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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 5  |  Page : 1202-1208

Association between the rs2736100 polymorphisms of telomerase reverse transcriptase gene and digestive cancers: A meta-analysis


1 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P.R. China
2 Department of Nursing, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P.R. China
3 Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P.R. China

Date of Submission10-Jul-2021
Date of Acceptance21-Sep-2021
Date of Web Publication27-Nov-2021

Correspondence Address:
Xiaofei Lei
Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1102_21

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 > Abstract 


Aim of Study: The conclusions on the association between the rs2736100 polymorphisms of telomerase reverse transcriptase (TERT) gene polymorphism and digestive cancers risk are still debated. This meta-analysis was conducted to update the association between the TERT rs2736100 polymorphisms and the risk of digestive cancers.
Materials and Methods: The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using the meta-analysis method.
Results: Eight case-control studies were included in this meta-analysis for associating TERT rs2736100 gene polymorphism and digestive cancer susceptibility. Pooled odds ratio with 95% confidence interval was calculated using a fixed or random-effects model. Overall, no evidence has shown that the TERT rs2736100 polymorphism was associated with the susceptibility to digestive cancers. Besides, stratified analysis with ethnicity also indicated no significant association between TRET rs2736100 and the risk of digestive cancers under all genetic models in both Asian and Caucasian populations were observed.
Conclusion: According to the meta-analysis, TERT rs2736100 polymorphism might be unrelated to digestive cancer susceptibility. Evidence with adequate sample size is still needed.

Keywords: Digestive cancers, meta-analysis, polymorphism, rs2736100, telomerase reverse transcriptase


How to cite this article:
Song H, Han M, Li K, Zhao Y, Xu C, Lei X. Association between the rs2736100 polymorphisms of telomerase reverse transcriptase gene and digestive cancers: A meta-analysis. J Can Res Ther 2021;17:1202-8

How to cite this URL:
Song H, Han M, Li K, Zhao Y, Xu C, Lei X. Association between the rs2736100 polymorphisms of telomerase reverse transcriptase gene and digestive cancers: A meta-analysis. J Can Res Ther [serial online] 2021 [cited 2022 May 26];17:1202-8. Available from: https://www.cancerjournal.net/text.asp?2021/17/5/1202/331302




 > Introduction Top


Digestive cancers or digestive malignancy are composed of the cancer of the digestive tract and accessory organs, including esophageal, gastric, colon, and rectal and hepatic cancer. With the continuous change in lifestyle and improvement in living standards, digestive cancers have become crime culprits of cancer mortality in both economically developed and developing countries. The intricate interactions between inherited and environmental factors cause a set of complex processes, including carcinogenesis and progression of digestive cancer.

Telomerase reverse transcriptase (TERT) has been implicated in carcinogenesis as an attractive candidate gene. TERT encodes the catalytic subunit of telomerase, which has telomere ends. Telomeres are the protein-bound DNA repeat structures at the ends of chromosomes.[1],[2] Accumulating evidence has shown that TERT polymorphisms, including rs401681 and rs10069690 have been considered to play an extensive role in the carcinogenesis of digestive cancers.[3],[4] Recently, eight reports have explored the relationship between TERT rs2736100 polymorphisms and the susceptibility of digestive cancers in different populations. However, these results are still unclear, even conflicting, thus far from satisfactory. To accomplish an analysis with comprehensive evidence, here we did a meta-analysis on these eight eligible case–control studies to evaluate the effect of TERT rs2736100 polymorphisms on digestive cancer susceptibility.


 > Materials and Methods Top


Search strategy

The following key items were used: “Telomerase reverse transcriptase” or “tert,” “TERT,” “htert,” “rs2736100,” “polymorphism,” “mutation,” “variant,” “risk,” “susceptibility,” and “cancer,” “tumor,” “carcinoma,” “neoplasms.” EMBASE, OVID, Medline, China National Knowledge Internet and Wanfang were searched, and all relevant studies on the connection between TERT polymorphism and digestive cancer susceptibility were found (dating from January 2000–January 2021). The search was restricted to humans. Additional studies were identified by hand search of references of original or review articles on this topic. If data or data subsets were published in more than one article, only the publication with the largest sample size was included. The reference sections of these selected papers were also screened manually to find additional data.

Inclusion criteria and exclusion criteria

Studies were included if they met the following criteria: (1) studies that evaluated the association between TERT rs2736100 polymorphisms and esophageal, gastric, colon, and rectal cancer, hepatic and pancreatic cancer, (2) In a case − control study design, (3) had detailed genotype frequency of cases and controls or could be calculated from the article text. whereas significant exclusion criteria were: (1) case-only study, case reports, and review articles, (2) studies without the raw data of genotypes of TERT rs2736100, and (3) studies that investigated TERT rs2736100 variants as marks for response to therapy.

Data extraction and quality assessment

The two investigators (Hongxia Song and Mei Han) independently extracted data and reached a consensus on all items. If the two investigators generated different results, they would recheck the data and discuss reaching an agreement. If they could not agree, an expert (Xiaofei Lei) was invited to the discussion. Data extracted from the selected articles included the first author's name, year of publication, country of origin, ethnicity, number of cases and controls, and minor allele frequency in controls. Different ethnicities were categorized as Asian and Caucasian.

Statistical analysis

A meta-analysis was conducted using the Cochrane Collaboration RevMan 5.3 (Copenhagen, 2008) and STATA package version 13.0 (Stata Corporation, College Station, Texas). The risk of digestive cancers associated with polymorphisms of the TERT rs2736100 gene was estimated for each study using odd's ratio (OR) and 95% confidence interval (95%CI). A χ2-test-based Q statistic test was conducted to analyze the between-study heterogeneity. The effect of heterogeneity was the first quantified using the I2 test. When I2 > 50% indicates heterogeneity across studies, the random-effects model was used or else the fixed-effects model was used.[5] Before the effect estimation of TERT rs2736100 polymorphisms in digestive cancers, it was tested if genotype frequencies of the controls were in HWE using the χ2 test. The risks of the heterozygote and variant homozygote compared to the wild-type homozygote, respectively, were first estimated. was then the risks of the combined variant homozygote and heterozygote vs. the wild-type homozygote and the variant homozygote versus the combined heterozygote and wild-type homozygote, assuming the dominant and recessive effects of the variant allele, respectively, were evaluated. Stratification analyses on ethnicity were performed. Analysis of sensitivity was conducted to assess the stability of the results. Finally, potential publication bias was investigated using Begg's funnel plot and Egger's regression test. P < 0.05 was regarded as statistically significant.


 > Results Top


Study characteristics

Ninety-eight records in total were observed according to the keywords. Among them, eight studies were reserved on the effect of the TERT rs2736100 variant on the susceptibility of digestive cancers and 90 studies were excluded according to the inclusion criteria [Figure 1]. As shown in [Table 1], eight case–control studies with 22080 cancer cases and 25430 controls were concerned with rs2736100 polymorphism. Among them, one was esophageal cancer, three were gastric cancer, three were colorectal cancer, and one was pancreatic cancer. In the ethnicity subgroup, three studies focused on Asians[6],[7],[8] and five on Caucasians.[9],[10],[11],[12],[13] The genotype distribution in the controls was consistent with the Hardy–Weinberg equilibrium in all studies except two studies on rs2736100,[9],[12] of which the PHWE was not available.
Figure 1: Flow chart showing study selection procedure

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Table 1: Characteristics of studies included in the meta-analysis

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Association between telomerase reverse transcriptase polymorphisms and digestive cancer

In general, no significant differences were found in TERT rs2736100 genotype distribution between digestive tumor and the control (dominant model [OR = 1.00, 95% CI: {0.88–1.14}, P = 0.02]; TG vs. TT [OR = 1.02, 95% CI: {0.90–1.14}, P = 0.08]; GG vs. TT [OR = 1.26, 95% CI: {0.94–1.70}, P < 0.00001]; recessive model [OR = 1.13, 95% CI: {0.90–1.41}, P < 0.00001]) [Figure 2]. In addition, no correlation was obtained between rs2736100 gene variant and digestive cancer susceptibility in the subgroup of ethnicity [Figure 3].
Figure 2: Meta-analysis of the association between TERT rs2736100 polymorphism and susceptibility to digestive cancer. (a) dominant model, (b) TG versus TT, (c) GG versus TT, (d) recessive model

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Figure 3: Subgroup analysis of telomerase reverse transcriptase rs2736100 polymorphism by ethnicity. (a) dominant model, (b) TG versus TT, (c) GG versus TT, (d) recessive model

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Sensitivity analyses were done to illustrate the effect of inclusion criteria modification on the final results. For rs2736100 polymorphism, meta-analysis and eliminating studies not in HWE were repeated to evaluate the influence of these studies on the pooled OR. The pooled-odd ratio remained unchanged [Table 2], guaranteeing the statistical robustness of our results. For other polymorphisms, when omitted any single study, the significance of pooled OR in all individual analyses was not seriously influenced.
Table 2: Stratified analyses of the telomerase reverse transcriptase polymorphism and digestive cancer risk

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Test of heterogeneity

A significant heterogeneity was found in overall comparisons (dominant model: P = 0.02; heterozygote model TG vs. TT P = 0.08; homozygote model GG vs. TT P < 0.00001; recessive model GG vs. TT + TG: P < 0.00001). In the ethnicity subgroup, results were similar in the Caucasian population. However, in the Asian population, clear heterogeneity was obtained in the dominant model comparison (GG + TG vs. TT: P = 0.007), homozygote comparison (GG vs. TT: P = 0.0001), and recessive model (GG vs. TT + TG: P = 0.0001), but not heterozygote model comparison (TG vs. TT: P = 0.12). In the Caucasian population, heterogeneity was obtained in both dominant model comparison (GG + TG vs. TT: P = 0.04) and homozygote comparison (GG vs. TT: P = 0.03), but not recessive model comparison (GG vs. TT + TG: P = 0.19) and heterozygote model comparison (TG vs. TT: P = 0.14).

Publication bias

Potential publication bias in the available literature was determined using Begg's funnel plot and Egger's test. We conducted the publication bias of the meta-analysis on the relationship between TERT polymorphism and digestive cancer susceptibility was conducted. As shown, the shape of the funnel plots did not show asymmetry. Egger's test also revealed no statistical significance on the evaluation of publication bias (Pdominant model = 0.138, Pheterozygote comparison = 0.120, Phomozygote comparison = 0.151, Precessive model = 0.168) [Figure 4].
Figure 4: Begg's funnel plot for publication bias. Each point represents a separate study for the indicated association: Log (OR), the natural logarithm of OR. Horizontal line, mean effect size. (a) dominant model, (b) TG versus TT, (c) GG vs. TT, (d) recessive model. OR = Odds ratio

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 > Discussion Top


TERT has been considered to play a vital role in the carcinogenesis pathway. As a promising candidate for increasing susceptibility to common cancers,[14] TERT possesses the special ability to form telomerase. The telomerase activity can be strongly affected and the mutations can generate severe clinical phenotypes, including a significant increase in cancer frequency in the coding regions of TERT. Notably, TERT rs2736100 polymorphism motivates the growing risk of colorectal cancer, gastric cancer, and other cancers.[15] Although the in-depth mechanism remains unclear, various polymorphisms in TERT have been reported in which the results are still controversial.[15]

The rs2736100 polymorphism in TERT has been demonstrated to be associated with several diseases, including thyroid carcinoma,[16] myeloproliferative neoplasms,[17] and lung cancer.[18] By conducting eight case–control studies with 22,080 cancer cases and 25,430 controls, the first meta-analysis was made; comprehensively analyzing the association between rs2736100 polymorphism and digestive cancer. In this study, no significant association was observed between TERT rs2736100 and the risk of digestive cancers under the genetic model in overall comparisons. To eliminate the heterogeneity of ethnicity, eight studies were divided into two subgroups (Asian and Caucasian). As a result, subgroup analysis also revealed no significant association between TERT rs2736100 and digestive cancer risk under four genetic models in Asian and Caucasian populations.

This result was supposed as ascribed to the following reasons: (1) the rs2736100 polymorphism and digestive cancer are unrelated; (2) interactions with other genetic variants are possible for digestive cancer; (3) gene-environmental factors may contribute to the results; and (4) differences in ethnic background, age, gender, and behavior across the populations. It was reported that the deviation from HWE was probably because of the existence of genotyping errors, selection bias, and population stratification in the controls.[5] Thus, individual reports were excluded outside HWE to analyze the results' stability. As can be seen, no significant association was found between TERT polymorphism and digestive cancer risk with the exclusion of two studies,[9],[12] which further demonstrated the results.

The current meta-analysis possesses many limitations: First, the consideration of articles only published in English might cause potential language bias in the literature search. Second, selected studies were not enough in number for a comprehensive analysis, and some small-sized samples might be statistically insufficient for the identification of significant differences in outcome morbidity. Third, the unadjusted estimates in the analysis may result in some confounding bias. Despite these potential limitations, this meta-analysis exhibited superiority with several promising advantages. First, we pooled notable cases and controls from different studies, which dramatically strengthened the statistical power. Second, all the studies listed in this meta-analysis conformed to our selection criteria, and the quality of the selected case-control studies could satisfy our choice.


 > conclusion Top


In summary, we did a meta-analysis to illustrate that the rs2736100 polymorphism of TERT is not associated with digestive cancer risk either in Asian or in Caucasian descent. However, rationally designed studies with wide and adequate samples are still required to confirm our findings. In addition, random trials using standardized unbiased methods and well-matched controls are also required. Furthermore, complicated interactions between gene–gene and gene-environment should be carefully conducted in future.

Acknowledgments

This work was supported by Projects of Medical and Health Technology Development Program in Shandong Province (grant number 2016WS0456) and Shandong Provincial Integrated Traditional Chinese and Western Medicine Special Disease Prevention Project (grant number SDPR-2020-0230007).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol 2020;21:384-97.  Back to cited text no. 1
    
2.
Chen X, Tang WJ, Shi JB, Liu MM, Liu XH. Therapeutic strategies for targeting telomerase in cancer. Med Res Rev 2020;40:532-85.  Back to cited text no. 2
    
3.
Yuan X, Dai M, Xu D. TERT promoter mutations and GABP transcription factors in carcinogenesis: More foes than friends. Cancer Lett 2020;493:1-9.  Back to cited text no. 3
    
4.
Guterres AN, Villanueva J. Targeting telomerase for cancer therapy. Oncogene 2020;39:5811-24.  Back to cited text no. 4
    
5.
Wang H, Chen Y, Lin Y, Abesig J, Wu IX, Tam W. The methodological quality of individual participant data meta-analysis on intervention effects: Systematic review. BMJ 2021;373:n736.  Back to cited text no. 5
    
6.
Zhou L, Fu G, Wei J, Shi J, Pan W, Ren Y, et al. The identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci. Oncotarget 2016;7:5495-506.  Back to cited text no. 6
    
7.
Du J, Zhu X, Xie C, Dai N, Gu Y, Zhu M, et al. Telomere length, genetic variants and gastric cancer risk in a Chinese population. Carcinogenesis 2015;36:963-70.  Back to cited text no. 7
    
8.
Zhang J, Ju H, Gao JR, Jiao XL, Lu Y. Polymorphisms in human telomerase reverse transcriptase (hTERT) gene, gene- gene and gene-smoking interaction with susceptibility to gastric cancer in Chinese Han population. Oncotarget 2017;8:20235-43.  Back to cited text no. 8
    
9.
Kinnersley B, Migliorini G, Broderick P, Whiffin N, Dobbins SE, Casey G, et al. The TERT variant rs2736100 is associated with colorectal cancer risk. Br J Cancer 2012;107:1001-8.  Back to cited text no. 9
    
10.
Hofer P, Baierl A, Bernhart K, Leeb G, Mach K, Micksche M, et al. Association of genetic variants of human telomerase with colorectal polyps and colorectal cancer risk. Mol Carcinog 2012;51 Suppl 1:E176-82.  Back to cited text no. 10
    
11.
Jannuzzi AT, Karaman E, Oztas E, Yanar HT, Özhan G. Telomerase reverse transcriptase (TERT) gene variations and susceptibility of colorectal cancer. Genet Test Mol Biomarkers 2015;19:692-7.  Back to cited text no. 11
    
12.
Bayram S, Ülger Y, Sümbül AT, Kaya BY, Genç A, Rencüzoğullari E, et al. Polymorphisms in human telomerase reverse transcriptase (hTERT) gene and susceptibility to gastric cancer in a Turkish population: Hospital-based case-control study. Gene 2016;585:84-92.  Back to cited text no. 12
    
13.
Campa D, Rizzato C, Stolzenberg-Solomon R, Pacetti P, Vodicka P, Cleary SP, et al. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. Int J Cancer 2015;137:2175-83.  Back to cited text no. 13
    
14.
Dratwa M, Wysocza-ska B, Łacina P, Kubik T, Bogunia-Kubik K. TERT-regulation and roles in cancer formation. Front Immunol 2020;11:589929.  Back to cited text no. 14
    
15.
Snetselaar R, van Oosterhout MF, Grutters JC, van Moorsel CH. Telomerase reverse transcriptase polymorphism rs2736100: A balancing act between cancer and non-cancer disease, a meta-analysis. Front Med (Lausanne) 2018;5:41.  Back to cited text no. 15
    
16.
Liu Y, Li Z, Tang X, Li M, Shi F. Association between hTERT polymorphisms and female papillary thyroid carcinoma. Recent Pat Anticancer Drug Discov 2019;14:268-79.  Back to cited text no. 16
    
17.
Oddsson A, Kristinsson SY, Helgason H, Gudbjartsson DF, Masson G, Sigurdsson A, et al. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. Leukemia 2014;28:1371-4.  Back to cited text no. 17
    
18.
Wang X, Ma K, Chi L, Cui J, Jin L, Hu JF, et al. Combining telomerase reverse transcriptase genetic variant rs2736100 with epidemiologic factors in the prediction of lung cancer susceptibility. J Cancer 2016;7:846-53.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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