Tumor Biol. (2014) 35:1371–1376 DOI 10.1007/s13277-013-1187-z
RESEARCH ARTICLE
The Thr241Met polymorphism in the XRCC3 gene is associated with increased risk of cancer in Chinese mainland populations Liang Du & Tianyuan Xiong & Qing He & Yayi Wang & Jiani Shen & Yuanling Peng & Qingyi Jia & Jiqiao Yang & Yonggang Zhang & Jin Huang
Received: 1 August 2013 / Accepted: 13 August 2013 / Published online: 7 November 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract The Thr241Met polymorphism in XRCC3 gene may affect the DNA repair pathways and be associated with the risk of cancer. However, the results of previous studies are inconsistent in Chinese mainland populations. The objective of this study is to investigate the association between the Thr241Met polymorphism in XRCC3 gene and risk of cancer for the Chinese Mainland populations by meta-analysis. We searched PubMed database, Embase database, CNKI database, and Wanfang database, and the last search was updated on July 24, 2013. Statistical analysis was performed using RevMan4.2 and Stata10.0 software. Finally, a total of 23 case–control studies in 23 articles were included. The results suggested a significant association between the Thr241Met polymorphism in XRCC3 gene and cancer risk in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr: OR= 1.25, 95 % CI=1.02–1.54, P =0.04). In the subgroup analyses by cancer types, significant associations were found in cervical cancer and nasopharyngeal cancer. The current metaanalysis suggested that the Thr241Met polymorphism in the XRCC3 gene may be a risk factor for cancer in Chinese mainland populations. In the future, more case–control studies are needed to validate these results. Keywords Cancer . XRCC3 . Polymorphism . Chinese L. Du : T. Xiong : Q. He : Y. Wang : J. Shen : Y. Peng : Q. Jia : J. Yang : Y. Zhang : J. Huang West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China L. Du : J. Huang (*) Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Guoxuexiang 37, Chengdu, Sichuan 610041, China e-mail: [email protected]
Introduction Cancers are still the leading death causes around the world, causing high public attentions [1]. In addition to environmental factors as marked risk factors for Chinese populations, the genetic backgrounds are also of worthy concern. Up to now, more and more studies suggested that the genetic variants of the genes in the pathogenesis of cancers might play vital roles in the etiology of cancers for Chinese mainland population. Among them, the DNA repair genes have been gaining great attention. The DNA repair genes code proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division [2]. Genetic variants in the DNA repair genes can lead to a failure in repair, which in turn, allows subsequent mutations to accumulate and thus might contribute to the pathogenesis of cancers [3]. The XRCC3 gene is an important DNA repair gene. It is located on the 14q32.3 and encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage [3–5]. Many polymorphisms in the XRCC3 gene have been identified and the Thr241Met (rs861539) polymorphism is one of the most important. It is based on a variation from C to T in exon 7 at position 18067. It may alter the functions and structures of the XRCC3 protein, and thus play an important role in the pathogenesis of cancers [3–5]. In the past few years, much interest has been addressed to the association between the Thr241Met polymorphism and the risk of cancers in Chinese mainland populations. However, the results were inconclusive. In order to address more conclusive results, we conducted the present meta-analysis. This is, to our knowledge, the most comprehensive meta-analysis conducted to assess the association between the variant of XRCC3 gene with the Chinese mainland populations.
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Tumor Biol. (2014) 35:1371–1376
Fig. 1 Flow diagram of included/ excluded studies
436 results identified from Pubmed, Embase, CNKI and Wanfang databases after an initial search
362 results were excluded for: not relevant to XRCC3 Thr241Met and cancer risk for Chinese populations, reviews, abstracts and duplicated results
74 potential articles concerning the current topic for full-text 4 results were excluded for not relevant to Chinese Mainland population 70 articles relevant to XRCC3 Thr241Met for data extraction 14 articles were excluded for: not present the usable data (10) not case-control studies (4) 56 case-control studies in 56 articles were identified
Case-control studies were excluded for: overlapped or duplicated data(16) not consistent with HWE(8) not healthy control(9)
Finally, 23 case-control studies in 23 studies concerning association between the XRCC3 Thr241Met and cancer risk in Chinese Mainland populations were identified
Table 1 Characteristics and genotype distributions of included case–control studies Author
Year
Province
Type of cancer
Case
Control
CC
CT
TT
CC
CT
TT
Guo et al. [3] Han et al. [4] He et al. [5] Huang [7] Huang [8] Jin et al. [9] Liang [10] Liu et al. [11] Long et al. [12] Qian et al. [13] Ritchey et al. [14] Shen et al. [15] Wen [16] Xia et al. [17] Xiao et al. [18] Yang et al. [19]
2013 2012 2008 2010 2007 2005 2004 2011 2008 2011 2005 2004 2006 2008 2010 2009
Heilongjiang Henan Zhejiang Fujian Fujian Zhejiang Beijing Tianjin Guangxi Tianjin Shanghai Jiangsu Beijing Zhejiang Guangdong Henan
Lung cancer HCC Cervical cancer Lung cancer Esophageal cancer Colorectal cancer Lung cancer AML HCC Lung cancer Prostate cancer Gastric cancer Laryngeal and hypopharyngeal carcinomas Lung cancer Cervical cancer Bladder cancer
589 75 177 688 69 185 787 524 198 521 139 169 144 91 82 191
93 55 19 71 70 18 79 89 200 60 17 18 26 12 59 27
2 19 4 4 11 1 2 12 93 0 3 1 5 0 17 2
549 87 182 685 241 769 807 627 585 533 214 150 482 118 115 205
52 66 17 75 149 66 79 73 248 67 31 16 43 21 41 15
1 5 1 3 12 4 1 4 29 3 2 0 0 0 8 0
Yang et al. [20] Zhang et al. [22] Zhang et al. [23] Zhao et al. [24] Zhang and Meng [21] Zhou et al. [25] Zhu et al. [26]
2007 2008 2012 2013 2011 2009 2012
Sichuan Shanghai Guangdong Jiangsu Anhui Shanghai Hunan
Nasopharyngeal carcinoma Biliary tract cancer Nasopharyngeal carcinoma Glioma Colon carcinoma Glioma Bladder cancer
144 361 109 336 47 677 91
9 44 17 47 31 80 44
0 0 1 1 2 3 15
149 675 88 340 61 629 96
18 103 29 41 18 75 49
1 2 0 3 1 4 5
Tumor Biol. (2014) 35:1371–1376
Materials and methods
1373
included in more than one study, the most recent or complete study was included.
Publication search Data extraction Literature databases including Embase, PubMed, CNKI, and Wanfang databases were searched and the last search was performed on July 24, 2013. The search terms were as follows: “cancer” or “carcinoma” and “China” or “Chinese” and “XRCC3 ” in combination with “polymorphism” or “mutation” or “variant.” There was no language restriction. Inclusion criteria were as follows: (1) studies evaluating the Thr241Met polymorphism of XRCC3 gene and cancer risks in Chinese mainland populations; (2) genotype distributions in both cases and controls were available for estimating an odds ratio (OR) with 95 % confidence interval (CI); (3) genotype distributions of control population must be consistent with Hardy–Weinberg equilibrium (HWE); (4) the controls must be healthy populations. Specifically, inpatients from the irrelevant departments such as orthopedics, ophthalmology, and dermatology were eliminated. The populations seeking for general health examination were included. Accordingly, the exclusion criteria were as follows: (1) abstracts, reviews, conference reports, or systematic reviews; (2) family- or sibling-based studies; and (3) studies with insufficient data referring to genotype frequency. When the overlapped data of the same populations were
Two reviewers independently checked all potentially relevant studies and reached a consensus on all items. In case of disagreement, a third author would assess these articles. The following data were collected from each study: first author, year of publication, type of cancer, genotyping methods, and available genotypes. Statistical analysis All statistical tests were performed with the RevMan4.2 software and Stata10.0 software. The chi-square test was used to determine if the identified study was accordance with HWE for the genotype distribution in the control group (http://ihg. gsf.de/cgi-bin/hw/hwa1.pl). Crude ORs with 95 % CIs were calculated to assess the strength of the association between the Thr241Met polymorphism in XRCC3 gene and cancer risks in Chinese mainland populations. The genetic model that was evaluated for pooled ORs of the polymorphism was dominant model (Met/Met + Thr/Met vs. Thr/Thr). The OR value was assessed by using the Z test, and a P value less than 0.05 was considered statistically
Fig. 2 Meta-analysis with a random-effects model for the association between the Thr241Met polymorphism in XRCC3 and risk of cancer in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr)
1.05 (0.82, 1.35) 2.11 (1.02, 4.35) 1.58 (1.01, 2.47) 1.82 (1.32, 2.50) 1.44 (0.83, 2.50) 0.99 (0.77, 1.27) 0.54 (0.33, 0.87) 1.38 (0.98, 1.94) 0.63 0.33 0.45 0.09 0.20 0.73 0.007 0.16 1.06 (0.83, 1.36) 1.55 (0.64, 3.76) 1.31 (0.65, 2.62) 1.61 (0.93, 2.76) 1.54 (0.79, 2.98) 1.05 (0.80, 1.37) 0.49 (0.29, 0.82) 1.24 (0.91, 1.69) 0.77
RESEARCH ARTICLE
The Thr241Met polymorphism in the XRCC3 gene is associated with increased risk of cancer in Chinese mainland populations Liang Du & Tianyuan Xiong & Qing He & Yayi Wang & Jiani Shen & Yuanling Peng & Qingyi Jia & Jiqiao Yang & Yonggang Zhang & Jin Huang
Received: 1 August 2013 / Accepted: 13 August 2013 / Published online: 7 November 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract The Thr241Met polymorphism in XRCC3 gene may affect the DNA repair pathways and be associated with the risk of cancer. However, the results of previous studies are inconsistent in Chinese mainland populations. The objective of this study is to investigate the association between the Thr241Met polymorphism in XRCC3 gene and risk of cancer for the Chinese Mainland populations by meta-analysis. We searched PubMed database, Embase database, CNKI database, and Wanfang database, and the last search was updated on July 24, 2013. Statistical analysis was performed using RevMan4.2 and Stata10.0 software. Finally, a total of 23 case–control studies in 23 articles were included. The results suggested a significant association between the Thr241Met polymorphism in XRCC3 gene and cancer risk in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr: OR= 1.25, 95 % CI=1.02–1.54, P =0.04). In the subgroup analyses by cancer types, significant associations were found in cervical cancer and nasopharyngeal cancer. The current metaanalysis suggested that the Thr241Met polymorphism in the XRCC3 gene may be a risk factor for cancer in Chinese mainland populations. In the future, more case–control studies are needed to validate these results. Keywords Cancer . XRCC3 . Polymorphism . Chinese L. Du : T. Xiong : Q. He : Y. Wang : J. Shen : Y. Peng : Q. Jia : J. Yang : Y. Zhang : J. Huang West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China L. Du : J. Huang (*) Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Guoxuexiang 37, Chengdu, Sichuan 610041, China e-mail: [email protected]
Introduction Cancers are still the leading death causes around the world, causing high public attentions [1]. In addition to environmental factors as marked risk factors for Chinese populations, the genetic backgrounds are also of worthy concern. Up to now, more and more studies suggested that the genetic variants of the genes in the pathogenesis of cancers might play vital roles in the etiology of cancers for Chinese mainland population. Among them, the DNA repair genes have been gaining great attention. The DNA repair genes code proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division [2]. Genetic variants in the DNA repair genes can lead to a failure in repair, which in turn, allows subsequent mutations to accumulate and thus might contribute to the pathogenesis of cancers [3]. The XRCC3 gene is an important DNA repair gene. It is located on the 14q32.3 and encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage [3–5]. Many polymorphisms in the XRCC3 gene have been identified and the Thr241Met (rs861539) polymorphism is one of the most important. It is based on a variation from C to T in exon 7 at position 18067. It may alter the functions and structures of the XRCC3 protein, and thus play an important role in the pathogenesis of cancers [3–5]. In the past few years, much interest has been addressed to the association between the Thr241Met polymorphism and the risk of cancers in Chinese mainland populations. However, the results were inconclusive. In order to address more conclusive results, we conducted the present meta-analysis. This is, to our knowledge, the most comprehensive meta-analysis conducted to assess the association between the variant of XRCC3 gene with the Chinese mainland populations.
1372
Tumor Biol. (2014) 35:1371–1376
Fig. 1 Flow diagram of included/ excluded studies
436 results identified from Pubmed, Embase, CNKI and Wanfang databases after an initial search
362 results were excluded for: not relevant to XRCC3 Thr241Met and cancer risk for Chinese populations, reviews, abstracts and duplicated results
74 potential articles concerning the current topic for full-text 4 results were excluded for not relevant to Chinese Mainland population 70 articles relevant to XRCC3 Thr241Met for data extraction 14 articles were excluded for: not present the usable data (10) not case-control studies (4) 56 case-control studies in 56 articles were identified
Case-control studies were excluded for: overlapped or duplicated data(16) not consistent with HWE(8) not healthy control(9)
Finally, 23 case-control studies in 23 studies concerning association between the XRCC3 Thr241Met and cancer risk in Chinese Mainland populations were identified
Table 1 Characteristics and genotype distributions of included case–control studies Author
Year
Province
Type of cancer
Case
Control
CC
CT
TT
CC
CT
TT
Guo et al. [3] Han et al. [4] He et al. [5] Huang [7] Huang [8] Jin et al. [9] Liang [10] Liu et al. [11] Long et al. [12] Qian et al. [13] Ritchey et al. [14] Shen et al. [15] Wen [16] Xia et al. [17] Xiao et al. [18] Yang et al. [19]
2013 2012 2008 2010 2007 2005 2004 2011 2008 2011 2005 2004 2006 2008 2010 2009
Heilongjiang Henan Zhejiang Fujian Fujian Zhejiang Beijing Tianjin Guangxi Tianjin Shanghai Jiangsu Beijing Zhejiang Guangdong Henan
Lung cancer HCC Cervical cancer Lung cancer Esophageal cancer Colorectal cancer Lung cancer AML HCC Lung cancer Prostate cancer Gastric cancer Laryngeal and hypopharyngeal carcinomas Lung cancer Cervical cancer Bladder cancer
589 75 177 688 69 185 787 524 198 521 139 169 144 91 82 191
93 55 19 71 70 18 79 89 200 60 17 18 26 12 59 27
2 19 4 4 11 1 2 12 93 0 3 1 5 0 17 2
549 87 182 685 241 769 807 627 585 533 214 150 482 118 115 205
52 66 17 75 149 66 79 73 248 67 31 16 43 21 41 15
1 5 1 3 12 4 1 4 29 3 2 0 0 0 8 0
Yang et al. [20] Zhang et al. [22] Zhang et al. [23] Zhao et al. [24] Zhang and Meng [21] Zhou et al. [25] Zhu et al. [26]
2007 2008 2012 2013 2011 2009 2012
Sichuan Shanghai Guangdong Jiangsu Anhui Shanghai Hunan
Nasopharyngeal carcinoma Biliary tract cancer Nasopharyngeal carcinoma Glioma Colon carcinoma Glioma Bladder cancer
144 361 109 336 47 677 91
9 44 17 47 31 80 44
0 0 1 1 2 3 15
149 675 88 340 61 629 96
18 103 29 41 18 75 49
1 2 0 3 1 4 5
Tumor Biol. (2014) 35:1371–1376
Materials and methods
1373
included in more than one study, the most recent or complete study was included.
Publication search Data extraction Literature databases including Embase, PubMed, CNKI, and Wanfang databases were searched and the last search was performed on July 24, 2013. The search terms were as follows: “cancer” or “carcinoma” and “China” or “Chinese” and “XRCC3 ” in combination with “polymorphism” or “mutation” or “variant.” There was no language restriction. Inclusion criteria were as follows: (1) studies evaluating the Thr241Met polymorphism of XRCC3 gene and cancer risks in Chinese mainland populations; (2) genotype distributions in both cases and controls were available for estimating an odds ratio (OR) with 95 % confidence interval (CI); (3) genotype distributions of control population must be consistent with Hardy–Weinberg equilibrium (HWE); (4) the controls must be healthy populations. Specifically, inpatients from the irrelevant departments such as orthopedics, ophthalmology, and dermatology were eliminated. The populations seeking for general health examination were included. Accordingly, the exclusion criteria were as follows: (1) abstracts, reviews, conference reports, or systematic reviews; (2) family- or sibling-based studies; and (3) studies with insufficient data referring to genotype frequency. When the overlapped data of the same populations were
Two reviewers independently checked all potentially relevant studies and reached a consensus on all items. In case of disagreement, a third author would assess these articles. The following data were collected from each study: first author, year of publication, type of cancer, genotyping methods, and available genotypes. Statistical analysis All statistical tests were performed with the RevMan4.2 software and Stata10.0 software. The chi-square test was used to determine if the identified study was accordance with HWE for the genotype distribution in the control group (http://ihg. gsf.de/cgi-bin/hw/hwa1.pl). Crude ORs with 95 % CIs were calculated to assess the strength of the association between the Thr241Met polymorphism in XRCC3 gene and cancer risks in Chinese mainland populations. The genetic model that was evaluated for pooled ORs of the polymorphism was dominant model (Met/Met + Thr/Met vs. Thr/Thr). The OR value was assessed by using the Z test, and a P value less than 0.05 was considered statistically
Fig. 2 Meta-analysis with a random-effects model for the association between the Thr241Met polymorphism in XRCC3 and risk of cancer in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr)
1.05 (0.82, 1.35) 2.11 (1.02, 4.35) 1.58 (1.01, 2.47) 1.82 (1.32, 2.50) 1.44 (0.83, 2.50) 0.99 (0.77, 1.27) 0.54 (0.33, 0.87) 1.38 (0.98, 1.94) 0.63 0.33 0.45 0.09 0.20 0.73 0.007 0.16 1.06 (0.83, 1.36) 1.55 (0.64, 3.76) 1.31 (0.65, 2.62) 1.61 (0.93, 2.76) 1.54 (0.79, 2.98) 1.05 (0.80, 1.37) 0.49 (0.29, 0.82) 1.24 (0.91, 1.69) 0.77
