Tumor Biol. (2014) 35:5763–5769 DOI 10.1007/s13277-014-1765-8
RESEARCH ARTICLE
Increased lung cancer risk associated with the TERT rs2736100 polymorphism: an updated meta-analysis Jihua Yang & Shunchang Jiao
Received: 10 November 2013 / Accepted: 17 February 2014 / Published online: 4 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The rs2736100 polymorphism in the telomerase reverse transcriptase (TERT) gene has been implicated in lung cancer risk in multiple populations, but the existing evidence lacks statistical power to draw a convincing conclusion. Therefore, the present study was devised to derive a more precise estimation of the association between rs2736100 and lung cancer risk. The PubMed, Embase, and Web of Science databases were comprehensively searched for papers concerning lung cancer risk in relation to rs2736100. Pooled odds ratios (ORs) and the 95 % confidence intervals (CIs) were appropriately calculated using the fixed or random effects model. Meta-analysis of 20 independent studies involving 39,715 cancer cases and 61,462 control subjects showed statistical evidence for an association between rs2736100 and increased risk of lung cancer. Subgroup analysis by ethnicity demonstrated a significant association among both Asian and Caucasian populations. We additionally found an increased risk of non-small cell lung cancer and lung adenocarcinoma strongly associated with rs2736100. These data provide further evidence supporting a role for genetic susceptibility of TERT rs2736100 in the development of lung cancer. Keywords Telomerase reverse transcriptase . Lung cancer . Meta-analysis
Introduction Lung cancer is one of the most aggressive cancers and ranks the top of the causes leading to cancer-related deaths, J. Yang : S. Jiao (*) Department of Oncology, Chinese PLA General Hospital, 28# Fuxing Road, Haidian District, Beijing 100853, People’s Republic of China e-mail: [email protected] J. Yang Navy General Hospital, Beijing 100037, People’s Republic of China
accounting for 18.2 % (1.38 million) of the total mortality [1]. Recent years have witnessed a serious trend in China, with a total estimated incidence and deaths of 2,596,112 new cases and 1,798,147 deaths each year [2]. Although smoking has been universally recognized as a carcinogen for lung cancer, the occurrence is quite distinct among smokers [3, 4]. Evidence from epidemiological studies demonstrates a familial risk [5], such as TP53 and RB which are directly associated with an increased risk of lung cancer [6, 7]. Lung cancer is induced by multiple complex factors rather than a dominant effect by a specific gene or environmental exposure [3]. Several genome-wide association studies (GWASs) have associated polymorphic variation at 5p15.33 with the carcinogenesis of lung cancer in the subjects of Caucasian ancestry [8, 9]. Chromosome 5p15 contains two genes, the cleft lip and palate transmembrane 1-like gene (CLPTM1L) and the telomerase reverse transcriptase gene (TERT), where the sequence variants are involved in the risk of many types of cancer [10]. To replicate the findings of former investigations, many GWASs were subsequently carried out among the participants belonging to Asian ancestry and found that the genetic variation of rs2736100 in the TERT gene is strongly linked with lung cancer [11–13]. Since a genetic association study reported for the first time that the rs2736100C allele in TERT gene was associated with a significantly increased risk of non-small cell lung cancer in Chinese population [14], an increasing number of replication studies have paid special attention to the association between rs2736100 and lung cancer which consists of several common subtypes, including non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma. Due to the substantial disparity in sample size in each of the published studies, they failed to well define the genetic susceptibility of rs2736100 in the development of lung cancer [15–17]. Therefore, we performed a meta-analysis using all published data to date to provide statistical evidence for an association between rs2736100 and lung cancer risk.
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Material and methods Identification of eligible studies A comprehensive search was undertaken using the PubMed, Embase, and Web of Science databases for papers concerning lung cancer risk in relation to rs2736100 in the TERT gene. The key words telomerase reverse transcriptase, TERT, rs2736100, polymorphism, polymorphisms, lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma were searched separately or collectively. The last search was updated in June 2013. A manual search of all citations from the original studies was conducted to identify additional relevant articles. Inclusion and exclusion criteria Criteria for study inclusion were as follows: (a) an independent case-control study based on human subjects, (b) examining the association between rs2736100 and lung cancer risk and presenting genotype data that were sufficient enough to calculate an odds ratio (OR) and the corresponding 95 % confidence interval (CI), (c) released in full text before June 2013, and (d) genotype distribution in the control subjects in accordance with Hardy-Weinberg equilibrium (HWE). A study was excluded if (a) it used a case-only design, (b) the study was updated by subsequent larger publications, and (c) it was published as an abstract, summary, comment letter, review article, and editorial. When the same case series was used in multiple articles, the latest or the largest one was finally selected. Data extraction Data extraction was conducted independently by two investigators using a standardized form designed on the basis of the inclusion and exclusion criteria. Characteristics recorded from each study included name of the first author, publication year, study country, ethnicity, genotyping method, and the number of genotyped cases and controls for lung cancer, non-small cell lung cancer, lung adenocarcinoma, as well as squamous cell carcinoma. Statistical methods The association between rs2736100 and lung cancer risk was assessed by calculating crude ORs and 95 % CIs under an assumption of several genetic models, including GG vs. TT, GG+GT vs. TT, GG vs. GT+TT, G vs. T, and GT vs. TT. Stratified analyses by ethnicity and subtype of lung cancer were additionally performed. Between-study heterogeneity was measured by using the chi-square-based Q test. The significant threshold was set at
Tumor Biol. (2014) 35:5763–5769
P
RESEARCH ARTICLE
Increased lung cancer risk associated with the TERT rs2736100 polymorphism: an updated meta-analysis Jihua Yang & Shunchang Jiao
Received: 10 November 2013 / Accepted: 17 February 2014 / Published online: 4 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The rs2736100 polymorphism in the telomerase reverse transcriptase (TERT) gene has been implicated in lung cancer risk in multiple populations, but the existing evidence lacks statistical power to draw a convincing conclusion. Therefore, the present study was devised to derive a more precise estimation of the association between rs2736100 and lung cancer risk. The PubMed, Embase, and Web of Science databases were comprehensively searched for papers concerning lung cancer risk in relation to rs2736100. Pooled odds ratios (ORs) and the 95 % confidence intervals (CIs) were appropriately calculated using the fixed or random effects model. Meta-analysis of 20 independent studies involving 39,715 cancer cases and 61,462 control subjects showed statistical evidence for an association between rs2736100 and increased risk of lung cancer. Subgroup analysis by ethnicity demonstrated a significant association among both Asian and Caucasian populations. We additionally found an increased risk of non-small cell lung cancer and lung adenocarcinoma strongly associated with rs2736100. These data provide further evidence supporting a role for genetic susceptibility of TERT rs2736100 in the development of lung cancer. Keywords Telomerase reverse transcriptase . Lung cancer . Meta-analysis
Introduction Lung cancer is one of the most aggressive cancers and ranks the top of the causes leading to cancer-related deaths, J. Yang : S. Jiao (*) Department of Oncology, Chinese PLA General Hospital, 28# Fuxing Road, Haidian District, Beijing 100853, People’s Republic of China e-mail: [email protected] J. Yang Navy General Hospital, Beijing 100037, People’s Republic of China
accounting for 18.2 % (1.38 million) of the total mortality [1]. Recent years have witnessed a serious trend in China, with a total estimated incidence and deaths of 2,596,112 new cases and 1,798,147 deaths each year [2]. Although smoking has been universally recognized as a carcinogen for lung cancer, the occurrence is quite distinct among smokers [3, 4]. Evidence from epidemiological studies demonstrates a familial risk [5], such as TP53 and RB which are directly associated with an increased risk of lung cancer [6, 7]. Lung cancer is induced by multiple complex factors rather than a dominant effect by a specific gene or environmental exposure [3]. Several genome-wide association studies (GWASs) have associated polymorphic variation at 5p15.33 with the carcinogenesis of lung cancer in the subjects of Caucasian ancestry [8, 9]. Chromosome 5p15 contains two genes, the cleft lip and palate transmembrane 1-like gene (CLPTM1L) and the telomerase reverse transcriptase gene (TERT), where the sequence variants are involved in the risk of many types of cancer [10]. To replicate the findings of former investigations, many GWASs were subsequently carried out among the participants belonging to Asian ancestry and found that the genetic variation of rs2736100 in the TERT gene is strongly linked with lung cancer [11–13]. Since a genetic association study reported for the first time that the rs2736100C allele in TERT gene was associated with a significantly increased risk of non-small cell lung cancer in Chinese population [14], an increasing number of replication studies have paid special attention to the association between rs2736100 and lung cancer which consists of several common subtypes, including non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma. Due to the substantial disparity in sample size in each of the published studies, they failed to well define the genetic susceptibility of rs2736100 in the development of lung cancer [15–17]. Therefore, we performed a meta-analysis using all published data to date to provide statistical evidence for an association between rs2736100 and lung cancer risk.
5764
Material and methods Identification of eligible studies A comprehensive search was undertaken using the PubMed, Embase, and Web of Science databases for papers concerning lung cancer risk in relation to rs2736100 in the TERT gene. The key words telomerase reverse transcriptase, TERT, rs2736100, polymorphism, polymorphisms, lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma were searched separately or collectively. The last search was updated in June 2013. A manual search of all citations from the original studies was conducted to identify additional relevant articles. Inclusion and exclusion criteria Criteria for study inclusion were as follows: (a) an independent case-control study based on human subjects, (b) examining the association between rs2736100 and lung cancer risk and presenting genotype data that were sufficient enough to calculate an odds ratio (OR) and the corresponding 95 % confidence interval (CI), (c) released in full text before June 2013, and (d) genotype distribution in the control subjects in accordance with Hardy-Weinberg equilibrium (HWE). A study was excluded if (a) it used a case-only design, (b) the study was updated by subsequent larger publications, and (c) it was published as an abstract, summary, comment letter, review article, and editorial. When the same case series was used in multiple articles, the latest or the largest one was finally selected. Data extraction Data extraction was conducted independently by two investigators using a standardized form designed on the basis of the inclusion and exclusion criteria. Characteristics recorded from each study included name of the first author, publication year, study country, ethnicity, genotyping method, and the number of genotyped cases and controls for lung cancer, non-small cell lung cancer, lung adenocarcinoma, as well as squamous cell carcinoma. Statistical methods The association between rs2736100 and lung cancer risk was assessed by calculating crude ORs and 95 % CIs under an assumption of several genetic models, including GG vs. TT, GG+GT vs. TT, GG vs. GT+TT, G vs. T, and GT vs. TT. Stratified analyses by ethnicity and subtype of lung cancer were additionally performed. Between-study heterogeneity was measured by using the chi-square-based Q test. The significant threshold was set at
Tumor Biol. (2014) 35:5763–5769
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