TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres
Open accessAbstract
Background and aims: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. Methods: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in ‘telomere biology’ genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. Results: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. Conclusions: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.
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Lead SNPs at the TERC and TERT loci associate with several cancers and other diseases, including idiopathic pulmonary fibrosis.
“Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [19]
Common variants at two loci on Chr3q26 (TERC) and Chr10q24.33 (OBFC1), that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association studies.
“So far, common variants at two loci on Chr3q26 (TERC)17–19 and Chr10q24.33 (OBFC1)18, that explain <1% of the variance in TL, have shown a replicated association with mean LTL in genome-wide association (GWA) studies.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [19]
The rs10936599 (TERC) allele associated with longer LTL associates with increased risk of colorectal cancer and with multiple sclerosis (longer LTL allele) and celiac disease (shorter LTL allele).
“The rs10936599 (TERC) allele associated with longer LTL associates with increased risk of colorectal cancer19 and with two autoimmune diseases, multiple sclerosis (longer LTL allele) and celiac disease (shorter LTL allele).”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [19]
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- Authors
- Jones, A. M., Beggs, A. D., Carvajal-Carmona, L., Farrington, S., Tenesa, A., Walker, M., Howarth, K., Ballereau, S., Hodgson, S. V., Zauber, A., Bertagnolli, M., Midgley, R., Campbell, H., Kerr, D., Dunlop, M. G., & Tomlinson, I. P. M.
- Affiliations
- Centre for Human Genetics (GB)
- Edinburgh Cancer Research (GB)
- Institute of Genetics and Cancer (GB)
- St George's Hospital (GB)
- Memorial Sloan Kettering Cancer Center (US)
- Brigham and Women's Hospital (US)
- University of Oxford (GB)
- University of Edinburgh (GB)
- Corresponding author
- Tomlinson, I P M
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2011-06-27
- Volume
- 61
- Issue
- 2
- Pages
- 248-254
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3245900
- OpenAlex
- W2113307719
- Cited by
- 113
- References
- 41
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 2 · 2018: 5 · 2017: 6 · 2016: 11 · 2015: 10 · 2014: 14 · 2013: 14 · 2012: 12
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (090532, 090532/Z/09/Z)
- Cancer Research UK (C348/A12076, 12076)
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- TERC, telomerase RNA, telomere length, colorectal cancer, colorectal adenoma, genetic susceptibility, single nucleotide polymorphisms, telomerase reverse transcriptase, mRNA folding, transcription factor binding sites, cellular senescence, leukocytes
- MeSH terms
- Adenoma, Aged, Carcinoma, Female, Humans, Leukocytes, Male, Middle Aged, Retrospective Studies, RNA, Colorectal Neoplasms, Case-Control Studies, Polymerase Chain Reaction, Telomere, Telomerase, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, HCT116 Cells, Genotyping Techniques
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