Figure 1 - available via license: Creative Commons Zero 1.0
Content may be subject to copyright.
TERT-CLPTM1L locus SNPs genotyped in epithelial ovarian cancer cases and controls. Panel A depicts the pattern of linkage disequilibrium using data from the HapMap phase II+III CEU population (2010), where white represents r2 = 0, and black r2 = 1. The plot in B represents −log10p against the chromosomal position for genotyped SNPs in the ovarian cancer fine mapping panel. The purple diamond represents the SNP (rs2736109) with the strongest observed association. The point colours represent the strength of LD according to 1000 Genomes Data.
Source publication
Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at...
Citations
... Consequently, two distinct haplotypes can be observed (see Table 1). Functional genomics work observed that the allele in common haplotype, i.e., C of rs2736107, rs2736108 and rs2736109 and A of rs2853669, can increase TERT promoter activity [15][16][17]. Further analysis verified that rs2736108 is significantly associated with telomere length [17][18][19][20][21]. ...
... The result indicated that the common allele of rs2736098, C, is with the ability to enhance TERT expression. Interestingly, the common allele at other four positions (see Table 1) can also increase TERT promoter activity [15][16][17], thus constituting a haplotype with high expression and leading to a significant signal at rs2736108 in GWAS [10][11][12][13][14]. ...
... Our and previous functional genomics work indicated that the allele in common haplotype, i.e., C of rs2736098, rs2736107, rs2736108 and rs2736109 and A of rs2853669, is the high expression one for TERT [15][16][17]. Therefore, the common haplotype should induce a high TERT expression. ...
rs2736098 is a synonymous polymorphism in TERT (telomerase reverse transcriptase), an enzyme involved in tumor onset of multiple tissues, and should play no roles in carcinogenesis. However, a search in cancer somatic mutation database indicated that the mutation frequency at rs2736098 is much higher than the average one for TERT. Moreover, there are significant H3K4me1 and H3K27Ac signals, two universal histone modifications for active enhancers, surrounding rs2736098. Therefore, we hypothesized that rs2736098 might be within an enhancer region, regulate TERT expression and influence cancer risk. Through luciferase assay, it was verified that the enhancer activity of rs2736098C allele is significantly higher than that of T in multiple tissues. Transfection of plasmids containing TERT coding region with two different alleles indicated that rs2736098C allele can induce a significantly higher TERT expression than T. By chromatin immunoprecipitation, it was observed that the fragment spanning rs2736098 can interact with USF1 (upstream transcription factor 1). The two alleles of rs2736098 present evidently different binding affinity with nuclear proteins. Database and literature search indicated that rs2736098 is significantly associated with carcinogenesis in multiple tissues and count of multiple cell types. All these facts indicated that rs2736098 is also an oncogenic polymorphism and plays important role in cell proliferation.
... Some 50 kbp apart lies TERT, the gene encoding human telomerase reverse transcriptase. The CLPTM1L-TERT locus is relevant for several gynaecological cancers [121,[145][146][147][148], however, the functional significance of the identified variant and its contribution to cervical cancer pathogenesis via the CLPTM1L-TERT locus remain to be elucidated. ...
Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.
... It is noteworthy here that germline variation near or within the h-TERT gene is equated with telomere length in peripheral blood leukocytes und risk of h-TERT promoter mutation mutants [21,22]. Moreover, the h-TERT promoter polymorphism viz rs 2,853,669 modulates the prognostic value in various tumor types as well as showed reduction in overall survival and increased tumor recurrence rate in Bladder cancer [23][24][25]. Thus, the prognostic power of h-TERT promoter mutation highlights their potential use as a clinical biomarker. ...
Buccal mucosa cancer has an aggressive nature as it rapidly grows and penetrates with high recurrence rate. Strikingly, carcinoma of buccal mucosa is the most common cancer of oral cavity in India. Recently, telomerase and telomere biology have been implicated in the pathogenesis and progression in various cancers via regulation of telomere maintenance by telomerase expression which is controlled by telomerase reverse transcriptase (TERT) promoter. Strikingly, h-TERT promoter mutations have been incriminated in regulation of telomerase gene expression. Here, we present a 35 years old male with intense coughing, short breathlessness and fever since 15 days, was admitted to the pulmonary unit. He was a chronic smoker and gutka user. The cytopathological analysis of gastric aspirate revealed buccal mucosa carcinoma of IV stage. We identified h-TERT promoter mutations in isolated genomic DNA from whole blood using DNA sequencer. Genetic analysis disclosed that h-TERT promoter region was highly mutated in this patient. Identified mutations include C.-248 del G, C.-272 del G, C.-279 del G, C.-331 del G, C.-349 del G, C.-351 del C, C.-360 G > A, C.-362 T > A, C.-371 del T and C.-372 del T. Further, all identified mutations were subjected to predict the pathologic functional consequences using bioinformatics tools viz TFsitescan and CiiiDER which showed either loss or gain of transcription factors binding sites in h-TERT promoter. This is a unique case in which total 9 mutations were observed in h-TERT promoter in a single case. In conclusion, all together these mutations in h-TERT promoter may alter the epigenetics and subsequently the tenacity of binding transcription factors which are of functional significance.
... [6][7][8][9][10][11][12][13][14][15][16] The 5p15.33 region has been associated with more than ten types of cancer, with multiple independent risk alleles identified. [17][18][19][20][21][22][23][24] Various biological mechanisms, including inflammation, epigenetics, gene expression, and telomere structure, have been proposed to explain these identified pleiotropic associations. For example, the 5p15.33 region harbors the TERT gene, which encodes the catalytic subunit of telomerase, 25 as well as the CLPTM1L gene, which encodes the cleft lip and palate-associated transmembrane-1 like protein. ...
... 12,59,60 The 5p15.33 region, containing the TERT and CLPTM1L genes, has also been associated with multiple cancers. [17][18][19][20][21][22][23] Other significant genomic regions identified in our study, including 1q32.1 (ER-negative breast and prostate), 4q24 (colorectal and prostate), 5q11.2 (overall breast and colorectal), 10q26.13 (ER-positive breast and prostate), 17q12 (endometrial and prostate), and 19p13.11 ...
Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor (ER)-positive and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
... Moreover, genome-wide association studies (GWASs) and case-control studies have demonstrated that polymorphisms in TERT are associated with various cancers such as skin cancer, CRC and breast cancer 28,32 . While individual TERT SNPs have been associated with different types of cancer and telomere length 22,26,33,34 and a common haplotype with decreased cancer risk substantially reducing TERT promoter activity 34 . ...
... Moreover, genome-wide association studies (GWASs) and case-control studies have demonstrated that polymorphisms in TERT are associated with various cancers such as skin cancer, CRC and breast cancer 28,32 . While individual TERT SNPs have been associated with different types of cancer and telomere length 22,26,33,34 and a common haplotype with decreased cancer risk substantially reducing TERT promoter activity 34 . ...
... A previous study of LS patients with MSH2 variants, linked SNP rs2075786 to an increased risk of cancer diagnosis younger than 45 years age using logistic regression 34 . When we analysed this outcome we also observed an association (see supplementary For rs2736108, the risk patterns observed for MLH1 variant carriers was similar to MSH2 variant carriers whereas, the pattern for MSH6 variant carriers was different (see Fig. 1). ...
Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan–Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.
... Most normal somatic cells do not display telomerase activity, whereas a high level of telomerase activity is detected in germinal cells, immortalized cell lines, and 85-90% of human cancers [6]. Recent studies have identified several single nucleotide polymorphisms (SNPs) in the TERT gene, including regulatory regions, which can affect TERT expression [7][8][9][10] and constitutive telomere length [11][12][13] and have been associated with risk and/or outcome for several human cancers [14][15][16][17]. Nevertheless, to date, previous studies on colorectal cancer have evaluated the association of genetic TERT variants with cancer risk [18][19][20], but not with clinical outcome. ...
... As mentioned before, the role of SNPs is probably dependent on their involvement in TERT expression [7][8][9][10]. However, in our study we found that at baseline only the SNP rs2736122AG was significantly associated with a higher level of circulating TERT compared to the other genotypes, while at T2 only the rs2853690AA/GG "protective genotypes" were associated with low levels of circulating TERT. ...
Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1–19.1) and 3.0(1.3–6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9–17.8) and 5.3(1.4–19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1–0.9) and 0.3(0.1–0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.
... Despite the development of tools and strategies for fine-scale mapping and functional analyses, the effort is still huge to characterize each GWAS-identified risk locus and reveal its underlying biology in breast tumorigenesis Fachal and Dunning, 2015;Spain and Barrett, 2015). However, for those 22 breast cancer risk that have been analyzed in more detail, this has provided already significant insight into the, sometimes complex, mechanisms underlying breast cancer susceptibility (Table 1) (Meyer et al., 2008Udler et al., 2009Udler et al., , 2010aAhmadiyeh et al., 2010;Stacey et al., 2010;Beesley et al., 2011;Cai et al., 2011b;Bojesen et al., 2013;French et al., 2013;Ghoussaini et al., 2014Ghoussaini et al., , 2016Quigley et al., 2014;Darabi et al., 2015Darabi et al., , 2016Glubb et al., 2015;Guo et al., 2015;Lin et al., 2015;Orr et al., 2015;Dunning et al., 2016;Hamdi et al., 2016;Horne et al., 2016;Lawrenson et al., 2016;Shi et al., 2016;Sun et al., 2016;Wyszynski et al., 2016;Zeng et al., 2016;Betts et al., 2017;Helbig et al., 2017;Michailidou et al., 2017). ...
... For most of the post-GWAS breast cancer risk loci, luciferase reporter assays were performed to confirm the working hypothesis for the functional model (Table 1) (Meyer et al., 2008;Beesley et al., 2011;Cai et al., 2011b;Bojesen et al., 2013;French et al., 2013;Ghoussaini et al., 2014Ghoussaini et al., , 2016Darabi et al., 2015;Orr et al., 2015;Dunning et al., 2016;Lawrenson et al., 2016;Betts et al., 2017;Helbig et al., 2017;Michailidou et al., 2017). However, at the 2q35 locus in the study by Ghoussaini et al., the PRE did not influence IGFBP5 expression despite positive 3C and eQTL results (Ghoussaini et al., 2014). ...
... (Meyer et al., 2008Stacey et al., 2010;Udler et al., 2010a;Beesley et al., 2011;Cai et al., 2011a;Bojesen et al., 2013;French et al., 2013;Ghoussaini et al., 2014Ghoussaini et al., , 2016Quigley et al., 2014;Darabi et al., 2015Darabi et al., , 2016Glubb et al., 2015;Guo et al., 2015;Lin et al., 2015;Orr et al., 2015;Dunning et al., 2016;Hamdi et al., 2016;Lawrenson et al., 2016;Shi et al., 2016;Sun et al., 2016;Wyszynski et al., 2016;Zeng et al., 2016;Betts et al., 2017;Helbig et al., 2017;Michailidou et al., 2017) ...
Genome-wide association studies (GWAS) have identified more than 170 single nucleotide polymorphisms (SNPs) associated with the susceptibility to breast cancer. Together, these SNPs explain 18% of the familial relative risk, which is estimated to be nearly half of the total familial breast cancer risk that is collectively explained by low-risk susceptibility alleles. An important aspect of this success has been the access to large sample sizes through collaborative efforts within the Breast Cancer Association Consortium (BCAC), but also collaborations between cancer association consortia. Despite these achievements, however, understanding of each variant's underlying mechanism and how these SNPs predispose women to breast cancer remains limited and represents a major challenge in the field, particularly since the vast majority of the GWAS-identified SNPs are located in non-coding regions of the genome and are merely tags for the causal variants. In recent years, fine-scale mapping studies followed by functional evaluation of putative causal variants have begun to elucidate the biological function of several GWAS-identified variants. In this review, we discuss the findings and lessons learned from these post-GWAS analyses of 22 risk loci. Identifying the true causal variants underlying breast cancer susceptibility and their function not only provides better estimates of the explained familial relative risk thereby improving polygenetic risk scores (PRSs), it also increases our understanding of the biological mechanisms responsible for causing susceptibility to breast cancer. This will facilitate the identification of further breast cancer risk alleles and the development of preventive medicine for those women at increased risk for developing the disease.
... The risk-associated alleles of the six candidate variants are associated with a decreased risk of overall breast cancer, estrogen receptor (ER) positive breast cancer and breast cancer in BRCA1 mutation carriers but most strongly with ER-negative breast cancer [41]. Previous studies of these six variants in breast cancer cell lines indicated that the risk-associated alleles of variants rs2736107, rs2736108 and rs2736109 decrease TERT promoter activity in vitro, whereas rs2853669 had no effect [41,42]. ...
... The risk-associated alleles of rs2736107, rs2736108 and rs2736109 have previously been reported to decrease TERT promoter activity [41,42], although the underlying mechanism has remained elusive. We generated luciferase reporter constructs containing 3.9 kb of the TERT promoter with either all the protective alleles (wildtype), or all risk-associated alleles of the six candidate variants (risk-associated haplotype). ...
... Since these data were inconsistent with earlier studies indicating rs2736107, rs2736108 and rs2736109, but not rs2853669, as variants that reduced TERT promoter activity in breast cancer cells [41,42], we performed Sanger sequencing of the previously used constructs. This revealed 11 additional variants (including common polymorphisms) of unknown significance compared with the human reference genome sequence (Supplementary Table 2). ...
The multi-cancer susceptibility locus at 5p15.33 includes TERT, encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms (SNPs) in the TERT promoter associated with decreased breast cancer risk, although the precise causal variants and their mechanisms of action have remained elusive. Luciferase reporter assays indicated that the protective haplotype reduced TERT promoter activity in human mammary epithelial and cancer cells in an estrogen-independent manner. Using single variant constructs, we identified rs3215401 and rs2853669 as likely functional variants. Silencing of MYC decreased TERT promoter activity but neither MYC nor ETS2 silencing conferred allele-specificity. In chromatin immunoprecipitation experiments, the ETS protein GABPA, but not ETS2 or ELF1, bound rs2853669 in an allele-specific manner in mammary epithelial cells. Investigation of open chromatin in mammoplasty samples suggested involvement of three additional variants, though not rs3215401 or rs2853669. Chromosome conformation capture revealed no interaction of the TERT promoter with regulatory elements in the locus, indicating limited local impact of candidate variants on the TERT promoter. Collectively, our functional studies of the TERT-CLPTM1L breast cancer susceptibility locus describe rs2853669 as a functional variant of this association signal among three other potentially causal variants and demonstrate the versatile mechanisms by which TERT promoter variants may affect breast cancer risk.
... Several TERT single nucleotide polymorphisms (SNPs) are associated with telomere length or telomerase activity. Most of the SNPs reduce the telomere length or telomerase activity [81][82][83][84] while some SNPs such as rs2853690 and rs33954691 increase the telomere length [85]. Based on the results from the mouse model study, we preliminarily tested the linkage disequilibrium (LD) structure ( Supplementary Fig. 3A, B) and family-based association of hTERT gene with ASD in autistic patients from a Korean population. ...
In addition to its classical role as a regulator of telomere length, recent reports suggest that telomerase reverse transcriptase (TERT) plays a role in the transcriptional regulation of gene expression such as β-catenin-responsive pathways. Silencing or over-expression of TERT in cultured NPCs demonstrated that TERT induced glutamatergic neuronal differentiation. During embryonic brain development, expression of transcription factors involved in glutamatergic neuronal differentiation was increased in mice over-expressing TERT (TERT-tg mice). We observed increased expression of NMDA receptor subunits and phosphorylation of α-CaMKII in TERT-tg mice. TERT-tg mice showed autism spectrum disorder (ASD)-like behavioral phenotypes as well as lowered threshold against electrically induced seizure. Interestingly, the NMDA receptor antagonist memantine restored behavioral abnormalities in TERT-tg mice. Consistent with the alteration in excitatory/inhibitory (E/I) ratio, TERT-tg mice showed autism-like behaviors, abnormal synaptic organization, and function in mPFC suggesting the role of altered TERT activity in the manifestation of ASD, which is further supported by the significant association of certain SNPs in Korean ASD patients.
... A common functional single nucleotide polymorphisms (SNPs) in the promoter region of hTERT were detected with a minor allele frequency above 30%, − 1600 G NA (rs2736109), − 1327 T N C (rs2735940), and − 245 A NG (rs2853669) with positions defined by the transcription initiation site as +1 (Horikawa et al., 1999 ). A few studies have emerged functionality of hTERT rs2736109 G N A, rs2735940 T NC, rs2853669 A NG and rs2736100 T N G polymorphisms as mentioned below (Beesley et al., 2011; Matsubara et al., 2006; Hsu et al., 2006; Landi et al., 2009; Codd et al., 2013 ). First genetic variation, hTERT rs2736109 GN A polymorphism locate within the − 1600 bp upstream of the promoter region of hTERT. ...
... First genetic variation, hTERT rs2736109 GN A polymorphism locate within the − 1600 bp upstream of the promoter region of hTERT. To define the functional importance of G → A transition of hTERT rs2736109 GNA polymorphism, Beesley et al. (2011) , constituted luciferase reporter construct including 3.9 kb of the hTERT promoter. They showed that luciferase activity was significantly decreased for the construct carrying A allele of hTERT rs2736109 G N A polymorphism in an EOC cell line, a breast adenocarcinoma cell line, as well as in post-selection normal breast epithelial cells (Beesley et al., 2011). ...
... To define the functional importance of G → A transition of hTERT rs2736109 GNA polymorphism, Beesley et al. (2011) , constituted luciferase reporter construct including 3.9 kb of the hTERT promoter. They showed that luciferase activity was significantly decreased for the construct carrying A allele of hTERT rs2736109 G N A polymorphism in an EOC cell line, a breast adenocarcinoma cell line, as well as in post-selection normal breast epithelial cells (Beesley et al., 2011). For second genetic variation, Matsubara et al. (2006), reported that an hTERT rs2735940 TNC polymorphism within the promoter region, a T → C transition −1327 bp upstream of the transcription start site, influences transcriptional efficiency of hTERT. ...
Erosion of telomeres, tandem nucleotide repeats (TTAGGG)n that cap the end of eukaryotic chromosomes, has been related with carcinogenesis. The human telomerase reverse transcriptase (hTERT) gene is encoded the rate-limiting catalytic subunit of the telomerase complexes, which is essential for the protection of telomeric DNA length and chromosomal stability. The purpose of this study was to examine the effect of four functional single nucleotide polymorphisms (SNPs) of hTERT (rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G) on susceptibility to gastric cancer (GC) in Turkish population. The genotype frequency of hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan methods in 104 subjects with GC and 209 healthy control subjects. We found that hTERT rs2736109 G>A (AA+AG vs. GG OR=1.68 95% CI = 1.01-2.81, P=0.04), rs2735940 T>C (CC vs. CT+TT: OR=2.53 95% CI=1.01-6.13, P=0.03), and rs2736100 T>G (TT vs. TG+GG: OR=2.27 95% CI=1.23-4.17, P=0.006) polymorphisms were associated with risk of GC. In the haplotype analysis, hTERT Grs2736109/Trs2735940/Ars2853669/Grs2736100 haplotype was also related with an increased risk of GC (OR=1.75; 95% CI: 1.05-2.93, P=0.03). Because this is the first study regarding the hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G polymorphisms and the risk of GC susceptibility in the literature, further independent studies are needed to verify our results in a larger sample sizes, as well as in patients of different populations.
