Tumor Biol. DOI 10.1007/s13277-014-1652-3
RESEARCH ARTICLE
Association between CD95L polymorphism and cervical cancer risk: evidence from a meta-analysis Jing Zhu & Lei Lu & Xiang Cheng & Rongkai Xie & Zhengqiong Chen & Youfei Li & Guilan Lin & Jianmei Liu & Ying Yang
Received: 22 December 2013 / Accepted: 12 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Several studies have assessed the association of CD95L polymorphism with cervical cancer risk, but the data lack the power to provide compelling evidence. In this study, we aimed to clarify the association through a meta-analysis. A comprehensive search was conducted in PubMed, Embase, and Web of Science. The fixed-effects model was used to calculate odds ratio (OR) with 95 % confidence intervals (CIs). A total of five papers with six case–control studies were derived and finally included in this meta-analysis. The overall estimate did not reveal any significant association between CD95L −844C/T polymorphism and cervical cancer risk. Subgroup analysis in Asian population indicated nonsignificant nevertheless potentially increased risk in CC genotype carriers in comparison with the carriers of CT+TT genotypes (ORCC vs. CT+TT =1.16, 95 % CI=0.99–1.36, P for heterogeneity=0.231). Based on current epidemiological studies, this meta-analysis suggests that CD95L polymorphism may not be a risk factor contributing to cervical cancer development. Keywords CD95L . Cervical cancer . Meta-analysis
Introduction Progression of tumors involves multiple factors, of which the uncontrolled cellular proliferation and suppression of apoptosis Jing Zhu and Lei Lu are co-first authors. J. Zhu : X. Cheng : R. Xie : Z. Chen : Y. Li : G. Lin : J. Liu : Y. Yang (*) Department of Gynaecology and Obstetrics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China e-mail: [email protected] L. Lu Department of Surgical Oncology, Jindu Hospital, No. 34, Yanggongjing, Nanjing 210002, Jiangsu Province, China
are two known major causes. Apoptosis is a genetically-mediated process of programmed cell death with a significant role in the regulation of cell growth, homeostasis and normal functioning of adult multicellular organisms, and elimination of unwelcomed or potentially dangerous cells [1, 2]. Dysfunction and defects in apoptosis have been implicated in tumorigenesis [3, 4]. A large array of genes performs as participants in apoptotic process and their mutations may promote malignancy formation [5]. CD95 is a cell surface receptor and expresses in various types of cancer cell lines. Germline and somatic mutations of the CD95 gene in humans contribute to an increased risk of both lymphoid and solid tumors [6, 7]. Interaction between CD95 and CD95L (also known as TNFSF6, located on chromosome 1q23), which is the natural ligand to CD95 and a member of the tumor necrosis factor superfamily, stimulates death signal cascade and induces subsequent apoptotic cell death [8]. Transformed cells can be protected from being eliminated if expression of CD95 decreases and the ability of tumor cells in counterattacking immune system by killing CD95-sensitive lymphocytes could be strengthened when CD95L overexpresses. Upregulation of CD95L expression has been broadly researched in cancer community and reported to facilitate cancer progression in a great number of investigations [9–14]. A proposal has been put forward that genetic polymorphisms may affect cancer predisposition through modulation of host genome stability [15]. In the promoter region of CD95L gene, there is a T to C transition at position −844 in a binding motif for a transcription factor CAAT/enhancer binding protein β [16]. The C allele of −844C/T polymorphism is connected with a significantly higher basal expression of CD95L relative to the T allele [16]. The T allele, meanwhile, has been indicated to confer protective effects on the development of smoking-related cancers rather than cervical cancer in Asian population [17]. While −844C/T polymorphism has been highly concerned in the past few years by investigators who want to identify the
Tumor Biol.
association between −844C/T polymorphism and cervical cancer risk, the molecular etiology of cervical cancer remains evasive yet, because evidence from the independent studies regarding the association is relatively powerless. With the objective to provide strong evidence for the connection of −844C/T polymorphism and cervical cancer risk, we performed this meta-analysis on the basis of all available data.
Materials and methods Literature search and inclusion criteria Using the keywords “cervical cancer” in combination with “CD95L”, “polymorphisms”, or “polymorphism”; “genotypes” or “variants”; and “−844T/C” or “rs763110”, we performed a comprehensive bibliographic search in medicinespecific databases including PubMed, Embase, and Web of Science for all papers matching the search words (the last update was on March 21, 2013). The full-text studies assessed for eligibility were manually reviewed to identify additional data that could be included in this meta-analysis. Selection for eligible studies was based on: (1) a case– control study evaluating cervical cancer risk in relation to −844C/T polymorphism and (2) having original genotype data to estimate an odds ratio (OR) with 95 % confidence interval (CI). The studies disobeying these criteria were not considered and excluded from this meta-analysis. Data extraction Data were extracted in duplicate by two independent authors. For each of the included studies, the following information was gathered: first author’s name, publication journal and year, study country, ethnic origin of subjects in each study, total numbers of genotyped cases and controls, source of controls, and genotyping methods used in determining CD95L polymorphism. When more than one ethnicity was reported in an individually published article with available genetic information, we treated them as independent studies. Disagreements were compromised by discussion among all authors. Statistical analysis A meta-analysis was performed to evaluate the risk of cervical cancer [OR with 95%CI] in connection with −844C/T polymorphism among all subjects and in the subgroup of Asian population. Forest plots were used to illustrate the results of included studies. The significance of OR was determined by the Z test, and P value T), contributes to cancer susceptibility: evidence from 19 case–control studies. Eur J Hum Genet. 2009;17(10):1294–303. 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med. 2002;21(11):1539–58. 19. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719– 48. 20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. 21. Egger M et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. 22. Lai HC et al. Genetic polymorphisms of CD95 and CD95L (CD95/ CD95L) genes in cervical carcinogenesis: an analysis of haplotype and gene-gene interaction. Gynecol Oncol. 2005;99(1):113–8. 23. Ivansson EL et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or CD95 ligand, increase risk of cervical cancer. Int J Cancer. 2007;121(11):2451–7. 24. Kang S et al. CD95–1377 G/A polymorphism and the risk of lymph node metastasis in cervical cancer. Cancer Genet Cytogenet. 2008;180(1):1–5. 25. Chatterjee K et al. CD95 and CD95L gene polymorphisms are not associated with cervical cancer but differ among Black and mixedancestry South Africans. BMC Res Notes. 2009;2:238. 26. Li H et al. Association between CD95/CD95 L genes promoter polymorphisms and pathogenic risk of cervical cancer. Zhonghua Zhong Liu Za Zhi. 2009;31(1):38–41. 27. Dockrell DH. Apoptotic cell death in the pathogenesis of infectious diseases. J Infect. 2001;42(4):227–34. 28. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21(3): 485–95. 29. Zhang J, Xu X, Liu Y. Activation-induced cell death in T cells and autoimmunity. Cell Mol Immunol. 2004;1(3):186–92. 30. Bennett MW et al. The CD95 counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with CD95 ligand expression by human esophageal carcinoma. J Immunol. 1998;160(11):5669–75. 31. Gutierrez LS et al. The CD95/CD95-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res Treat. 1999;54(3):245–53. 32. Wang W et al. Polymorphisms of the CD95 and CD95L genes and risk of breast cancer. Oncol Lett. 2012;3(3):625–8. 33. Yang M et al. Functional variants in cell death pathway genes and risk of pancreatic cancer. Clin Cancer Res. 2008;14(10):3230–6.
RESEARCH ARTICLE
Association between CD95L polymorphism and cervical cancer risk: evidence from a meta-analysis Jing Zhu & Lei Lu & Xiang Cheng & Rongkai Xie & Zhengqiong Chen & Youfei Li & Guilan Lin & Jianmei Liu & Ying Yang
Received: 22 December 2013 / Accepted: 12 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Several studies have assessed the association of CD95L polymorphism with cervical cancer risk, but the data lack the power to provide compelling evidence. In this study, we aimed to clarify the association through a meta-analysis. A comprehensive search was conducted in PubMed, Embase, and Web of Science. The fixed-effects model was used to calculate odds ratio (OR) with 95 % confidence intervals (CIs). A total of five papers with six case–control studies were derived and finally included in this meta-analysis. The overall estimate did not reveal any significant association between CD95L −844C/T polymorphism and cervical cancer risk. Subgroup analysis in Asian population indicated nonsignificant nevertheless potentially increased risk in CC genotype carriers in comparison with the carriers of CT+TT genotypes (ORCC vs. CT+TT =1.16, 95 % CI=0.99–1.36, P for heterogeneity=0.231). Based on current epidemiological studies, this meta-analysis suggests that CD95L polymorphism may not be a risk factor contributing to cervical cancer development. Keywords CD95L . Cervical cancer . Meta-analysis
Introduction Progression of tumors involves multiple factors, of which the uncontrolled cellular proliferation and suppression of apoptosis Jing Zhu and Lei Lu are co-first authors. J. Zhu : X. Cheng : R. Xie : Z. Chen : Y. Li : G. Lin : J. Liu : Y. Yang (*) Department of Gynaecology and Obstetrics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China e-mail: [email protected] L. Lu Department of Surgical Oncology, Jindu Hospital, No. 34, Yanggongjing, Nanjing 210002, Jiangsu Province, China
are two known major causes. Apoptosis is a genetically-mediated process of programmed cell death with a significant role in the regulation of cell growth, homeostasis and normal functioning of adult multicellular organisms, and elimination of unwelcomed or potentially dangerous cells [1, 2]. Dysfunction and defects in apoptosis have been implicated in tumorigenesis [3, 4]. A large array of genes performs as participants in apoptotic process and their mutations may promote malignancy formation [5]. CD95 is a cell surface receptor and expresses in various types of cancer cell lines. Germline and somatic mutations of the CD95 gene in humans contribute to an increased risk of both lymphoid and solid tumors [6, 7]. Interaction between CD95 and CD95L (also known as TNFSF6, located on chromosome 1q23), which is the natural ligand to CD95 and a member of the tumor necrosis factor superfamily, stimulates death signal cascade and induces subsequent apoptotic cell death [8]. Transformed cells can be protected from being eliminated if expression of CD95 decreases and the ability of tumor cells in counterattacking immune system by killing CD95-sensitive lymphocytes could be strengthened when CD95L overexpresses. Upregulation of CD95L expression has been broadly researched in cancer community and reported to facilitate cancer progression in a great number of investigations [9–14]. A proposal has been put forward that genetic polymorphisms may affect cancer predisposition through modulation of host genome stability [15]. In the promoter region of CD95L gene, there is a T to C transition at position −844 in a binding motif for a transcription factor CAAT/enhancer binding protein β [16]. The C allele of −844C/T polymorphism is connected with a significantly higher basal expression of CD95L relative to the T allele [16]. The T allele, meanwhile, has been indicated to confer protective effects on the development of smoking-related cancers rather than cervical cancer in Asian population [17]. While −844C/T polymorphism has been highly concerned in the past few years by investigators who want to identify the
Tumor Biol.
association between −844C/T polymorphism and cervical cancer risk, the molecular etiology of cervical cancer remains evasive yet, because evidence from the independent studies regarding the association is relatively powerless. With the objective to provide strong evidence for the connection of −844C/T polymorphism and cervical cancer risk, we performed this meta-analysis on the basis of all available data.
Materials and methods Literature search and inclusion criteria Using the keywords “cervical cancer” in combination with “CD95L”, “polymorphisms”, or “polymorphism”; “genotypes” or “variants”; and “−844T/C” or “rs763110”, we performed a comprehensive bibliographic search in medicinespecific databases including PubMed, Embase, and Web of Science for all papers matching the search words (the last update was on March 21, 2013). The full-text studies assessed for eligibility were manually reviewed to identify additional data that could be included in this meta-analysis. Selection for eligible studies was based on: (1) a case– control study evaluating cervical cancer risk in relation to −844C/T polymorphism and (2) having original genotype data to estimate an odds ratio (OR) with 95 % confidence interval (CI). The studies disobeying these criteria were not considered and excluded from this meta-analysis. Data extraction Data were extracted in duplicate by two independent authors. For each of the included studies, the following information was gathered: first author’s name, publication journal and year, study country, ethnic origin of subjects in each study, total numbers of genotyped cases and controls, source of controls, and genotyping methods used in determining CD95L polymorphism. When more than one ethnicity was reported in an individually published article with available genetic information, we treated them as independent studies. Disagreements were compromised by discussion among all authors. Statistical analysis A meta-analysis was performed to evaluate the risk of cervical cancer [OR with 95%CI] in connection with −844C/T polymorphism among all subjects and in the subgroup of Asian population. Forest plots were used to illustrate the results of included studies. The significance of OR was determined by the Z test, and P value T), contributes to cancer susceptibility: evidence from 19 case–control studies. Eur J Hum Genet. 2009;17(10):1294–303. 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med. 2002;21(11):1539–58. 19. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719– 48. 20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. 21. Egger M et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. 22. Lai HC et al. Genetic polymorphisms of CD95 and CD95L (CD95/ CD95L) genes in cervical carcinogenesis: an analysis of haplotype and gene-gene interaction. Gynecol Oncol. 2005;99(1):113–8. 23. Ivansson EL et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or CD95 ligand, increase risk of cervical cancer. Int J Cancer. 2007;121(11):2451–7. 24. Kang S et al. CD95–1377 G/A polymorphism and the risk of lymph node metastasis in cervical cancer. Cancer Genet Cytogenet. 2008;180(1):1–5. 25. Chatterjee K et al. CD95 and CD95L gene polymorphisms are not associated with cervical cancer but differ among Black and mixedancestry South Africans. BMC Res Notes. 2009;2:238. 26. Li H et al. Association between CD95/CD95 L genes promoter polymorphisms and pathogenic risk of cervical cancer. Zhonghua Zhong Liu Za Zhi. 2009;31(1):38–41. 27. Dockrell DH. Apoptotic cell death in the pathogenesis of infectious diseases. J Infect. 2001;42(4):227–34. 28. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21(3): 485–95. 29. Zhang J, Xu X, Liu Y. Activation-induced cell death in T cells and autoimmunity. Cell Mol Immunol. 2004;1(3):186–92. 30. Bennett MW et al. The CD95 counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with CD95 ligand expression by human esophageal carcinoma. J Immunol. 1998;160(11):5669–75. 31. Gutierrez LS et al. The CD95/CD95-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res Treat. 1999;54(3):245–53. 32. Wang W et al. Polymorphisms of the CD95 and CD95L genes and risk of breast cancer. Oncol Lett. 2012;3(3):625–8. 33. Yang M et al. Functional variants in cell death pathway genes and risk of pancreatic cancer. Clin Cancer Res. 2008;14(10):3230–6.
