A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

E. Theodoratou, H. Campbell, A. Tenesa, R. Houlston, E. Webb, S. Lubbe, P. Broderick, S. Gallinger, E. M. Croitoru, M. A. Jenkins, A. K. Win, S. P. Cleary, T. Koessler, P. D. Pharoah, S. Küry, S. Bézieau, B. Buecher, Nathan Ellis, P. Peterlongo, K. Offit & 12 others L. A. Aaltonen, S. Enholm, A. Lindblom, X. L. Zhou, I. P. Tomlinson, V. Moreno, I. Blanco, G. Capellà, R. Barnetson, M. E. Porteous, M. G. Dunlop, S. M. Farrington

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background: Defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. Methods: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. Results: All three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95% CI: 5.02-23.2; OR6.47, 95% CI: 2.33-18.0; OR3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR1.16, 95% CI: 1.00-1.34) and Y179C alone (OR1.34, 95% CI: 1.01-1.77). Conclusions: Overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

Original languageEnglish (US)
Pages (from-to)1875-1884
Number of pages10
JournalBritish Journal of Cancer
Volume103
Issue number12
DOIs
StatePublished - Dec 7 2010
Externally publishedYes

Fingerprint

Meta-Analysis
Colorectal Neoplasms
Confidence Intervals
DNA Repair
Logistic Models
Penetrance
Heterozygote
Alleles
Odds Ratio
Genotype
Genes

Keywords

  • base excision repair
  • carrier risk estimates
  • colorectal cancer
  • meta-analysis
  • MUTYH

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Theodoratou, E., Campbell, H., Tenesa, A., Houlston, R., Webb, E., Lubbe, S., ... Farrington, S. M. (2010). A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. British Journal of Cancer, 103(12), 1875-1884. https://doi.org/10.1038/sj.bjc.6605966

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. / Theodoratou, E.; Campbell, H.; Tenesa, A.; Houlston, R.; Webb, E.; Lubbe, S.; Broderick, P.; Gallinger, S.; Croitoru, E. M.; Jenkins, M. A.; Win, A. K.; Cleary, S. P.; Koessler, T.; Pharoah, P. D.; Küry, S.; Bézieau, S.; Buecher, B.; Ellis, Nathan; Peterlongo, P.; Offit, K.; Aaltonen, L. A.; Enholm, S.; Lindblom, A.; Zhou, X. L.; Tomlinson, I. P.; Moreno, V.; Blanco, I.; Capellà, G.; Barnetson, R.; Porteous, M. E.; Dunlop, M. G.; Farrington, S. M.

In: British Journal of Cancer, Vol. 103, No. 12, 07.12.2010, p. 1875-1884.

Research output: Contribution to journalArticle

Theodoratou, E, Campbell, H, Tenesa, A, Houlston, R, Webb, E, Lubbe, S, Broderick, P, Gallinger, S, Croitoru, EM, Jenkins, MA, Win, AK, Cleary, SP, Koessler, T, Pharoah, PD, Küry, S, Bézieau, S, Buecher, B, Ellis, N, Peterlongo, P, Offit, K, Aaltonen, LA, Enholm, S, Lindblom, A, Zhou, XL, Tomlinson, IP, Moreno, V, Blanco, I, Capellà, G, Barnetson, R, Porteous, ME, Dunlop, MG & Farrington, SM 2010, 'A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants', British Journal of Cancer, vol. 103, no. 12, pp. 1875-1884. https://doi.org/10.1038/sj.bjc.6605966
Theodoratou, E. ; Campbell, H. ; Tenesa, A. ; Houlston, R. ; Webb, E. ; Lubbe, S. ; Broderick, P. ; Gallinger, S. ; Croitoru, E. M. ; Jenkins, M. A. ; Win, A. K. ; Cleary, S. P. ; Koessler, T. ; Pharoah, P. D. ; Küry, S. ; Bézieau, S. ; Buecher, B. ; Ellis, Nathan ; Peterlongo, P. ; Offit, K. ; Aaltonen, L. A. ; Enholm, S. ; Lindblom, A. ; Zhou, X. L. ; Tomlinson, I. P. ; Moreno, V. ; Blanco, I. ; Capellà, G. ; Barnetson, R. ; Porteous, M. E. ; Dunlop, M. G. ; Farrington, S. M. / A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. In: British Journal of Cancer. 2010 ; Vol. 103, No. 12. pp. 1875-1884.
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abstract = "Background: Defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. Methods: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. Results: All three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95{\%} confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)1.34; 95{\%} CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95{\%} CI: 5.02-23.2; OR6.47, 95{\%} CI: 2.33-18.0; OR3.35, 95{\%} CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR1.16, 95{\%} CI: 1.00-1.34) and Y179C alone (OR1.34, 95{\%} CI: 1.01-1.77). Conclusions: Overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.",
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T1 - A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

AU - Theodoratou, E.

AU - Campbell, H.

AU - Tenesa, A.

AU - Houlston, R.

AU - Webb, E.

AU - Lubbe, S.

AU - Broderick, P.

AU - Gallinger, S.

AU - Croitoru, E. M.

AU - Jenkins, M. A.

AU - Win, A. K.

AU - Cleary, S. P.

AU - Koessler, T.

AU - Pharoah, P. D.

AU - Küry, S.

AU - Bézieau, S.

AU - Buecher, B.

AU - Ellis, Nathan

AU - Peterlongo, P.

AU - Offit, K.

AU - Aaltonen, L. A.

AU - Enholm, S.

AU - Lindblom, A.

AU - Zhou, X. L.

AU - Tomlinson, I. P.

AU - Moreno, V.

AU - Blanco, I.

AU - Capellà, G.

AU - Barnetson, R.

AU - Porteous, M. E.

AU - Dunlop, M. G.

AU - Farrington, S. M.

PY - 2010/12/7

Y1 - 2010/12/7

N2 - Background: Defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. Methods: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. Results: All three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95% CI: 5.02-23.2; OR6.47, 95% CI: 2.33-18.0; OR3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR1.16, 95% CI: 1.00-1.34) and Y179C alone (OR1.34, 95% CI: 1.01-1.77). Conclusions: Overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

AB - Background: Defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. Methods: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. Results: All three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95% CI: 5.02-23.2; OR6.47, 95% CI: 2.33-18.0; OR3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR1.16, 95% CI: 1.00-1.34) and Y179C alone (OR1.34, 95% CI: 1.01-1.77). Conclusions: Overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

KW - base excision repair

KW - carrier risk estimates

KW - colorectal cancer

KW - meta-analysis

KW - MUTYH

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