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Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000
bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis.
To investigate further the ge...
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The telomere is located at the end of the chromosome and consists of a non-coding, repetitive DNA sequence. As the cell divides, the length of telomere gradually decreases. A very short telomere can terminate mitosis, and thus telomere length becomes a hallmark of cellular aging. The 500 kb region of each autosomal arm terminal is the so-called sub...
Citations
... We explored two previously reported but minimally characterized VNTRs 9,10 within TERT intron 6 in relation to all cancer-related GWAS signals within the 5p15.33 multi-cancer region [1][2][3][4] . First, we analyzed 452 long-read WGS assemblies from 226 controls of diverse ancestries generated by the Human Pangenome Reference Consortium (HPRC) 11 and the Center for Alzheimer's and Related Dementias (CARD) 18 . ...
The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.
... Previous genome-wide association studies (GWAS) in various populations had identified dozens of risk loci for LC [3,4], and most of these loci were clustered in the TERT-CLPTM1L region of chromosome 5p15.33 [5][6][7][8][9][10][11]. ...
Background
Although the G allele variant of TERT-CLPTM1L rs4975616 has been confirmed to be negatively associated to the risk of lung cancer (LC), some other studies haven’t found this negative association. The purpose of this study is to clarify the association of the rs4975616 with the risk of developing LC and the differences of this association among patients with different ethnicities (Caucasians and Asians), different subtypes of LC, and different smoking status.
Methods
Relevant literatures published before July 20, 2023 in PubMed, EMbase, Web of Science, MEDLINE databases were searched through the Internet. Statistical analysis of data was performed in Revman5.3, including drawing forest plots, funnel plots and so on. Sensitivity and publication bias were performed in Stata 14.0. The stability of the results was assessed using Test Sequence Analysis (TSA) software. Registration number: CRD42024568348.
Results
The G allele variant of rs4975616 was negatively associated with the risk of LC ([OR] = 0.86, 95%CI [0.84, 0.88]), and that this negative association was present in both Caucasians ([OR] = 0.85, 95%CI [0.83, 0.87]) and Asians ([OR] = 0.91, 95%CI [0.86, 0.95]), and the strength of the negative association was higher in Caucasians than in Asians (subgroup differences: P = 0.02, I² = 80.3%). Across LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD, LUSC) in both Caucasians and Asians (P<0.05) and the strength of the association with NSCLC (LUAD) was higher in Caucasians than in Asians (Subgroup differences: I²>50%). In Caucasians, rs4975616[G] was negatively associated with the risk of LC in both smokers and non-smokers (P<0.05), and the strength of the association did not differ between smokers and non-smokers (Subgroup differences: P = 0.18, I² = 45.0%). In Asians, rs4975616[G] was mainly negatively associated with the risk of LC in smokers (P<0.05) but not in non-smokers ([OR] = 0.97, 95%CI [0.78, 1.20]). Comparisons between the two populations showed that the strength of this negative association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: P = 0.04, I² = 75.3%), whereas the strength of this negative association was the same for Caucasian smokers as for Asian smokers (Subgroup differences: P = 0.42, I² = 0%). Among the different LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD) incidence in both Asian smokers and Caucasian non-smokers (P<0.05), whereas it was not associated with the risk of NSCLC development in Asian non-smokers (P>0.05). Comparisons between the two populations showed that the strength of the association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: I²>50%).
Conclusion
The G allele variant of rs4975616 is negatively associated with the risk of LC and NSCLC (LUAD, LUSC). Compared with Asians, Caucasians are more likely to have a higher risk of LC and NSCLC (LUAD) due to the rs4975616 variant. In Caucasians, smoking and other factors like non-smoking contribute to rs4975616 variations leading to LC, and other factors like non-smoking also induce rs4975616 variations leading to NSCLC (LUAD). In Asians, smoking is the major risk factor for the induction of rs4975616 variations leading to LC and NSCLC(LUAD).
... rs2736098 has been suggested to be significantly associated with carcinogenesis in multiple tissues besides breast, including lung, basal cell, bladder, prostate, cervix, liver, pancreas, colon, ovary, B cell, head and neck [29][30][31][32][33][34][35][36][37][38][39][40][41]. Further search in GWAS Catalog, UK BioBank (https://www.ukbiobank.ac.uk) and FinnGen (https://www.finngen.fi/fi) ...
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.
... CLPTM1L encodes a membrane protein whose overexpression in cisplatin-sensitive cells causes apoptosis. Polymorphisms at this locus have been reported to increase susceptibility to many cancer types, including pancreatic, lung, bladder cancer, and melanoma 39,40 . Our findings were also supported by our VEGAS2 gene-based analysis which also highlighted SLC45A2, RCC2, and CLPTM1L as BCC-associated genes. ...
Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.
... Over the past two decades, multi-population Genome-wide association studies(GWAS) have identified dozens of risk loci for LC 7,8 , and most of these loci are concentrated in 5p15.33 (Telomerase reverse transcriptase-Cleft lip and cleft palate transmembrane protein 1)TERT-CLPTM1L region 9-12 . Several precise localization studies in the following years have also identified some new LC risk loci in this region [13][14][15] . Telomeres are consisted of repeated "TTA GGG " at the ends of chromosomes that gradually shorten in length with each round of cell division until cell cycle arrest is triggered, of which process is known as replicative senescence [16][17][18][19] . ...
The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case–control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on ‘TERT rs2736100 polymorphism and LC susceptibility’ in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.
... Thus, mutations in the TERT regions (5p15.33) in relation to tumorigenesis have long intrigued researchers. Prior genome-wide association studies (GWAS) have found polymorphisms in TERT were associated with risks of multiple cancers, such as breast, lung, glioma, bladder, testicular, pancreas, prostate, and skin cancer [6,7]. In prostate cancer, single nucleotide polymorphisms (SNPs), including rs4449583, rs10069690, rs13172201, and rs2736098, were identified to be associated with disease risks in the European population [7], while rs2736100 and rs10069690 were found to be associated in the Chinese population [8]. ...
... Prior genome-wide association studies (GWAS) have found polymorphisms in TERT were associated with risks of multiple cancers, such as breast, lung, glioma, bladder, testicular, pancreas, prostate, and skin cancer [6,7]. In prostate cancer, single nucleotide polymorphisms (SNPs), including rs4449583, rs10069690, rs13172201, and rs2736098, were identified to be associated with disease risks in the European population [7], while rs2736100 and rs10069690 were found to be associated in the Chinese population [8]. Results from previous studies were limited to either inconsistency or their small scale. ...
... Results from previous studies were limited to either inconsistency or their small scale. For the validation of PCa-related TERT SNPs in multiple ancestries, only a cross-ancestry meta-analysis found that rs7726159 and rs2736098 were significantly associated with PCa risk in at least two ancestries [7]. Furthermore, there is a research gap on the association of TERT variants with PCa severity and prognosis. ...
Background:
Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness.
Methods:
Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics).
Results:
A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12-1.20, p = 4.12 × 10-16) and rs11291391 (OR = 1.73, 95%CI:1.34-2.25, p = 3.04 × 10-5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31-1.71, p = 2.91 × 10-9) and rs2853677 (OR = 1.74, 95%CI:1.52-1.98, p = 3.52 × 10-16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04-2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10-15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171).
Conclusion:
TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.
... The 5p15.33 TERT/CLPTM1L locus is an extensively characterized multi-cancer risk locus, [18][19][20][21] and over 10 tumor types are associated with this risk region, including carcinomas from ER-negative breast, colon, lung, pancreas, prostate, kidney, ovary, head and neck, esophagus, and endometrium, as well as germ cell tumor, cutaneous melanoma, and glioma. Importantly, up to ten independent risk loci have now been identified within this genomic region, encompassing both CLPTM1L and TERT. ...
... Importantly, up to ten independent risk loci have now been identified within this genomic region, encompassing both CLPTM1L and TERT. 18,20 In addition, some alleles have different directionalities of effect (risk or protective, depending on the tumor type), 18,20,22 suggesting tissue-specific regulation and oncogenic consequences. The association signal found by our GWAS, led by rs370348 (odds ratio OR [CI 95%] ¼ 1.59 [1.35; 1.86]) and corresponding to the region marked by rs465498 in the metanalysis of Chen and colleagues, was also found in cutaneous melanoma, lung, and pancreatic cancers. ...
... Importantly, up to ten independent risk loci have now been identified within this genomic region, encompassing both CLPTM1L and TERT. 18,20 In addition, some alleles have different directionalities of effect (risk or protective, depending on the tumor type), 18,20,22 suggesting tissue-specific regulation and oncogenic consequences. The association signal found by our GWAS, led by rs370348 (odds ratio OR [CI 95%] ¼ 1.59 [1.35; 1.86]) and corresponding to the region marked by rs465498 in the metanalysis of Chen and colleagues, was also found in cutaneous melanoma, lung, and pancreatic cancers. ...
The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide association study in uveal melanoma (UM), which uncovered a role for the TERT/CLPTM1L risk locus in this intraocular tumor and identified multiple highly correlated risk alleles. Aiming to unravel the biological mechanisms in UM of this locus, which contains a domain enriched in active chromatin marks and enhancer elements, we demonstrated the allele-specific enhancer activity of this risk region using reporter assays. In UM, we identified the functional variant rs452384, of which the C risk allele is associated with higher gene expression, increased CLPTM1L expression in UM tumors, and a longer telomere length in peripheral blood mononuclear cells. Electrophoretic mobility shift assays and quantitative mass spectrometry identified NKX2.4 as an rs452384-T-specific binding protein, whereas GATA4 preferentially interacted with rs452384-C. Knockdown of NKX2.4 but not GATA4 resulted in increased TERT and CLPTM1L expression. In summary, the UM risk conferred by the 5p locus is at least partly due to rs452384, for which NKX2.4 presents strong differential binding activity and regulates CLPTM1L and TERT expression. Altogether, our work unraveled some of the complex regulatory mechanisms at the 5p15.33 susceptibility region in UM, and this might also shed light on shared mechanisms with other tumor types affected by this susceptibility region.
... The locus at 5p15.33 is a well-known multi-cancer locus (52,53) and was associated with lung cancer across different populations (12,14,16). The most robust signal is tagged by rs2736100, which was consistently observed in European and East Asian populations among smokers and never-smokers. ...
... GWAS in diverse populations and stepwise conditional analyses have identified additional independent signals (still significant when conditioning on the lead SNP as a covariate in the regression) in this locus (40,54,(59)(60)(61), suggesting that there are multiple functional variants contributing to lung cancer risk through TERT or other genes. A multi-cancer meta-analysis including lung can-cer in this locus identified six independent regions (52). Functional characterization of one of them identified rs36115365 as a functional variant (tagged by rs37004) which is located in an intergenic region between TERT (∼18 kb telomeric from the SNP) and CLPTM1L (Cleft Lip and Palate Transmembrane Protein 1-Like; ∼5 kb centromeric from the SNP) (53). ...
Fourteen years after the first genome-wide association study (GWAS) of lung cancer was published, approximately forty-five genomic loci have now been significantly associated with lung cancer risk. While functional characterization was performed for several of these loci, a comprehensive summary of current molecular understanding of lung cancer risk has been lacking. Further, many novel computational and experimental tools now became available to accelerate the functional assessment of disease-associated variants, moving beyond locus-by-locus approaches. In this review, we first highlight the heterogeneity of lung cancer GWAS findings across histological subtypes, ancestries, and smoking status, which poses unique challenges to follow-up studies. We then summarize the published lung cancer post-GWAS studies for each risk-associated locus to assess the current understanding of biological mechanisms beyond the initial statistical association. We further summarize strategies for GWAS functional follow-up studies considering cutting-edge functional genomics tools and providing a catalog of available resources relevant to lung cancer. Overall, we aim to highlight the importance of integrating computational and experimental approaches to draw biological insights from the lung cancer GWAS results beyond association.
... Eventually, malignant proliferation will appear 6 . Some studies have also shown that the genetic variation of CLPTM1L is associated with the incidence of some malignant tumors [7][8][9][10][11][12][13][14][15][16][17] . In the previous studies of oral squamous cell carcinoma, we also found multiple genetic variations located in CLPTM1L. ...
... In GWAS studies related to lung cancer, CLPTM1L-rs402710 and rs401681 have been reported to be associated with the risk of lung cancer 7,16,23,24 . The high expression of CLPTM1L is in consistence with the hypomethylation in the downstream region, and methylation of CLPTM1L has an active regulatory function in lung cancer 14 . In pancreatic cancer, CLPTM1L is overexpressed and significantly correlated with poor prognosis 25,26 . ...
This study aimed to explore the function of CLPTM1L in oral squamous cell carcinoma and mechanism of tumorigenesis. The expression of CLPTM1L was detected by immunohistochemistry. The localization in cells was detected by immunofluorescence. Cell invasion, proliferation, and migration were detected by transwell, CCK-8 and scratch-wound test. The possible characteristics of CLPTM1L were analysed in TCGA, GO, KEGG and String databases. IHC revealed that the expression of CLPTM1L in 92 cases of OSCC tissues was significantly higher ( P < 0.01) than 29 cases of normal oral epithelium tissues. The expression of CLPTM1L was significantly higher in oral squamous cell carcinoma in TCGA database. CLPTM1L expression was not significantly correlated with the patients’ clinical parameters. High expression of CLPTM1L was associated with worse prognosis. Cox regression analysis demonstrated that the CLPTM1L expression was the significant risk factor. CLPTM1L was mainly localized in the perinuclear cytoplasm. The vitro studies revealed that the knockdown of CLPTM1L suppressed invasion, proliferation and migration. CLPTM1L related genes were enriched in protein processing in the endoplasmic reticulum, protein folding, endoplasmic reticulum formation, N-glycan biosynthesis, and protein hydroxylation. Highly expressed CLPTM1L may contribute to a poor prognosis and increase invasion, proliferation and migration of oral squamous cell carcinoma. CLPTM1L may play an important role in tumorgenesis and would be a valuable target gene for the treatment of oral squamous cell carcinoma.
... Genome-wide association studies (GWAS) have recently mapped risk alleles for at least 10 cancer types in a region of chromosome 5 (5p15.33), harboring hTERT gene [18]. Allele-specific effects on DNA methylation were seen in this region identifying the single-nucleotide polymorphism (SNP) biomarker rs10069690 as a possible effector on the methylation and subsequently on gene expression [18,19]. ...
... harboring hTERT gene [18]. Allele-specific effects on DNA methylation were seen in this region identifying the single-nucleotide polymorphism (SNP) biomarker rs10069690 as a possible effector on the methylation and subsequently on gene expression [18,19]. In this work, we decided to evaluate epigenetic modifications with regard to DNA methylation in this precise region not located on the promoter but within the intron (mhTERT) [18,19]. ...
... Allele-specific effects on DNA methylation were seen in this region identifying the single-nucleotide polymorphism (SNP) biomarker rs10069690 as a possible effector on the methylation and subsequently on gene expression [18,19]. In this work, we decided to evaluate epigenetic modifications with regard to DNA methylation in this precise region not located on the promoter but within the intron (mhTERT) [18,19]. We previously characterized DNA methylation alterations in this locus in a large cohort of oral squamous cell carcinoma, identifying the most correlated CpG located at Chr5:1279643-1279644, with an area under the curve (AUC) of 0.92 [18,19]. ...
Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERT high) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (−) cases (21 vs 14, p = 0.554); furthermore, mhTERT high was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.
