TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres

A. M. Jones, A. D. Beggs, Luis Carvajal-Carmona, S. Farrington, A. Tenesa, M. Walker, K. Howarth, S. Ballereau, S. V. Hodgson, A. Zauber, M. Bertagnolli, R. Midgley, H. Campbell, D. Kerr, M. G. Dunlop, Ian P M Tomlinson

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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 longtelomere/ 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.

Original languageEnglish (US)
Pages (from-to)248-254
Number of pages7
JournalGut
Volume61
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

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Telomere
Colorectal Neoplasms
Single Nucleotide Polymorphism
Alleles
Messenger RNA
telomerase RNA
RNA Folding
Cell Aging
Telomerase
Genetic Predisposition to Disease
Adenoma
Computer Simulation
Genes
Leukocytes
Cell Death
Transcription Factors
Retrospective Studies
Binding Sites
Phenotype
Cell Line

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Jones, A. M., Beggs, A. D., Carvajal-Carmona, L., Farrington, S., Tenesa, A., Walker, M., ... Tomlinson, I. P. M. (2012). TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut, 61(2), 248-254. https://doi.org/10.1136/gut.2011.239772

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. / Jones, A. M.; Beggs, A. D.; Carvajal-Carmona, Luis; 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, Ian P M.

In: Gut, Vol. 61, No. 2, 02.2012, p. 248-254.

Research output: Contribution to journalArticle

Jones, AM, Beggs, AD, Carvajal-Carmona, L, Farrington, S, Tenesa, A, Walker, M, Howarth, K, Ballereau, S, Hodgson, SV, Zauber, A, Bertagnolli, M, Midgley, R, Campbell, H, Kerr, D, Dunlop, MG & Tomlinson, IPM 2012, 'TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres', Gut, vol. 61, no. 2, pp. 248-254. https://doi.org/10.1136/gut.2011.239772
Jones, A. M. ; Beggs, A. D. ; Carvajal-Carmona, Luis ; 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, Ian P M. / TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. In: Gut. 2012 ; Vol. 61, No. 2. pp. 248-254.
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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 longtelomere/ 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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T1 - TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres

AU - Jones, A. M.

AU - Beggs, A. D.

AU - Carvajal-Carmona, Luis

AU - Farrington, S.

AU - Tenesa, A.

AU - Walker, M.

AU - Howarth, K.

AU - Ballereau, S.

AU - Hodgson, S. V.

AU - Zauber, A.

AU - Bertagnolli, M.

AU - Midgley, R.

AU - Campbell, H.

AU - Kerr, D.

AU - Dunlop, M. G.

AU - Tomlinson, Ian P M

PY - 2012/2

Y1 - 2012/2

N2 - 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 longtelomere/ 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.

AB - 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 longtelomere/ 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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