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Original Article MSH3 Rs26279 Polymorphism Increases Cancer Risk: a Meta-Analysis

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Original Article MSH3 Rs26279 Polymorphism Increases Cancer Risk: a Meta-Analysis Int J Clin Exp Pathol 2015;8(9):11060-11067 www.ijcep.com /ISSN:1936-2625/IJCEP0014495 Original Article MSH3 rs26279 polymorphism increases cancer risk: a meta-analysis Hui-Kai Miao*, Li-Ping Chen, Dong-Ping Cai, Wei-Ju Kong, Li Xiao, Jie Lin* Department of Clinical Laboratory, The 101th Hospital of The People’s Liberation Army, Wuxi 214044, Jiangsu, China. *Equal contributors and co-first authors. Received August 14, 2015; Accepted August 18, 2015; Epub September 1, 2015; Published September 15, 2015 Abstract: Previous studies have investigated the association of mutS homolog 3 (MSH3) rs26279 G > A polymor- phism with the risk of different types of cancers including colorectal cancer, breast cancer, prostate cancer, blad- der cancer, thyroid cancer, ovarian cancer and oesophageal cancer. However, its association with cancer remains conflicting. We performed a comprehensive meta-analysis to derive a more precise estimation of the relationship between MSH3 rs26279 G > A polymorphism and cancer susceptibility. Systematically searching the PubMed and EMBASE databases yielded 11 publications with 12 studies of 3282 cases and 6476 controls. The strength of the association was determined by crude odds ratios (OR) and 95% confidence intervals (CI). Overall, pooled risk esti- mates demonstrated that MSH3 rs26279 G > A was significantly associated with an increased overall cancer risk under all the genetic models (GG vs. AA: OR = 1.27, 95% CI = 1.09-1.48, P = 0.002; AG vs. AA: OR = 1.10, 95% CI = 1.00-1.21, P = 0.045; GG vs. AG + AA: OR = 1.23, 95% CI = 1.06-1.42, P = 0.005; AG + GG vs. AA: OR = 1.13, 95% CI = 1.04-1.24, P = 0.006; G vs. A: OR = 1.13, 95% CI = 1.05-1.20, P = 0.001). The association was more evident for colorectal cancer and breast cancer. Moreover, the significant association was also observed in the following subgroups: Europeans, Asians, population-based studies, hospital-based studies, and studies comprising relatively large sample size (≥ 200). Our meta-analysis results demonstrated that MSH3 rs26279 G > A polymorphism is as- sociated with an increased risk of overall cancer, especially for the colorectal cancer and breast cancer. Keywords: MSH3, polymorphism, cancer, meta-analysis Introduction cycle regulation and apoptosis, answerable for a variety of DNA damage [3, 4]. It is primarily Cancer is a complex multistep disease. Genetic responsible for recognizing and correcting aberrations may contribute to the development base-base mismatches and insertion/deletion of cancer through interaction with environment loops generated during DNA replication and factors [1]. Genetic aberrations can occur dur- homologous recombination [5, 6]. ing the process of DNA replication and homolo- gous recombination or as a result of DNA dam- Additionally, a fraction of mismatches can arise age, owing to exposure to various exogenous from DNA damage. If not properly repaired, and endogenous factors such as UV, ionizing these mismatches may enhance spontaneous radiation, and products of lipid peroxidation. In mutation rates and lead to the occurrence of order to protect against DNA aberrations and microsatellite repeat instability in cells, thereby maintain the integrity of the genome, human contributing to carcinogenesis. Therefore, MMR body possesses four major DNA repair, includ- plays a critical role in maintaining the integrity ing nucleotide excision repair (NER), base exci- of the genome. In humans, there are seven sion repair (BER), double-strand break repair mismatch repair genes including MSH2 (mutS (DSBR) and mismatch repair (MMR) pathways homolog 2), MSH3, MSH6, MLH1 (mutL homo- [2]. log 1), PMS1 (postmeiotic segregation increa- sed 1), PMS2 and MLH3. The MSH2, MSH3 and As one of fundamentally biological pathway, the MSH6 genes are MutS homologs, while the rest MMR system plays an important role in cell of genes are MutL homologes [7]. Unlike homo- MSH3 polymorphisms and cancer risk oligomers in prokaryotes, MMR proteins form Inclusion and exclusion criteria heterodimers in human. The function of MutS is to recognize and bind to mismatched DNA frag- Inclusion criteria were listed in the following ments, and thereafter initiate MMR. There are paragraph: (a) a case-control design study eval- two kinds of MutS homodimers, MSH2-MSH6 uating the association between MSH3 rs26279 (MutSα) and MSH2-MSH3 (MutSβ) in human. G > A polymorphism and cancer risk; (b) suffi- The MutSα searchs for single base mismatches cient raw data for estimating odds ratios (ORs) and short insertion/deletion loops, while the and their 95% confidence intervals; and (c) the MutSβ are able to detect large insertion/dele- genotype distribution in the control group of the tion loops [6, 8]. studies should be in accordance with the Hardy- Weinberg equilibrium (HWE). Exclusion criteria The MSH3 gene is located at chromosome included: (a) case-only study; (b) reviews and 5q11-13 and encodes a protein of 1137 amino duplicate data. acid residues [9]. Some potentially functional single-nucleotide polymorphisms (SNPs) of Data extraction MSH3 may have influence the DNA repair After selection of eligible studies according to capacity and thereby predispose individuals to the inclusion criteria and exclusion criteria, two a variety of cancers. Thus far, at least 180 of the researchers independently collected SNPs have been reported in MSH3 gene information from all eligible publications. The (http://www.ncbi.nlm.nih.gov/SNP/snp_ref. following data was extracted from each study: cgi?locusId=4437). Among all of these SNPs, the last name of the first author, publication rs26279 G > A polymorphism are frequently year, country, ethnicity, cancer type, source of investigated and have been thought to be control (hospital-based or population-based), involved in carcinogenesis in recent years. genotyping methods, genotype counts of cases Some studies suggested that this variant was and controls for MSH3 rs26279 G > A polymor- associated with the risk of cancer including phism. The stratification analysis was conduct- colorectal cancer [10, 11], breast cancer [12- ed by cancer type (If one type of cancer was 14], prostate cancer [15, 16], bladder cancer only investigated in a study, the cancer type [17], thyroid cancer [18], ovarian cancer [19] would be merged into the “other type”), ethnic- and oesophageal cancer [20]. However, the ity (Asians, Europeans and Africans), control association of interest remains inconclusive. source (hospital-based and population-based) Hence, to provide a more precise estimation of and sample size (number of cases < 200 and ≥ the association between MSH3 rs26279 G > A 200). polymorphism and the risk of cancer, we con- ducted a meta-analysis with all eligible case- Statistical analysis control studies. Crude ORs with the corresponding 95% CIs Materials and methods were employed to estimate the strength of association between the MSH3 rs26279 G > A Identification of eligible relevant studies polymorphism and cancer risk. The following genetic models were chosen: homozygous A systematic literature search was conducted model (GG vs. AA), heterozygous model (AG vs. throughout the Pubmed and EMBASE database AA), recessive model (GG vs. AG + AA), domi- to find studies assessing the association nant model (AG + GG vs. AA) and allele compari- between MSH3 rs26279 G > A polymorphism son (G vs. A). Goodness-of-fit chi-square test and the risk of cancer prior to May 30, 2015. was used to check whether there was deviation The following keywords were used to identify from Hardy-Weinberg equilibrium in control relevant studies “MSH3 or hMSH3”, “variant or subjects of each included study. The heteroge- polymorphism” and “cancer or carcinoma or neity of studies was tested by Chi squared- neoplasm or tumor”. Additional related studies based Q-test, with a P value of more than 0.10 have been also identified by hand screening. denoting a lack of between-study heterogene- The search was limited to human studies writ- ity. In the absence of heterogeneity, we used ten in Chinese and English. the fixed-effects model (the Mantel-Haenszel 11061 Int J Clin Exp Pathol 2015;8(9):11060-11067 MSH3 polymorphisms and cancer risk Table 1. Characteristics of studies included in the meta-analysis Control Genotype NO. of cases NO. of control Surname Year Country Ethnicity Cancer type MAF HWE source method All AA AG GG All AA AG GG Berndt 2007 USA European Colorectal PB TaqMan 229 101 101 27 2081 1063 851 167 0.28 0.855 Conde 2009 Portugal European Breast HB TaqMan 286 121 129 36 544 246 240 58 0.33 0.962 Hirata 2008 Japan Asian Prostate HB SSCP/PCR-RFLP 110 60 43 7 110 72 31 7 0.20 0.160 Jafary 2012 Iran Asian Prostate PB SSCP 18 12 5 1 60 34 18 8 0.28 0.043 Kawakami 2004 Japan Asian Bladder PB SSCP 99 53 38 8 101 66 28 7 0.21 0.112 Orimo 2000 Japan Asian Colorectal PB SSCP 19 10 8 1 89 55 28 6 0.22 0.360 Shi 2008 China Asian Thyroid HB PCR-RFLP 204 120 68 16 204 130 60 14 0.22 0.062 Smith 2008 USA European Breast HB MassARRAY 321 154 123 44 409 198 175 36 0.30 0.762 African Breast HB MassARRAY 52 21 23 8 72 33 29 10 0.34 0.383 Song 2006 UK European Ovarian PB TaqMan 1310 663 525 122 2003 1064 771 168 0.28 0.093 Terrazzino 2012 Italy European Breast HB TaqMan 89 41 36 12 196 93 86 17 0.31 0.646 Vogelsang 2012 South Africa African Oesophageal HB TaqMan 545 204 256 85 607 230 295 82 0.38 0.410 SSCP, single-strand conformational polymorphism; PCR-RFLP, polymerase chain reaction restriction fragment length polymorphisms; HB, hospital based; PB, population based; MAF, Minor Allele Frequency; HWE: Hardy-Weinberg equilibrium. Table 2.
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