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Original article
TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres
  1. A M Jones1,
  2. A D Beggs1,
  3. L Carvajal-Carmona1,
  4. S Farrington2,
  5. A Tenesa2,
  6. M Walker2,
  7. K Howarth1,
  8. S Ballereau2,
  9. S V Hodgson3,
  10. A Zauber4,
  11. M Bertagnolli5,
  12. R Midgley6,
  13. H Campbell7,
  14. D Kerr6,
  15. M G Dunlop2,
  16. I P M Tomlinson1
  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  2. 2Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, UK
  3. 3Department of Clinical Genetics, St George's Hospital Medical School, London, UK
  4. 4Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  5. 5Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, Massachusetts, USA
  6. 6Department of Clinical Pharmacology, University of Oxford, Oxford, UK
  7. 7Public Health Sciences, University of Edinburgh, Edinburgh, UK
  1. Correspondence to Professor Ian Tomlinson, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; iant{at}well.ox.ac.uk

Abstract

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.

  • cancer genetics
  • colon carcinogenesis
  • colorectal adenomas
  • colorectal cancer
  • colorectal cancer genes
  • genetic polymorphisms
  • polymorphisms
  • susceptibility
  • telomeres
  • TERC

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Footnotes

  • Funding The Oxford group acknowledges funding from the EU FP7 CHIBCHA project, the Oxford Comprehensive Biomedical Research Centre and Cancer Research UK. The authors are also very grateful to Willem Ouwehand and colleagues for supplying the National Blood Service controls. The Edinburgh group were supported by grants from: Cancer Research UK (C348/A12076), Scottish Government Chief Scientist Office (K/OPR/2/2/D333), Medical Research Council (G0000657-53203) and a Centre Grant from CORE as part of the Digestive Cancer Campaign. Core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford was provided by grant 090532/Z/09/Z.

  • Correction notice This article has been modified since it was published online first. The funding statement was corrected.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Southampton and South-West Hampshire REC (A).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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