Tumor Biol. (2014) 35:3003–3008 DOI 10.1007/s13277-013-1387-6
RESEARCH ARTICLE
The Val158Met polymorphism in the COMT gene is associated with increased cancer risks in Chinese population Can Tian & Liping Liu & Xiaohong Yang & Hui Wu & Quchang Ouyang
Received: 15 October 2013 / Accepted: 5 November 2013 / Published online: 5 December 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract The Val158Met polymorphism in the COMT gene may affect the DNA repair pathways and be associated with the risk of cancer in Chinese population. However, the results of previous studies are inconsistent. The objective of this study was to investigate the association between the Val158Met polymorphism in the COMT gene and the risk of cancer for Chinese population by meta-analysis. We searched PubMed, Embase, CNKI, Weipu, and Wanfang databases, and the last search was updated on Sep. 26, 2013. Statistical analysis was performed using the Revman4.2 and Stata10.0 software. A total of 18 case–control studies concerning 5034 case and 6234 controls were included. In the total analysis, the results suggested a significant association between the Val158Met polymorphism in the COMT gene and the cancer risk in Chinese population: OR=1.34, 95 %CI=1.04–1.73, and P = 0.03 for AA vs. AG+GG; OR=1.39, 95 %CI=1.06–1.82, and P =0.02; OR=1.13, 95 %CI=1.01–1.27, and P =0.04. In the subgroup analysis by cancer types, significant association was found in the breast cancer and esophageal squamous cell carcinoma. The current meta-analysis confirmed that the Val158Met polymorphism in the COMT gene may be a risk factor for cancer in Chinese population. In the future, more case–control studies are needed to validate our results. Keywords COMT . Chinese . Cancer . Meta-analysis . Variant
Introduction Cancer burden is increasing largely in China in recent years, as well as around the world [1]. It has been estimated that C. Tian : L. Liu : X. Yang : H. Wu : Q. Ouyang (*) Department of Internal Breast Cancer, Huan Provincial Tumor Hospital, Hunan, China e-mail: [email protected]
90–95 % of cancer cases are attributed to environmental factors, while 5–10 % are due to genetic defects. During the transformation from normal to cancer cells, the genes which regulate cell growth and differentiation are altered. Series of genes have been found to be linked with cancer incidence, and the well-known genes are COMT [2], MYC [3], EGFR [4], TLR [5], and so forth. Among them, the COMT gene is one of the most involved genes. The human COMT gene is located on chromosome 22q11.21. It encodes a protein named catechol-O -methyl transferase (COMT) catalyzing the transferring of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine [6]. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. Due to its crucial role in the metabolism of endogenous substances, the COMT is important in the catechol metabolism processes. Also, plenty of researches have indicated the link between polymorphisms in the COMT gene and cancer susceptibility. Several polymorphisms have been identified, and the widely studied is Val158Met (rs4680). This polymorphism at position 158 results in a valine-to-methionine variation, leading to a decreased activity of catechol-O -methyl transferase which generates catecholamine accumulation. The accumulation of catecholamine can cause DNA oxidative damage which may result in carcinogenesis. Also, catechol-O -methyl transferase can inactivate catechol estrogen, thus contributing to the occurrence and progression of genital system tumors such as breast cancer and endometrial cancer. There have been lots of studies exploring the association between the Val158Met polymorphism and cancer susceptibility of different types of cancer and races, but the results were inconclusive, especially among Chinese population. So far, it remains unclear whether the polymorphism of the COMT gene plays a pathophysiological role in carcinogenesis in Chinese population. Therefore, we lay emphasis on Chinese population and performed a meta-analysis to investigate the relationship between the
3004
Val158Met polymorphism in the COMT gene and cancer susceptibility in Chinese population.
Materials and methods Publications selection Literature databases including Embase, PubMed, Chinese National Knowledge Infrastructure (CNKI), Weipu, and Wanfang were searched, and the last search was performed on Sep. 26, 2013. The search terms were as follows: cancer or carcinoma and China or Chinese and COMT or Catechol-Omethyl transferase in combination with polymorphism, mutation, or variant. All languages were included. Inclusion criteria were as follows: (1) publications evaluating the Val158Met polymorphism of the COMT gene and cancer risks in Chinese population; (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). Accordingly, the exclusion criteria were as follows: (1) abstracts, reviews, conference reports, or systematic reviews; (2) family or sibling-based studies; and (3) publications with insufficient data referring to genotype frequency. In case the overlapped publications exist, the study with the largest sample size or with the latest publication date was included. Data extraction 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, source region of sample, and cancer type. Statistical analysis For each study, the accordance of genotype distribution in controls to Hardy–Weinberg equilibrium was examined before data analysis. The strength of the association between the Val158Met polymorphism in the COMT gene and cancer risks in Chinese population was measured by ORs and 95 % CI. The statistical significance of summary OR was determined with Z-test. The risks of cancer were initially estimated by a dominant model (AG+AA vs. GG). Then the variant genotype AA was evaluated by a recessive model (AA vs. AG+ GG) and other genetic models (AA vs. GG, AG vs. GG and A vs. G). Heterogeneity was evaluated by X 2-based Q statistic and was considered statistically significant at a P-value 0.10, a fixed-effect model was used;
Tumor Biol. (2014) 35:3003–3008
otherwise, a random-effect model was used. The significance of the pooled OR was determined by the Z-test, and P
RESEARCH ARTICLE
The Val158Met polymorphism in the COMT gene is associated with increased cancer risks in Chinese population Can Tian & Liping Liu & Xiaohong Yang & Hui Wu & Quchang Ouyang
Received: 15 October 2013 / Accepted: 5 November 2013 / Published online: 5 December 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract The Val158Met polymorphism in the COMT gene may affect the DNA repair pathways and be associated with the risk of cancer in Chinese population. However, the results of previous studies are inconsistent. The objective of this study was to investigate the association between the Val158Met polymorphism in the COMT gene and the risk of cancer for Chinese population by meta-analysis. We searched PubMed, Embase, CNKI, Weipu, and Wanfang databases, and the last search was updated on Sep. 26, 2013. Statistical analysis was performed using the Revman4.2 and Stata10.0 software. A total of 18 case–control studies concerning 5034 case and 6234 controls were included. In the total analysis, the results suggested a significant association between the Val158Met polymorphism in the COMT gene and the cancer risk in Chinese population: OR=1.34, 95 %CI=1.04–1.73, and P = 0.03 for AA vs. AG+GG; OR=1.39, 95 %CI=1.06–1.82, and P =0.02; OR=1.13, 95 %CI=1.01–1.27, and P =0.04. In the subgroup analysis by cancer types, significant association was found in the breast cancer and esophageal squamous cell carcinoma. The current meta-analysis confirmed that the Val158Met polymorphism in the COMT gene may be a risk factor for cancer in Chinese population. In the future, more case–control studies are needed to validate our results. Keywords COMT . Chinese . Cancer . Meta-analysis . Variant
Introduction Cancer burden is increasing largely in China in recent years, as well as around the world [1]. It has been estimated that C. Tian : L. Liu : X. Yang : H. Wu : Q. Ouyang (*) Department of Internal Breast Cancer, Huan Provincial Tumor Hospital, Hunan, China e-mail: [email protected]
90–95 % of cancer cases are attributed to environmental factors, while 5–10 % are due to genetic defects. During the transformation from normal to cancer cells, the genes which regulate cell growth and differentiation are altered. Series of genes have been found to be linked with cancer incidence, and the well-known genes are COMT [2], MYC [3], EGFR [4], TLR [5], and so forth. Among them, the COMT gene is one of the most involved genes. The human COMT gene is located on chromosome 22q11.21. It encodes a protein named catechol-O -methyl transferase (COMT) catalyzing the transferring of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine [6]. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. Due to its crucial role in the metabolism of endogenous substances, the COMT is important in the catechol metabolism processes. Also, plenty of researches have indicated the link between polymorphisms in the COMT gene and cancer susceptibility. Several polymorphisms have been identified, and the widely studied is Val158Met (rs4680). This polymorphism at position 158 results in a valine-to-methionine variation, leading to a decreased activity of catechol-O -methyl transferase which generates catecholamine accumulation. The accumulation of catecholamine can cause DNA oxidative damage which may result in carcinogenesis. Also, catechol-O -methyl transferase can inactivate catechol estrogen, thus contributing to the occurrence and progression of genital system tumors such as breast cancer and endometrial cancer. There have been lots of studies exploring the association between the Val158Met polymorphism and cancer susceptibility of different types of cancer and races, but the results were inconclusive, especially among Chinese population. So far, it remains unclear whether the polymorphism of the COMT gene plays a pathophysiological role in carcinogenesis in Chinese population. Therefore, we lay emphasis on Chinese population and performed a meta-analysis to investigate the relationship between the
3004
Val158Met polymorphism in the COMT gene and cancer susceptibility in Chinese population.
Materials and methods Publications selection Literature databases including Embase, PubMed, Chinese National Knowledge Infrastructure (CNKI), Weipu, and Wanfang were searched, and the last search was performed on Sep. 26, 2013. The search terms were as follows: cancer or carcinoma and China or Chinese and COMT or Catechol-Omethyl transferase in combination with polymorphism, mutation, or variant. All languages were included. Inclusion criteria were as follows: (1) publications evaluating the Val158Met polymorphism of the COMT gene and cancer risks in Chinese population; (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). Accordingly, the exclusion criteria were as follows: (1) abstracts, reviews, conference reports, or systematic reviews; (2) family or sibling-based studies; and (3) publications with insufficient data referring to genotype frequency. In case the overlapped publications exist, the study with the largest sample size or with the latest publication date was included. Data extraction 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, source region of sample, and cancer type. Statistical analysis For each study, the accordance of genotype distribution in controls to Hardy–Weinberg equilibrium was examined before data analysis. The strength of the association between the Val158Met polymorphism in the COMT gene and cancer risks in Chinese population was measured by ORs and 95 % CI. The statistical significance of summary OR was determined with Z-test. The risks of cancer were initially estimated by a dominant model (AG+AA vs. GG). Then the variant genotype AA was evaluated by a recessive model (AA vs. AG+ GG) and other genetic models (AA vs. GG, AG vs. GG and A vs. G). Heterogeneity was evaluated by X 2-based Q statistic and was considered statistically significant at a P-value 0.10, a fixed-effect model was used;
Tumor Biol. (2014) 35:3003–3008
otherwise, a random-effect model was used. The significance of the pooled OR was determined by the Z-test, and P
