequency was found in cases compared with the controls (χ2 = 5.1232, P = 0.024).
Table 2 The pre-miR-146a C/G genotype distribution in cases and controls and risk estimates for variant genotypes.
Risk estimates for the variant pre-miR-146a genotypes
The association between gastric cancer risk and the polymorphism is presented in Table 2. With the CC genotype as reference, the OR for the variant genotypes (GG + GC) was 1.58 (95% CI: 1.12-2.22, P = 0.009) after adjusting for age, sex, smoking status, residence, hypertension, and diabetes. Moreover, the GG homozygotes had a 62% elevated risk (adjusted OR = 1.62, 95% CI: 1.01-2.58, P = 0.045), and the GC heterozygotes had a 55% increased risk (adjusted OR = 1.55, 95% CI: 1.07-2.22, P = 0.019).
Stratified analyses for the variant genotypes in cases and controls
Table 3 shows the results of stratified analyses by the median age of controls (58 years), sex, smoking status, and residence with the pre-miR-146a variant genotypes. A significantly increased risk associated with the variant genotypes was observed in only subjects aged ≤ 58 years (adjusted OR = 1.76, 95% CI: 1.08-2.87, P = 0.024). In males, possession of the variant genotypes was associated with a 53% increased risk of gastric cancer (adjusted OR = 1.53, 95% CI: 1.04-2.27, P = 0.033), whereas the association was not statistically significant in females. In addition, stratification by smoking status revealed a significant cancer risk for nonsmokers (adjusted OR = 1.55, 95% CI: 1.06-2.28, P = 0.025) but not in smokers. However, no statistically significant difference was observed in rural and urban areas in the association between the polymorphism and susceptibility to gastric cancer.
Table 3 Stratified analyses for variant pre-miR-146a C/G genotypes in cases and controls.
We also evaluated the correlations of the variant genotypes with clinicopathologic features of gastric cancer, including tumor differentiation, depth of tumor infiltration, lymph node status and tumor location, however, no statistically significant association was observed (Table 4).
Table 4 Associations between variant pre-miR-146a C/G genotypes and clinicopathological characteristics of gastric cancer.
Recent genome-wide SNP polymorphisms are encouraging and widely performed to help in developing more accurate diagnostic and therapeutic strategies of various kinds of human disorders[29]. In the present study, we for the first time found that the C to G variant in pre-miR-146a conferred an increased risk of gastric cancer in Chinese population. We also found that the elevated gastric cancer risk was especially evident in the individuals aged ≤ 58 years, nonsmokers and males.
The human miR-146a is located on chromosome 5[22]. In general, one miRNA targets thousands of mRNAs and one mRNA is regulated by many miRNAs. Therefore, it is very hard to understand the precise mechanisms of the miRNA in the pathogenesis of human disorders. Nevertheless, various studies have suggested that miR-146a is a NF-κB-dependent gene[30,31]. Upon processing, it could down-regulate levels of IRAK1 and TRAF6 proteins, reducing the activity of the NF-κB signaling pathway, which has been implicated as an important causal link between inflammation and carcinogenesis[9,10,32-34]. To date, aberrant miR-146a expressions have been described in several diseases[16-18,35-38]. Recent reports have indicated that miR-146a levels were increased in the tissues associated with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis, whereas there was no increase of miR-146a levels in tissues obtained from patients with other chronic inflammatory diseases such as the skin from atopic eczema or lung biopsies from mild asthmatics[35-37]. Moreover, elevated miR-146a levels have been reported in PTC, cervical cancer, breast cancer and pancreatic cancer, whereas decreased miR-146a expression is associated with prostate cancer[16-18,38].
A C/G polymorphism (rs2910164) resides at position + 60 relative to the first nucleotide of pre-miR-146a, placing it in the passenger strand[22]. Compared with the major C allele, the minor G allele causes mispairing in the hairpin and a higher dG from -40.3 to -43.1 kcal/mol, suggesting a more stable secondary structure for the G allele[39]. The genetic variant might have an impact on processing the pre-miRNA into the mature microRNA. The mutation in pre-miR-146a gene has been reported to modulate cancer risks, although the results are inconsistent[22-26]. Xu et al[23] showed that male individuals with GG genotype were 2-fold more susceptible to HCC (OR = 2.016, 95% CI: 1.056-3.848, P = 0.034) compared to those with CC genotype. In a case-control study, Xu et al[24] suggested that CC homozygotes exhibited an association with prostate cancer with a 65% decreased risk (95% CI: 0.43-0.99, P = 0.03). Findings by Jazdzewski et al[22] demonstrated that the GC heterozygous state was associated with an increased risk of acquiring PTC (OR = 1.62, P = 0.000007), and both homozygous states were protective with OR = 0.42 for the CC genotype and OR = 0.69 for the GG genotype. Although one study showed that this polymorphism did not appear to be linked with an increased risk of breast cancer[26], another indicated that those breast and ovarian cancer patients who had at least one C allele were diagnosed at an earlier age (median age: 45 vs 56, P = 0.029 for breast cancer; median age: 45 vs 50, P = 0.014 for ovarian cancer)[25]. We noted that, compared with the CC genotype, the G allele carriers had a 55% increased risk of gastric cancer. After adjustment for age, sex, smoking status, residence, hypertension and diabetes, the difference still existed, confirming that the polymorphism was related to the risk of gastric cancer in China. Although the precise mechanisms of miRNA expression regulation are largely unknown and the inconsistent effect of miRNA SNP for cancer diagnosis and prognosis is ambiguous, those results may imply that miRNA expression patterns are associated with the biological and clinical behavior of human cancers.
Our data showed that the polymorphism was associated with the increased risk of gastric cancer among subgroups of the subjects aged ≤ 58 years, whereas not among older subjects. Overwhelming accumulated exposure to environmental carcinogens and weak immune system in older individuals may account for the age difference we observed[28]. An old age is related to an increased risk for gastric cancer, which is more likely due to the age effect rather than the direct genetic effect. Therefore, the polymorphism in the pre-miR-146a may be more evident in early-onset gastric cancer, although this age-specific association needs to be further replicated.
Tobacco smoking is a known cause of gastric cancer[40]. The association between the polymorphism and gastric cancer risk may be masked by the relatively high-level exposure to tobacco carcinogens in smokers so that it is more influential in nonsmokers.
Subsequently, a positive correlation between pre-miR-146a genotype and sex was found. A significantly elevated risk of gastric cancer was observed for the GG + GC genotypes among males but not among females. Xu et al[23] also concluded that male individuals with GG genotype were more susceptible to HCC compared to those with CC genotype. Based on the findings, it would therefore be plausible to expect that the sex-specific effect of pre-miR-146a may be responsible for the different results between males and females, although the exact mechanism remains unclear.
Further stratified analyses by clinicopathologic parameters of gastric cancer showed no significant association between the pre-miR-146a genotypes and clinical pathological parameters of gastric cancer. Gastric cancer is considered to be a complex, multi-step and multi-factorial process. Although our data did not support a causal link between the variant genotypes and gastric cancer progression, we could not exclude the possibility that other factors might impact the interaction between them. Moreover, the size of cases in the subgroups was relatively small; our findings from the stratified analyses should be interpreted with caution before confirmed in further studies.
Several limitations should be addressed in the study. First, lack of information on Helicobacter pylori (H. pylori) infection status did not allow us to analyze the interaction between the polymorphism and H. pylori infection status, because it was unethical to do H. pylori test in every subject. Second, the sample size was relatively small. This may have been underpowered to detect small but real gene-environment associations. Finally, the study was conducted in Chinese population, data should be extrapolated to other ethnic groups cautiously. Nevertheless, our initial data presented valuable insights and interesting information to guide future studies in this area.
In summary, our results suggested that pre-miR-146a C/G polymorphism is associated with the increased risk of gastric cancer in Chinese population, especially in younger individuals, nonsmokers, and males. Further studies are required to elucidate the mechanism underlying the polymorphism and gastric cancer progression.
COMMENTS
Background
MiR-146a is a small non-coding regulatory RNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. Polymorphism in human pre-miR146a has been recently implicated in human cancers.
Research frontiers
Using polymerase chain reaction-restriction fragment length polymorphism method in 608 individuals, this study explored the relationship between pre-miR-146a C/G polymorphism and gastric cancer risk.
Innovations and breakthroughs
The results suggest that the polymorphism is associated with the elevated risk of gastric cancer in Chinese population, especially in younger individuals, males and nonsmokers.
Applications
The results of this study could be helpful in further understanding the genetic determinants of gastric cancer.
Peer review
This manuscript describes the association of a single nucleotide polymorphism in the hsa-miR-146a with gastric cancer, which is novel for this particular type of cancer, but biologically plausible owing to the associations reported by other authors for different types of tumors.
Footnotes
Peer reviewer: Carlos J Pirola, PhD, FAHA, Medical Research Institute A Lanari, Combatientes de Malvinas 3150, Buenos Aires-1427, Argentina
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