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Saini A, Kansal H, Singh N, Sharma S. hTERT rs2735940 polymorphism influences lung cancer risk and overall survival in lung cancer patients undergoing platinum-based doublet chemotherapy. Expert Rev Mol Diagn 2025:1-13. [PMID: 40310442 DOI: 10.1080/14737159.2025.2500657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND The hTERT gene is an essential part of the telomerase enzyme, preserving telomere length and encouraging cellular immortality. The study aimed to investigate whether the TERT gene SNP was associated with an increased risk of lung cancer in the North Indian population. RESEARCH DESIGN AND METHODS 387 lung cancer patients undergoing platinum-based chemotherapy and 384 healthy controls were genotyped for the TERT variant rs2735940 (T>C) using PCR-RFLP. The study aimed to determine the significant association between the TERT genetic variant and lung cancer risk. RESULTS Patients carrying homozygous mutant genotype (CC) for rs2735940 showed a significant association (0 R = 2.4, p = 0.03). Furthermore, in dominant model, the combination genotype (TC+CC) showed an increased risk of lung cancer susceptibility with an AOR of 1.67 (p = 0.0016). For TERT rs2735940, individuals with SCLC carrying the mutant genotype (CC) were significantly more likely to develop lung cancer (p = 0.0004). Our results also showed that lung cancer patients carrying the TERT rs2735940 genetic variant who received a combination of docetaxel and cisplatin/carboplatin had better prognosis as compared to alternative chemotherapy regimens. CONCLUSION Our study associates' chemotherapy toxicities in North Indian lung cancer patients and the TERT polymorphism rs2735940, delivering insights for improving biomarker development and individualized treatment.
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Affiliation(s)
- Anjali Saini
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Heena Kansal
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
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Rotem O, Zer A, Yosef L, Beery E, Goldvaser H, Gutkin A, Levin R, Dudnik E, Berger T, Feinmesser M, Levy-Barda A, Lahav M, Raanani P, Uziel O. Blood-Derived Exosomal hTERT mRNA in Patients with Lung Cancer: Characterization and Correlation with Response to Therapy. Biomedicines 2023; 11:1730. [PMID: 37371825 DOI: 10.3390/biomedicines11061730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Background: Telomerase (human telomerase reverse transcriptase (hTERT) is considered a hallmark of cancer, being active in cancer cells but repressed in human somatic cells. As such, it has the potential to serve as a valid cancer biomarker. Exosomal hTERT mRNA can be detected in the serum of patients with solid malignancies but not in healthy individuals. We sought to evaluate the feasibility of measuring serum exosomal hTERT transcripts levels in patients with lung cancer. Methods: A prospective analysis of exosomal hTERT mRNA levels was determined in serum-derived exosomes from 76 patients with stage III-IV lung cancer (11 SCLC and 65 NSCLC). An hTERT level above RQ = 1.2 was considered "detectable" according to a previous receiver operating characteristic curve (ROC) curve. Sequential measurements were obtained in 33 patients. Demographic and clinical data were collected retrospectively from patients' charts. Data on response to systemic therapy (chemotherapy, immunotherapy, and tyrosine kinase inhibitors) were collected by the treating physicians. Results: hTERT was detected in 53% (40/76) of patients with lung cancer (89% of SCLC and 46% of NSLCC). The mean hTERT levels were 3.7 in all 76 patients, 5.87 in SCLC patients, and 3.62 in NSCLC patients. In total, 25 of 43 patients with sequential measurements had detectable levels of hTERT. The sequential exosomal hTERT mRNA levels reflected the clinical course in 23 of them. Decreases in hTERT levels were detected in 17 and 5 patients with partial and complete response, respectively. Eleven patients with a progressive disease had an increase in the level of exosomal hTERT, and seven with stable disease presented increases in its exosomal levels. Another patient who progressed on the first line of treatment and had a partial response to the second line of treatment exhibited an increase in exosomal hTERT mRNA levels during the progression and a decrease during the response. Conclusions: Exosomal hTERT mRNA levels are elevated in over half of patients with lung cancer. The potential association between hTERT levels and response to therapy suggests its utility as a promising cancer biomarker for response to therapy. This issue should be further explored in future studies.
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Affiliation(s)
- Ofer Rotem
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Alona Zer
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 49100, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Lilach Yosef
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Einat Beery
- The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Hadar Goldvaser
- Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University, Rehovot 7612001, Israel
| | - Anna Gutkin
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Ron Levin
- Sheba Medical Center, Ramat Gan 5262000, Israel
| | - Elizabeth Dudnik
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Tamar Berger
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Institute of Hematology, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Meora Feinmesser
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Biobank, Department of Pathology, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Adva Levy-Barda
- Biobank, Department of Pathology, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Meir Lahav
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel
- Institute of Hematology, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Pia Raanani
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel
- Institute of Hematology, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Orit Uziel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel
- Institute of Hematology, Rabin Medical Center, Petah Tikva 49100, Israel
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3
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Yin H, Hardikar S, Lindstroem S, Hsu L, Anderson KE, Banbury BL, Berndt SI, Chan AT, Giovanucci EL, Harrison TA, Joshi AD, Nan H, Potter JD, Sakoda LC, Slattery ML, Schoen RE, White E, Peters U, Newcomb PA. Telomere Maintenance Variants and Survival after Colorectal Cancer: Smoking- and Sex-Specific Associations. Cancer Epidemiol Biomarkers Prev 2020; 29:1817-1824. [PMID: 32586834 PMCID: PMC7928192 DOI: 10.1158/1055-9965.epi-19-1507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/14/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. METHODS We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. RESULTS The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. CONCLUSIONS Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. IMPACT Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.
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Affiliation(s)
- Hang Yin
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Sheetal Hardikar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Sara Lindstroem
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Biostatistics, University of Washington, Seattle, Washington
| | - Kristin E Anderson
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Edward L Giovanucci
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Emily White
- Department of Epidemiology, University of Washington, Seattle, Washington
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ulrike Peters
- Department of Epidemiology, University of Washington, Seattle, Washington
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Polly A Newcomb
- Department of Epidemiology, University of Washington, Seattle, Washington.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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Chen BJ, Zeng S, Xie R, Hu CJ, Wang SM, Wu YY, Xiao YF, Yang SM. hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway. Oncotarget 2018; 8:26969-26978. [PMID: 28460480 PMCID: PMC5432311 DOI: 10.18632/oncotarget.15926] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 02/20/2017] [Indexed: 12/17/2022] Open
Abstract
Background hTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells. Results Experiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2. Materials and Methods Immunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP. Conclusions We may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.
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Affiliation(s)
- Bai-Jun Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China.,Department of Gastroenterology, The First Affiliated Hospital, Chengdu Medical College, Chengdu, PR China
| | - Shuo Zeng
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Rui Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Chang-Jiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Su-Ming Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Yu-Yun Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Yu-Feng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
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5
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Lu Y, Yan C, Du J, Ji Y, Gao Y, Zhu X, Yu F, Huang T, Dai J, Ma H, Jiang Y, Chen J, Shen H, Jin G, Yin Y, Hu Z. Genetic variants affecting telomere length are associated with the prognosis of esophageal squamous cell carcinoma in a Chinese population. Mol Carcinog 2016; 56:1021-1029. [PMID: 27597395 DOI: 10.1002/mc.22567] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 08/22/2016] [Accepted: 09/04/2016] [Indexed: 02/02/2023]
Abstract
Telomeres are essential for maintaining chromosomal stability and are crucial in tumor progression. Previous studies have explored the associations between telomere length and cancer prognosis, but the findings are inconclusive. Genome-wide association studies have identified several genetic variants associated with telomere length in Caucasians. However, the roles of telomere length and related genetic variants on esophageal squamous cell carcinoma (ESCC) prognosis are largely unknown. Therefore, we conducted a case-cohort study with 431 ESCC patients to assess the associations between relative telomere length (RTL), eight known telomere length related variants and the overall survival of ESCC in Chinese population. We found that as compared with the reference group, patients in the fifth (the longest) quintile had a significantly better prognosis [(adjusted hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98, P = 0.041]. Furthermore, A allele of rs2736108 was significantly associated with both the increased RTL (P = 0.048) and the better prognosis of ESCC (adjusted HR = 0.55, 95%CI = 0.38-0.79, P = 1.31 × 10-3 ). Mediation analysis indicated that the effect of rs2736108 on ESCC prognosis was partly explained by RTL (1.99%). Stepwise Cox proportional hazard analysis suggested that rs2736108 played an important protective role in ESCC prognosis (HR = 0.57, 95%CI = 0.40-0.81, P = 1.97 × 10-3 ). Our findings provide evidence that prolonged telomere length is a protective factor for ESCC patients' survival and the known telomere length related genetic variant rs2736108 can contribute to the prognosis of ESCC as well in Chinese population. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Yue Lu
- Department of Radiotherapy, the Affiliated Cancer Hospital of Jiangsu Province of Nanjing Medical University, Nanjing, China
| | - Caiwang Yan
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiangbo Du
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yong Ji
- Department of Cardiothoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yong Gao
- Department of Medical Oncology, the Affiliated Huaian First People's Hospital of Nanjing Medical University, Huaian, China
| | - Xun Zhu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Fei Yu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Tongtong Huang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongxia Ma
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yue Jiang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiaping Chen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yongmei Yin
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
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Kachuri L, Latifovic L, Liu G, Hung RJ. Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer. Cancer Epidemiol Biomarkers Prev 2016; 25:1537-1549. [PMID: 27566420 DOI: 10.1158/1055-9965.epi-16-0200] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/20/2016] [Accepted: 08/17/2016] [Indexed: 11/16/2022] Open
Abstract
Lung cancer remains the leading cause of cancer mortality worldwide. Known histomolecular characteristics and genomic profiles provide limited insight into factors influencing patient outcomes. Telomere length (TL) is important for genomic integrity and has been a growing area of interest as agents targeting telomerase are being evaluated. Chromosome 5p15.33, an established cancer susceptibility locus, contains a telomerase-regulatory gene, TERT, and CLPTM1L, a gene associated with cisplatin-induced apoptosis. This review offers a summary of the clinical utility of 5p15.33 polymorphisms and TL. A total of 621 abstracts were screened, and 14 studies (7 for 5p15.33, 7 for TL) were reviewed. Endpoints included overall survival (OS), progression-free survival (PFS), therapy response, and toxicity. Of the 23 genetic variants identified, significant associations with OS and/or PFS were reported for rs401681 (CLPTM1L), rs4975616 (TERT-CLPTM1L), and rs2736109 (TERT). Both shorter and longer TL, in tumor and blood, was linked to OS and PFS. Overall, consistent evidence across multiple studies of 5p15.33 polymorphisms and TL was lacking. Despite the potential to become useful prognostic biomarkers in lung cancer, the limited number of reports and their methodologic limitations highlight the need for larger, carefully designed studies with clinically defined subpopulations and higher resolution genetic analyses. Cancer Epidemiol Biomarkers Prev; 25(12); 1537-49. ©2016 AACR.
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Affiliation(s)
- Linda Kachuri
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,Prevention & Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada
| | - Lidija Latifovic
- Prevention & Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada
| | - Geoffrey Liu
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,Ontario Cancer Institute, Princess Margaret Cancer Center, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Rayjean J Hung
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. .,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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Zhang F, Cheng D, Wang S, Zhu J. Human Specific Regulation of the Telomerase Reverse Transcriptase Gene. Genes (Basel) 2016; 7:genes7070030. [PMID: 27367732 PMCID: PMC4962000 DOI: 10.3390/genes7070030] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 06/15/2016] [Accepted: 06/17/2016] [Indexed: 12/19/2022] Open
Abstract
Telomerase, regulated primarily by the transcription of its catalytic subunit telomerase reverse transcriptase (TERT), is critical for controlling cell proliferation and tissue homeostasis by maintaining telomere length. Although there is a high conservation between human and mouse TERT genes, the regulation of their transcription is significantly different in these two species. Whereas mTERT expression is widely detected in adult mice, hTERT is expressed at extremely low levels in most adult human tissues and cells. As a result, mice do not exhibit telomere-mediated replicative aging, but telomere shortening is a critical factor of human aging and its stabilization is essential for cancer development in humans. The chromatin environment and epigenetic modifications of the hTERT locus, the binding of transcriptional factors to its promoter, and recruitment of nucleosome modifying complexes all play essential roles in restricting its transcription in different cell types. In this review, we will discuss recent progress in understanding the molecular mechanisms of TERT regulation in human and mouse tissues and cells, and during cancer development.
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Affiliation(s)
- Fan Zhang
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, PO Box 1495, Spokane, WA 99210, USA.
| | - De Cheng
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, PO Box 1495, Spokane, WA 99210, USA.
| | - Shuwen Wang
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, PO Box 1495, Spokane, WA 99210, USA.
| | - Jiyue Zhu
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, PO Box 1495, Spokane, WA 99210, USA.
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8
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Kalpouzos G, Rizzuto D, Keller L, Fastbom J, Santoni G, Angleman S, Graff C, Bäckman L, Fratiglioni L. Telomerase Gene (hTERT) and Survival: Results From Two Swedish Cohorts of Older Adults. J Gerontol A Biol Sci Med Sci 2014; 71:188-95. [PMID: 25452402 PMCID: PMC4707686 DOI: 10.1093/gerona/glu222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 10/24/2014] [Indexed: 01/20/2023] Open
Abstract
Telomere length has been associated with longevity. As telomere length is partly determined by the human telomerase reverse transcriptase (hTERT), we investigated the association between an hTERT polymorphism located in its promoter region (−1327T/C) and longevity in two cohorts of older adults. Participants from the Kungsholmen project (KP; n = 1,205) and the Swedish National study of Aging and Care in Kungsholmen (SNAC-K; n = 2,764) were followed for an average period of 7.5 years. The main outcomes were hazard ratios (HR) of mortality and median age at death. In both cohorts, mortality was lower in female T/T carriers, aged 75+ years in KP (HR = 0.8, 95% CI: 0.5–0.9) and 78+ years in SNAC-K (HR = 0.6, 95% CI: 0.4–0.8) compared with female C/C carriers. T/T carriers died 1.8–3 years later than the C/C carriers. This effect was not present in men, neither in SNAC-K women aged 60–72 years. The association was not modified by presence of cancer, cardiovascular diseases, number of chronic diseases, or markers of inflammation, and did not interact with APOE genotype or estrogen replacement therapy. The gender-specific increased survival in T/T carriers can be due to a synergistic effect between genetic background and the life-long exposure to endogenous estrogen.
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Affiliation(s)
- Grégoria Kalpouzos
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Debora Rizzuto
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Lina Keller
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden. Division of Neurogeriatrics, NVS, Karolinska Institutet, Center for Alzheimer Research at Karolinska Institutet, Stockholm, Sweden
| | - Johan Fastbom
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Giola Santoni
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Sara Angleman
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Caroline Graff
- Division of Neurogeriatrics, NVS, Karolinska Institutet, Center for Alzheimer Research at Karolinska Institutet, Stockholm, Sweden. Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lars Bäckman
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Laura Fratiglioni
- Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden. Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. Stockholm Gerontology Research Center, Stockholm, Sweden
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Zhang DH, Chen JY, Hong CQ, Yi DQ, Wang F, Cui W. High-risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis. Cancer 2014; 120:2673-83. [PMID: 24840723 DOI: 10.1002/cncr.28797] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 04/04/2014] [Accepted: 04/22/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Telomere maintenance is crucial in carcinogenesis and tumor progression. The results of a previous study from the authors indicated that infection with high-risk human papillomavirus (HR-HPV) types 16, 18, and 58 was a risk factor for esophageal squamous cell carcinoma (ESCC) in the Shantou region of China. In the current study, the authors explored the association between HR-HPV infection, telomere length (TL), and DNA methylation and their significance in the prognosis of patients with ESCC. METHODS TL and DNA methylation were analyzed by real-time polymerase chain reaction and methylation-specific polymerase chain reaction in 70 cases of ESCC tumor (T) and paired nontumor (NT) tissues and 50 cases of normal esophagus (NE). The prognostic value of TL and DNA methylation in ESCC was analyzed. RESULTS TL gradually decreased from NE to NT to T tissue. TL in tumor tissue (T-TL) was found to be longer in tissue that was positive for HR-HPV compared with negative tissue and was found to be positively associated with viral load (Spearman correlation, 0.410; P = .037) and integration (represented by the ratio of HR-HPV E2 to E6/E7 genes; P = .01). The DNA methylation ratio of human telomerase reverse transcriptase was more prevalent with long (≥ 0.7) compared with short (< 0.7) T-TL and was positively correlated with T-TL (Spearman correlation, 0.318; P = .007) and HR-HPV integration (P = .036). Furthermore, Cox proportional hazards modeling revealed a high ratio of T-TL to NT-TL (≥ 0.80) as a factor of poor prognosis, independent of other clinicopathologic variables. CONCLUSIONS HR-HPV infection and integration related to telomere elongation and DNA methylation of human telomerase reverse transcriptase may be a potential biomarker of prognosis in patients with ESCC.
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Affiliation(s)
- Dong-Hong Zhang
- Department of Clinical Laboratory, Peking Union Medical College Hospital and Peking Union Medical College, Beijing, China
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10
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Jung SW, Park NH, Shin JW, Park BR, Kim CJ, Lee JE, Shin ES, Kim JA, Chung YH. Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B. Hepatology 2014; 59:1912-20. [PMID: 23907815 DOI: 10.1002/hep.26655] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 07/19/2013] [Indexed: 01/01/2023]
Abstract
UNLABELLED Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5) ). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5) ), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026). CONCLUSION These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.
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Affiliation(s)
- Seok Won Jung
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
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11
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Assis J, Pereira D, Medeiros R. Ovarian cancer and DNA repair: DNA ligase IV as a potential key. World J Clin Oncol 2013; 4:14-24. [PMID: 23538968 PMCID: PMC3609013 DOI: 10.5306/wjco.v4.i1.14] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 11/21/2012] [Accepted: 01/21/2013] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer (OC) is the sixth most common cancer and the seventh cause of death from cancer in women. The etiology and the ovarian carcinogenesis still need clarification although ovulation may be determinant due to its carcinogenic role in ovarian surface epithelium. The link between ovarian carcinogenesis and DNA repair is well established and it became clear that alterations in DNA damage response may affect the risk to develop OC. Polymorphisms are variations in the DNA sequence that exist in normal individuals of a population and are capable to change, among other mechanisms, the balance between DNA damage and cellular response. Consequently, genetic variability of the host has a great role in the development, progression and consequent prognosis of the oncologic patient as well as in treatment response. Standard treatment for OC patients is based on cytoreductive surgery, followed by chemotherapy with a platinum agent and a taxane. Although 80% of the patients respond to the first-line therapy, the development of resistance is common although the mechanisms underlying therapy failure remain mostly unknown. Because of their role in oncology, enzymes involved in the DNA repair pathways, like DNA Ligase IV (LIG4), became attractive study targets. It has been reported that variations in LIG4 activity can lead to a hyper-sensitivity to DNA damage, deregulation of repair and apoptosis mechanisms, affecting the susceptibility to cancer development and therapy response. To overcome resistance mechanisms, several investigations have been made and the strategy to target crucial molecular pathways, such as DNA repair, became one of the important areas in clinical oncology. This review aims to elucidate the link between DNA repair and OC, namely which concerns the role of LIG4 enzyme, and how genetic polymorphisms in LIG4 gene can modulate the activity of the enzyme and affect the ovarian carcinogenesis and treatment response. Moreover, we try to understand how LIG4 inhibition can be a potential contributor for the development of new cancer treatment strategies.
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12
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Sheng X, Tong N, Tao G, Luo D, Wang M, Fang Y, Li J, Xu M, Zhang Z, Wu D. TERT polymorphisms modify the risk of acute lymphoblastic leukemia in Chinese children. Carcinogenesis 2012; 34:228-35. [PMID: 23066086 DOI: 10.1093/carcin/bgs325] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Human telomerase reverse transcriptase (TERT) is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. We hypothesized that TERT polymorphisms are associated with risk of childhood acute lymphoblastic leukemia (ALL). We first conducted a case-control study of 570 ALL cases and 673 cancer-free controls of Chinese children, using the tagging single-nucleotide polymorphisms (tSNPs) approach. We then examined the functionality of the important SNPs. We found that TERT promoter region tSNP (rs2735940) and two intron region tSNPs (rs2736100 and rs10069690) were associated with risk of childhood ALL (P = 0.036, 0.011 and 0.022, respectively, in allele comparison). The in vitro luciferase assays in Jurkat cells showed an increased transcriptional activity of rs2735940 T allele compared with the C allele. Additional experiments with ALL bone marrow revealed that the rs2735940 T allele increased levels of the TERT messenger RNA. Notably, TERT intron 2 polymorphism (rs2736100) was associated with lower telomerase activity and longer telomeres. Our findings suggested that TERT promoter rs2735940 polymorphism may affect the TERT activity, and rs2736100 may be associated with telomere function, and thus, it is a potential biomarker for genetic susceptibility to ALL in Chinese children.
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Affiliation(s)
- Xiaojing Sheng
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
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13
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Hofer P, Baierl A, Bernhart K, Leeb G, Mach K, Micksche M, Gsur A. Association of genetic variants of human telomerase with colorectal polyps and colorectal cancer risk. Mol Carcinog 2012; 51 Suppl 1:E176-82. [DOI: 10.1002/mc.21911] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Revised: 02/23/2012] [Accepted: 03/07/2012] [Indexed: 12/15/2022]
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14
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Lü MH, Deng JQ, Cao YL, Fang DC, Zhang Y, Yang SM. Prognostic role of telomerase activity in gastric adenocarcinoma: A meta-analysis. Exp Ther Med 2012; 3:728-734. [PMID: 22969960 DOI: 10.3892/etm.2012.471] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 01/13/2012] [Indexed: 02/07/2023] Open
Abstract
Activation of telomerase is involved in carcinogenesis in most types of cancers. However, the prognostic value of telomerase activity (TA) in patients with gastric carcinoma (GC) remains controversial. We conducted a meta-analysis to assess the relationship between TA and the clinical outcome of GC. A meta-analysis of 18 studies (886 patients) was performed to evaluate the association between TA and metastasis-related parameters in GC patients by searching databases, including PubMed, MEDLINE, EMBASE, Web of Science databases, Cochrane Library and the Chinese Biomedical Literature database (CBM) (last search updated in October 2011). We used the odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between TA and metastasis of GC. Our analysis results indicated that high telomerase activity expression tended to be associated with the presence of lymph node metastasis (866 patients) (OR=2.03, 95% CI 1.21-3.39, p=0.007), the depth of invasion (886 patients) (OR=1.87, 95% CI 1.30-2.70, p=0.0007), distant metastasis (407 patients) (OR=2.71, 95% CI 1.59-4.63, p=0.0002), tumor size (466 patients) (OR=2.14, 95% CI 1.31-3.50, p=0.002) and TNM stage (711 patients) (OR=2.39, 95% CI 1.30-4.41, p=0.005). However, high TA expression was not associated with the presence of histologic differentiation (791 patients) (OR=1.51, 95% CI 0.73-3.11, p=0.26). In conclusion, telomerase overexpression not only plays a key role in primary initiation, but also promotes invasion and metastatic progression of GC. These findings raise the possibility of using TA to screen for the prognosis of gastric cancer.
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Affiliation(s)
- Mu-Han Lü
- Institute of Gastroenterology, Southwest Hospital, Third Military Medical University
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15
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Xun WW, Brennan P, Tjonneland A, Vogel U, Overvad K, Kaaks R, Canzian F, Boeing H, Trichopoulou A, Oustoglou E, Giotaki Z, Johansson M, Palli D, Agnoli C, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita HB, Peeters PHM, Lund E, Kumle M, Rodríguez L, Agudo A, Sánchez MJ, Arriola L, Chirlaque MD, Barricarte A, Hallmans G, Rasmuson T, Khaw KT, Wareham N, Key T, Riboli E, Vineis P. Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC). Mutagenesis 2011; 26:657-66. [PMID: 21750227 DOI: 10.1093/mutage/ger030] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The single-nucleotide polymorphisms (SNPs) rs402710 (5p15.33), rs16969968 and rs8034191 (15q25.1) have been consistently identified by genome-wide association studies (GWAS) as significant predictors of lung cancer risk, while rs4324798 (6p22.1) was previously found to influence survival time in small-cell lung cancer (SCLC) patients. Using the same population of one of the original GWAS, we investigated whether the selected SNPs and 31 others (also identified in GWAS) influence survival time, assuming an additive model. The effect of each polymorphism on all cause survival was estimated in 1094 lung cancer patients, and lung cancer-specific survival in 763 patients, using Cox regression adjusted for a priori confounders and competing causes of death where appropriate. Overall, after 1558 person-years of post-diagnostic follow-up, 874 deaths occurred from all causes, including 690 from lung cancer. In the lung cancer-specific survival analysis (1102 person-years), only rs7452888 (6q27) and rs2710994 (7p15.3) modified survival, with adjusted hazard ratios of 1.19 (P = 0.009) and 1.32 (P = 0.011) respectively, taking competing risks into account. Some weak associations were identified in subgroup analysis for rs16969968 and rs8034191 (15q25.1) and rs4324798 (6p22.1) and survival in never-smokers, as well as for rs402710 in current smokers and SCLC patients. In conclusion, rs402710 (5p15.33), rs16969968 and rs8034191 (both 15q25.1) and rs4324798 (6p22.1) were found to be unrelated to survival times in this large cohort of lung cancer patients, regardless of whether the cause of death was from lung cancer or not. However, rs7452888 (6q27) was identified as a possible candidate SNP to influence lung cancer survival, while stratified analysis hinted at a possible role for rs8034191, rs16969968 (15q25.1) and rs4324798 (6p22.1) in influencing survival time in lung cancer patients who were never-smokers, based on a small sample.
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MESH Headings
- Adult
- Aged
- Chromosomes, Human
- Chromosomes, Human, Pair 15
- Chromosomes, Human, Pair 5
- Chromosomes, Human, Pair 6
- Chromosomes, Human, Pair 7
- Europe
- Female
- Genetic Loci
- Genome-Wide Association Study
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- Smoking
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Affiliation(s)
- Wei Wei Xun
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, Paddington, LondonW2 1PG, UK
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Alfred T, Ben-Shlomo Y, Cooper R, Hardy R, Cooper C, Deary IJ, Elliott J, Gunnell D, Harris SE, Kivimaki M, Kumari M, Martin RM, Power C, Sayer AA, Starr JM, Kuh D, Day INM, HALCyon Study Team. Absence of association of a single-nucleotide polymorphism in the TERT-CLPTM1L locus with age-related phenotypes in a large multicohort study: the HALCyon programme. Aging Cell 2011; 10:520-32. [PMID: 21332924 PMCID: PMC3094481 DOI: 10.1111/j.1474-9726.2011.00687.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2011] [Indexed: 12/22/2022] Open
Abstract
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single-nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses. No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score = 0.02, 95% CI: -0.01 to 0.04, P-value = 0.12, n = 18,737), physical performance tests (e.g. pooled beta for grip strength = -0.02, 95% CI: -0.045 to 0.006, P-value = 0.14, n = 11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment. The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multicohort study suggests that while this SNP may be associated with cancer, it is not an important contributor to other markers of aging.
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Affiliation(s)
- Tamuno Alfred
- School of Social and Community Medicine, University of Bristol, UK.
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