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Bi L, Wang X, Li J, Li W, Wang Z. Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis. MedComm (Beijing) 2025; 6:e70080. [PMID: 39991629 PMCID: PMC11843169 DOI: 10.1002/mco2.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 02/25/2025] Open
Abstract
The integration of liquid biopsy with epigenetic markers offers significant potential for early lung cancer detection and personalized treatment. Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA changes, often precede genetic mutations and are critical in cancer progression. In this study, we explore how liquid biopsy, combined with epigenetic markers, can provide early detection of lung cancer, potentially predicting onset up to 4 years before clinical diagnosis. We discuss the challenges of targeting epigenetic regulators, which could disrupt cellular balance if overexploited, and the need for maintaining key gene expressions in therapeutic applications. This review highlights the promise and challenges of using liquid biopsy and epigenetic markers for early-stage lung cancer diagnosis, with a focus on optimizing treatment strategies for personalized and precision medicine.
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Affiliation(s)
- Lingfeng Bi
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital, Sichuan UniversityChengduSichuanChina
- Institute of Respiratory Health, Frontiers Science Center for Disease‐Related Molecular NetworkWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xin Wang
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital, Sichuan UniversityChengduSichuanChina
- Institute of Respiratory Health, Frontiers Science Center for Disease‐Related Molecular NetworkWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jiayi Li
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital, Sichuan UniversityChengduSichuanChina
- Institute of Respiratory Health, Frontiers Science Center for Disease‐Related Molecular NetworkWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital, Sichuan UniversityChengduSichuanChina
- Institute of Respiratory Health, Frontiers Science Center for Disease‐Related Molecular NetworkWest China Hospital, Sichuan UniversityChengduSichuanChina
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan UniversityChengduSichuanChina
- The Research Units of West China, Chinese Academy of Medical SciencesWest China HospitalChengduSichuanChina
| | - Zhoufeng Wang
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital, Sichuan UniversityChengduSichuanChina
- Institute of Respiratory Health, Frontiers Science Center for Disease‐Related Molecular NetworkWest China Hospital, Sichuan UniversityChengduSichuanChina
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan UniversityChengduSichuanChina
- The Research Units of West China, Chinese Academy of Medical SciencesWest China HospitalChengduSichuanChina
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Fang Z, Zhao G, Wang Y, Li F, Ding Z. The updated relationship between the cleft‑lip and palate transmembrane protein‑1‑like rs401681 and lung cancer risk: A systematic review and meta‑analysis. Mol Clin Oncol 2024; 21:70. [PMID: 39113849 PMCID: PMC11304168 DOI: 10.3892/mco.2024.2768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/04/2024] [Indexed: 08/10/2024] Open
Abstract
Currently, the role of cleft-lip and palate transmembrane protein-1-like (CLPTM1L) rs401681 in various tumor types, particularly lung cancer, has garnered significant attention. However, the findings across studies have shown discrepancies. The aim of the present meta-analysis was to provide a more nuanced understanding of the involvement of CLPTM1L rs401681 in lung cancer development. Several electronic databases were systematically searched, including PubMed, Cochrane Library, Embase, Medline, Wanfang, Google Scholar and Chinese National Knowledge Infrastructure. Odds ratios (ORs) and 95% confidence intervals (CIs) were synthesized using random-effects models. Heterogeneity of included studies was assessed using the I2 statistic and Q test. Sensitivity analysis was conducted to evaluate the stability of overall estimates. Moreover, Egger's test was utilized to detect potential publication bias. The collective ORs indicated a significant association between the CLPTM1L rs401681 polymorphism and susceptibility to lung cancer across various genetic comparisons. These encompass allele T vs. allele C (OR=0.93, 95% CI=0.88-0.99, P<0.001), TT + CT vs. CC (OR=0.91, 95% CI=0.87-0.96, P<0.001), TT vs. CC + CT (OR=0.88, 95% CI=0.80-0.96, P<0.001), TT vs. CC (OR=0.84, 95% CI=0.75-0.94, P<0.001) and CT vs. CC (OR=0.84, 95% CI=0.75-0.94, P<0.001). Examination through statistical Q test and I2 statistic revealed pronounced heterogeneity across four genetic comparisons (allele T vs. allele C, TT + CT vs. CC, TT vs. CC and CT vs. CC). Ethnical distinctions emerged as the primary, if not exclusive, sources of the significant heterogeneity. Upon stratification by ethnicity, a notable reduction in heterogeneity was discernible within the Caucasian demographic. However, heterogeneity persisted within the Asian population. Furthermore, lung cancer risks were statistically significantly decreased for individuals possessing allele T through all genetic comparisons within Caucasians; whereas among Asians, significant reduction was observed solely in the TT vs. CC comparison. The present meta-analysis uncovers a significant association between the CLPTM1L rs401681 polymorphism and altered susceptibility to lung cancer.
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Affiliation(s)
- Zemin Fang
- Department of Lung Transplant, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Gaofeng Zhao
- Department of Lung Transplant, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Yuebin Wang
- Department of Lung Transplant, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Fengke Li
- Department of Lung Transplant, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Zhidan Ding
- Department of Lung Transplant, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
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Wu X, Li W, Chen Y. Association of rs401681 (C > T) and rs402710 (C > T) polymorphisms in the CLPTM1L region with risk of lung cancer: a systematic review and meta-analysis. Sci Rep 2024; 14:22603. [PMID: 39349641 PMCID: PMC11442442 DOI: 10.1038/s41598-024-73254-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 09/16/2024] [Indexed: 10/04/2024] Open
Abstract
Although many genome-wide association studies (GWAS) have confirmed the negative associations between rs401681[T] / rs402710[T] in the Cleft lip and cleft palate transmembrane protein 1 (CLPTM1L) region and lung cancer (LC) susceptibility in Caucasian and Asian populations, some other studies haven't found these negative associations. The purpose of this study is to clarify the associations between them and LC, as well as the differences in these associations between patients of different ethnicities (Caucasians and Asians), LC subtypes and smoking status. Relevant literatures published before July 7, 2023 in PubMed, EMbase, Web of Science, MEDLINE were searched through the Internet. Statistical analysis of data was performed in Revman 5.3, including drawing forest plots, funnel plots and so on. Sensitivity and publication bias were performed in Stata 14.0. TSA software was performed for the trial sequential analysis (TSA) tests to assess the stability of the results. Registration number: CRD42023407890. A total of 41 literatures (containing 44 studies: 16 studies in Caucasians and 28 studies in Asians) were included in this meta-analysis, including 126476 LC patients and 191648 healthy controls. The results showed that the T allele variants of rs401681 and rs402710 were negatively associated with the risk of LC (rs401681[T]: [OR] = 0.87, 95% CI [0.86, 0.88]; rs402710[T]: [OR] = 0.88, 95% CI [0.86, 0.89]), and the negative associations were stronger in Caucasians than in Asians (Subgroup differences: I2 > 50%). In LC subtypes, the rs401681[T] was negatively associated with the risk of Non-small-cell lung carcinoma (NSCLC), Lung adenocarcinoma (LUAD) and Lung squamous cell carcinoma (LUSC) (P < 0.05), and these negative associations were stronger in Caucasians than in Asians (Subgroup differences: I2 > 50%). The rs402710[T] was negatively associated with the risk of NSCLC, LUAD and LUSC (P < 0.05), and these negative associations in Caucasians were the same as in Asians (Subgroup differences: I2 < 50%). The rs401681[T] was negatively associated with the risk of LC in both smokers and non-smokers (P < 0.05), and the negative association for smokers equals to that of non-smokers (Subgroup differences: P = 0.25, I2 = 24.2%). In LC subtypes, the rs401681[T] was negatively associated with the risks of NSCLC and LUAD in both Caucasian smokers and Asian non-smokers (P < 0.05). The rs402710[T] was negatively associated with the risk of LC in both smokers and non-smokers (P < 0.05), and there was no difference in the strength of this negative risk association between them in Caucasians (Subgroup differences: I2 = 0%). In Asians, this negative association was found to be predominantly among smokers ([OR] = 0.80, 95%CI [0.65, 0.99]). In LC subtypes, the rs402710[T]was negatively associated with the risk of NSCLC in non-smokers, and this negative association was found to be predominantly among non-smokers in Asians ([OR] = 0.75, 95%CI [0.60, 0.94]). The T allele variants of rs401681 and rs402710 are both negatively associated with the risk of developing LC, NSCLC (LUAD, LUSC) in the Caucasian and Asian populations, and the negative associations with the risk of LC are higher in Caucasians. Smoking is an important risk factor for inducing the rs401681 and rs402710 variants and causes LC development in both populations. Other factors like non-smoking are mainly responsible for inducing the development of NSCLC in Asians, and is concentrated in LUAD among Asian non-smoking women.
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Affiliation(s)
- Xiaozheng Wu
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
| | - Wen Li
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
| | - Yunzhi Chen
- Department of Preclinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China.
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Kahl VFS, da Silva J. Inorganic elements in occupational settings: A review on the effects on telomere length and biology. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2021; 872:503418. [PMID: 34798938 DOI: 10.1016/j.mrgentox.2021.503418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/31/2021] [Accepted: 10/15/2021] [Indexed: 06/13/2023]
Abstract
The past decades have shown that telomere crisis is highly affected by external factors. Effects of human exposure to xenobiotics on telomere length (TL), particularly in their workplace, have been largely studied. TL has been shown to be an efficient biomarker in occupational risk assessment. This is the first review focusing on studies about the effects on TL from occupational exposures to metals (lead [Pb] and mixtures), and particulate matter (PM) related to inorganic elements. Data from 15 studies were evaluated regarding occupational exposure to metals and PM-associated inorganic elements and impact on TL. Potential complementary analyses and subjects' background (age, length of employment and gender) were also assessed. There was limited information on the correlations between work length and TL dynamics, and that was also true for the correlation between age and TL. Results indicated that TL is affected differently across the types of occupational exposure investigated in this review, and even within the same exposure, a variety of effects can be observed. Fifty-three percent of the studies observed decreased TL in occupational exposure among welding fumes, open-cast coal mine, Pb and PM industries workers. Two studies focused particularly on the levels of metals and association with TL, and both linear and non-linear associations were found. Interestingly, TL modifications were accompanied by increase in DNA damage in 7 out of 8 studies that investigated it, measured either by Cytokinesis-block Micronucleus Assay or Comet assay. Five studies also investigated oxidative stress parameters, and 4 of them found increased levels of oxidative damage along with TL impairment. Oxidative stress is one of the main mechanisms by which telomeres are affected due to their high guanine content. Our review highlights the need of further studies accessing TL in simultaneous occupational exposure to mixtures of xenobiotics.
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Affiliation(s)
- Vivian F Silva Kahl
- The University of Queensland Diamantina Institute, The University of Queensland, Faculty of Medicine, 37 Kent Street, Woolloongabba, Queensland 4102, Australia; Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland 4102, Australia.
| | - Juliana da Silva
- Laboratory of Genetic Toxicology, Post Graduate Program in Cellular and Molecular Biology Applied to Health, Lutheran University of Brazil, Av Farroupilha 8001, Canoas, Rio Grande do Sul, 92425-900, Brazil; LaSalle University (UniLaSalle), Av Victor Barreto 2288, Canoas, Rio Grande do Sul, 92010-000, Brazil.
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TERT Gene rs2736100 and rs2736098 Polymorphisms are Associated with Increased Cancer Risk: A Meta-Analysis. Biochem Genet 2021; 60:241-266. [PMID: 34181135 DOI: 10.1007/s10528-021-10097-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 06/09/2021] [Indexed: 10/21/2022]
Abstract
Abnormal telomerase activity plays a key role in the development of carcinogenesis. The variants rs2736100 and rs2736098 of the telomerase reverse transcriptase (TERT) gene, which encodes the telomerase catalytic subunit, are associated with the risk of different types of cancers. However, the results remain controversy. We conducted a meta-analysis to more precisely assess this association. We comprehensively searched the PubMed and Web of Science databases up to June 1, 2020, and retrieved a total of 103 studies in 82 articles, including 89,320 cases and 121,654 controls. Among these studies, 69 published studies including 75,274 cases and 10,3248 controls were focused on rs2736100, and 34 published studies including 14,046 cases and 18,362 controls were focused on rs2736098. The results showed a strong association between variant rs2736100 and cancer risk in all populations. (G vs. T: OR 1.18, 95% CI 1.12-1.24; TG+GG vs. TT: OR 1.23, 95% CI 1.15-1.31; GG vs. TG+TT: OR 1.25, 95% CI 1.16-1.36); the variant rs2736098 was associated with cancer risk in all populations as well (A vs. G: OR 1.13, 95% CI 1.05-1.22; GA+AA vs. GG: OR 1.15, 95% CI 1.04-1.27; AA vs. GA+GG: OR 1.22, 95% CI 1.10-1.38). Stratified analysis based on the cancer type indicated that rs2736100 was associated with an increased risk of thyroid cancer, bladder cancer, lung cancer, glioma, and myeloproliferative neoplasms. rs2736098 only increased the risk of bladder cancer and lung cancer. Moreover, the TERT variants rs2736100 and rs2736098 were associated with a decreased risk of breast cancer and colorectal cancer. The variants rs2736098 and rs2736100 located in 5p15.33 around TERT were associated with increased cancer risk in all populations. These two variants had bidirectional effects in different tumors.
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Dratwa M, Wysoczańska B, Łacina P, Kubik T, Bogunia-Kubik K. TERT-Regulation and Roles in Cancer Formation. Front Immunol 2020; 11:589929. [PMID: 33329574 PMCID: PMC7717964 DOI: 10.3389/fimmu.2020.589929] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/16/2020] [Indexed: 12/16/2022] Open
Abstract
Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.
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Affiliation(s)
- Marta Dratwa
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Barbara Wysoczańska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Piotr Łacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Tomasz Kubik
- Department of Computer Engineering, Faculty of Electronics, Wrocław University of Science and Technology, Wroclaw, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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Wang M, Sun Y. Telomerase reverse transcriptase rs2736098 polymorphism is associated with lung cancer: A meta-analysis. J Int Med Res 2020; 48:300060520936173. [PMID: 33044116 PMCID: PMC7555572 DOI: 10.1177/0300060520936173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND A meta-analysis was conducted to determine whether telomerase reverse transcriptase (TERT) rs2736098 polymorphism was related to the incidence of lung cancer. METHODS We systematically searched the following three electronic databases: PubMed, Embase, and China National Knowledge Infrastructure (CNKI), for relevant articles. Statistical analysis was performed using the odds ratio (OR) and the corresponding 95% confidence interval (CI). RESULTS Seven articles involving 3836 healthy controls and 3637 patients were included in this meta-analysis. TERT rs2736098 polymorphism was significantly related to lung cancer incidence (AA vs. GG: OR=1.83, 95% CI=1.58-2.12; AG vs. GG: OR=1.21, 95% CI=1.10-1.34; Dominant model: OR=1.33, 95% CI=1.22-1.46; Recessive model: OR=1.66, 95% CI=1.44-1.90). Moreover, this polymorphism was found to be correlated with the susceptibility to lung cancer when studies were stratified based on the sample size and the Hardy-Weinberg equilibrium. CONCLUSION The present findings indicate that the TERT rs2736098 polymorphism may be a risk factor for the development of lung cancer.
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Affiliation(s)
- Meihua Wang
- Department of Respiration, XiXi Hospital of Hangzhou, Hangzhou, China
| | - Yaping Sun
- Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, China
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Pandith AA, Wani ZA, Qasim I, Afroze D, Manzoor U, Amin I, Baba SM, Koul A, Anwar I, Mohammad F, Bhat AR, Shah P. Association of strong risk of hTERT gene polymorphic variants to malignant glioma and its prognostic implications with respect to different histological types and survival of glioma cases. J Gene Med 2020; 22:e3260. [PMID: 32783258 DOI: 10.1002/jgm.3260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/03/2020] [Accepted: 07/31/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Germline genetic variants of human telomerase reverse transcriptase (hTERT) are known to predispose for various malignancies, including glioma. The present study investigated genetic variation of hTERT T/G (rs2736100) and hTERT G/A (rs2736098) with respect to glioma risk. METHODS Confirmed cases (n = 106) were tested against 210 cancer-free healthy controls by the polymerase chain reaction-restriction fragment length polymorphism technique for genotyping. RESULTS Homozygous variant 'GG' genotype of rs2736100 frequency was > 4-fold significantly different in cases versus controls (39.6% 17.2%; p < 0.0001). Furthermore, variant 'G' allele was found to be significantly associated with cases (0.5 versus 0.2 in controls; p < 0.0001). Homozygous variant rs2736098 'AA' genotype (35.8% versus 23.8%) and allele 'A' (0.49 versus 0.34) showed a marked significant difference in cases and controls, respectively (p < 0.05). In hTERT rs2736100, the GG genotype significantly presented more in higher grades and GBM (p < 0.0001). Furthermore, the GG variant of hTERT rs2736100 had a poor probability with respect to the overall survival of patients compared to TG and TT genotypes (log rank p = 0.03). Interestingly, two haplotypes of hTERT rs2736100/rs2736098 were identified as GG and GA that conferred a > 3- and 5-fold risk to glioma patients respectively, where variant G/A haplotype was observed to have the highest impact with respect to glioma risk (p < 0.0001). CONCLUSIONS The results of the present study indicate that hTERT rs2736098 and rs2736100 variants play an important role in conferring a strong risk of developing glioma. Furthermore, hTERT rs2736100 GG variant appears to play a role in the bad prognosis of glioma patients. Haplotypes GG and GA could prove to be vital tools for monitoring risk in glioma patients.
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Affiliation(s)
- Arshad A Pandith
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Zahoor A Wani
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Iqbal Qasim
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Dil Afroze
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Usma Manzoor
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Ina Amin
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Shahid M Baba
- Immunology and Molecular Medicine, SKIMS, Srinagar, Jammu and Kashmir, India
| | - Aabid Koul
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Iqra Anwar
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Fozia Mohammad
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Abdul R Bhat
- Department of Neurosurgery, SKIMS, Srinagar, Jammu and Kashmir, India
| | - Parveen Shah
- Department of Pathology, SKIMS, Srinagar, Jammu and Kashmir, India
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Vaiciulis P, Liutkeviciene R, Liutkevicius V, Vilkeviciute A, Gedvilaite G, Uloza V. Association of Relative Leucocyte Telomere Length and Gene Single Nucleotide Polymorphisms ( TERT, TRF1, TNKS2) in Laryngeal Squamous Cell Carcinoma. Cancer Genomics Proteomics 2020; 17:431-439. [PMID: 32576588 PMCID: PMC7367600 DOI: 10.21873/cgp.20202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/09/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIM The study aimed to evaluate associations of relative leukocyte telomere length (LTL) and polymorphisms of telomere length-associated genes TERT (rs2736098), TERT-CLPTM1L (rs401681), TRF1 (rs1545827, rs10107605) and TNKS2 (rs10509637, rs10509639) in patients with laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS The study consisted of 300 patients with LSCC and 369 healthy control subjects. Genotyping and relative LTL measuring were carried out using qPCR. RESULTS Relative LTL was statistically significantly shorter in the G3 (tumor differentiation grade) subgroup of patients with LSCC compared to the G1 and G2 subgroups. Significant differences were found in genotype distributions of TERT rs401681 and TNKS2 rs10509639 between the study groups. TERT rs401681 C/T and T/T genotypes were associated with approximately 30% decreased odds of LSCC development. CONCLUSION LTL was shorter in the G3 subgroup compared to the G2 and G1 subgroups of LSCC patients. TERT rs401681 and its C/T and T/T genotypes were associated with decreased odds of overall LSCC development.
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Affiliation(s)
- Paulius Vaiciulis
- Department of Otorhinolaryngology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rasa Liutkeviciene
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vykintas Liutkevicius
- Department of Otorhinolaryngology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alvita Vilkeviciute
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Greta Gedvilaite
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Virgilijus Uloza
- Department of Otorhinolaryngology, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Telomere Length and Telomerase Activity in Foetal Membranes from Term and Spontaneous Preterm Births. Reprod Sci 2020; 27:411-417. [PMID: 32046424 DOI: 10.1007/s43032-019-00054-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/06/2019] [Indexed: 01/01/2023]
Abstract
The reduction of telomere length, the protective cap structures of chromosomes, is one of the biomarkers of senescence (a mechanism of ageing), and ageing of foetal gestational tissues is associated with both term and preterm parturition. A mechanism regulating telomere length is the activity of telomerase, an enzyme that adds telomere fragments during DNA replication and cell division; however, its role in regulating telomere length is not well studied in gestational tissues. The objective of this study is to correlate telomere length and telomerase activity in foetal membranes from term and spontaneous preterm births. Foetal membrane samples were collected from pregnant women experiencing term labour (TL), term not in labour (TNL), preterm premature rupture of membranes (pPROM) and spontaneous preterm labour (PTL) with intact membranes (n = 20/group). Telomere length and telomerase activity were analyzed by relative quantification (T/S), real-time PCR and PCR-based fluorometric detection, respectively. Data were analyzed by ANOVA or the Kruskal-Wallis test. Demographic variables were not statistically different among the groups. Foetal membranes from the TL group showed telomere length reduction compared with those from the others (p < 0.0002). Telomerase activity did not change in foetal membranes irrespective of pregnancy outcome. Telomere shortening in foetal membranes is suggestive of senescence associated with triggering of labour at term; however, this is likely independent of telomerase activity, while prematurity may be associated with senescence, but due to other mechanisms than telomere length reduction in foetal membranes.
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Yu J, Li X, Zhou B, Yan A. Polymorphisms of the TERT-CLPTM1L Gene Are Associated with Pharynx-Larynx Cancer. DNA Cell Biol 2019; 38:915-921. [PMID: 31429604 DOI: 10.1089/dna.2019.4744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Pharynx-larynx cancer is a complex malignant tumor with the sixth-highest morbidity and mortality rate worldwide. The telomerase reverse transcriptase TERT-CLPTM1L gene, located on chromosome 5p15.33, plays a key role in the occurrence and progression of various cancer. The purpose of this hospital-based case-control study of patients in northern China was to explore the association between two single-nucleotide polymorphisms (SNPs) rs401681 in TERT and rs2736100 in CLPTM1L and the risk of head and neck cancer. We collected samples and relative characteristics and then analyzed the relationship between SNPs and pharynx-larynx cancer susceptibility by logistic regression analysis. The results suggested that the male patients carrying CT and CT+CC genotype model of rs401681 was associated with reduced risk of pharynx-larynx cancer compared with the CC genotype (adjusted odds ratios were 0.701 and 0.704, and 95% confidence intervals were 0.495-0.992 and 0.506-0.980; p-values were 0.045 and 0.038, respectively). In addition, we found that subjects with allele-C showed a relatively low risk of pharyngeal cancer when smoking exposure history was obtained. But the limitation is that in the future we need to further investigate about the exact functional effect of these two variant genes and a larger scale sample. Overall, in this research, our results show that the TERT-CLPTM1L gene could be a meaningful biomarker for pharynx-larynx cancer susceptibility.
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Affiliation(s)
- Jintao Yu
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaoying Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
| | - Aihui Yan
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China
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Li C, Wang X, Li Y, Zhang X, Sun M, Liu S, Sun L, Shi L, Yao Y. Genetic polymorphisms in the TERT gene and susceptibility to non-small cell lung cancer in a Chinese Han population. Cancer Manag Res 2018; 10:1487-1495. [PMID: 29928145 PMCID: PMC6001840 DOI: 10.2147/cmar.s166235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Recent studies have revealed that the TERT gene plays crucial roles in cancer initiation and development. Genome-wide analysis studies and case-control studies have demonstrated that polymorphisms in the TERT gene are associated with various cancers. Materials and methods In the current study, we analyzed the associations of eight single nucleotide polymorphisms (SNPs) in the TERT gene with non-small cell lung cancer (NSCLC) in a Chinese Han population. A total of 467 NSCLC patients and 526 healthy individuals were recruited for SNP genotyping using a TaqMan assay. Results Our results revealed that the allelic frequencies of rs2853677 and rs2853691 were significantly different between the NSCLC and control groups (P=0.004 and 0.001, respectively). Moreover, the T allele of rs2853677 and the A allele of rs2853691 might be the protective factors against NSCLC (OR=0.766; 95%CI: 0.639–0.918 and OR=0.714; 95%CI: 0.584–0.875, respectively). Additionally, stratified association analysis of the eight SNPs with the different pathological NSCLC stages (I+II and III+IV) and different pathological types (adenocarcinoma and squamous cell carcinoma) revealed that none of the SNPs were significantly different between patients with different pathological stages and pathological types. Conclusion Our results indicated that rs2853677 and rs2853691 in the TERT gene might be associated with NSCLC in this Chinese Han population.
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Affiliation(s)
- Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Xiaona Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Yingfu Li
- Department of Geriatrics, The No.1 Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Xinwen Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Mingbo Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Shuyuan Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Le Sun
- Kunming Medical University, Kunming 650032, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
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Zhou M, Jiang B, Xiong M, Zhu X. Association Between TERT rs2736098 Polymorphisms and Cancer Risk-A Meta-Analysis. Front Physiol 2018; 9:377. [PMID: 29695979 PMCID: PMC5905241 DOI: 10.3389/fphys.2018.00377] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 03/27/2018] [Indexed: 12/16/2022] Open
Abstract
Background: Cancer remains a leading cause of death and constitutes an enormous burden on society worldwide. The association between the human telomerase reverse transcriptase (TERT) gene variant rs2736098 polymorphisms and cancer predisposition remain inconclusive. Objective and methods: Databases including Pubmed and Embase were systematically searched from inception to September 15, 2017 to retrieve studies investigating the association between the TERT variant rs2736098 polymorphisms and cancer risk in accordance with previously determined exclusion and inclusion criteria. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were evaluated using random or fixed effects models. Results: Thirty-one case-control studies from 29 articles with 15,837 cases and 19,263 controls were screened out after a systematic search. Pooled analysis demonstrated that the TERT variant rs2736098 G > A polymorphism was significantly correlated with cancer risk in all populations (A vs. G: OR = 1.134, 95% CI = 1.051-1.224, P = 0.001; AA vs. GG: OR = 1.280, 95% CI = 1.087-1.508, P = 0.003; GA vs. GG: OR = 1.125, 95% CI = 1.020-1.240, P = 0.018; GA/AA vs. GG: OR = 1.159, 95% CI = 1.047-1.283, P = 0.004). In the subgroup analysis based on cancer type, the TERT rs2736098 with the A allele was 1.299 times more frequent than that with the G allele (OR = 1.299, 95% CI = 1.216-1.386) under the allelic genetic model in lung cancer, and 1.152 times (OR = 1.152, 95% CI = 1.032-1.286) that in bladder cancer. Conclusions: This meta-analysis demonstrated significant correlations between the TERT variant rs2736098 polymorphisms and cancer susceptibility. The A allele in the rs2736098 G > A polymorphism contributes to susceptibility in many types of cancer, especially lung cancer and bladder cancer.
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Affiliation(s)
- Mi Zhou
- Department of Respiratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Jiang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mao Xiong
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Zhu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Cavalcante GC, Amador MAT, Ribeiro dos Santos AM, Carvalho DC, Andrade RB, Pereira EEB, Fernandes MR, Costa DF, Santos NPC, Assumpção PP, Ribeiro dos Santos Â, Santos S. Analysis of 12 variants in the development of gastric and colorectal cancers. World J Gastroenterol 2017; 23:8533-8543. [PMID: 29358861 PMCID: PMC5752713 DOI: 10.3748/wjg.v23.i48.8533] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/25/2017] [Accepted: 11/07/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer (GC) and colorectal cancer (CRC).
METHODS In this study, we included 125 individuals with GC diagnosis, 66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms (in CASP8, CYP2E1, CYP19A1, IL1A, IL4, MDM2, NFKB1, PAR1, TP53, TYMS, UGT1A1 and XRCC1 genes) were genotyped in a single PCR for each individual, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 ancestry-informative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4, R environment and SPSS v.20.
RESULTS After statistical analyses with the control of confounding factors, such as genetic ancestry, three markers (rs79071878 in IL4, rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers (rs28362491) and the marker in the UGT1A1 gene (rs8175347) were positively associated with the development of CRC. Therefore, we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL (rs79071878 and rs28361491, respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly, carriers of the combination of DEL + RARE (rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.
CONCLUSION These findings are important for the comprehension of gastric and CRC development, particularly in highly admixed populations, such as the Brazilian population.
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Affiliation(s)
- Giovanna C Cavalcante
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Marcos AT Amador
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
| | | | - Darlen C Carvalho
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Roberta B Andrade
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Esdras EB Pereira
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Marianne R Fernandes
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Danielle F Costa
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Ney PC Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Paulo P Assumpção
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Ândrea Ribeiro dos Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
| | - Sidney Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66075-970, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Brazil
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Pang T, Zhou M, Liu R, Luo J, Xia R. TERT rs2736098 (Ex2-659G>A) polymorphism and cancer susceptibility: evidence from a comprehensive meta-analysis. Oncotarget 2017; 8:96433-96441. [PMID: 29221218 PMCID: PMC5707112 DOI: 10.18632/oncotarget.21703] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/20/2017] [Indexed: 02/07/2023] Open
Abstract
Increasing researches have been performed regarding the relationship between TERT rs2736098 and cancer risk, but no consensus has been reached about the relationship. Here, we conducted this updated meta-analysis, aiming to comprehensively evaluate the role of TERT rs2736098 in cancer risk. We systematically searched potential relevant articles through PubMed, EMBASE, CNKI, and WanFang database before August 2017. A total of 33 studies with 18685 cases and 23820 controls were finally included in the current meta-analysis. We then adopted odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the contributions of TERT rs2736098 to cancer risk. We found that the TERT rs2736098 polymorphism was associated with risk of cancer in overall analysis (AA vs. GG: OR = 1.26, 95% CI = 1.09–1.47; AA vs. AG/GG: OR = 1.22, 95% CI = 1.09–1.36; AA/AG vs. GG: OR = 1.13, 95% CI = 1.02–1.24; A vs. G: OR = 1.11, 95% CI = 1.04–1.20). Furthermore, in analysis stratified by cancer type, ethnicity, control source, quality score, and Hardy-Weinberg equilibrium (HWE) in controls, we found increased risk of cancer among lung cancer, bladder cancer, breast cancer, colorectal cancer, other cancers, Asians, hospital-based subgroup, score > 9 group, as well as controls agreement with HWE group. Despite some limitations, the current meta-analysis represented the largest and the most comprehensive investigations, with the strongest conclusion than ever before. To further explicit the association between TERT rs2736098 and cancer risk, more well-design case-control studies with larger sample size are warranted in the future.
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Affiliation(s)
- Tingyuan Pang
- Department of Pharmacy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou City, 510000, P.R. China
| | - Minjie Zhou
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou City, 510000, P.R. China
| | - Rumin Liu
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou City, 510000, P.R. China
| | - Jia Luo
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou City, 510000, P.R. China
| | - Renfei Xia
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou City, 510000, P.R. China
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