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; N. A. Ellis; P. Peterlongo; K. Offit; 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

doi:10.1038/sj.bjc.6605966

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, N. A. Ellis, P. Peterlongo, K. OffitL. 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 journal › Article › peer-review

102 Scopus citations

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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95% CI: 5.02-23.2; OR6.47, 95% CI: 2.33-18.0; OR3.35, 95% CI: 1.14-9.89) and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 language	English (US)
Pages (from-to)	1875-1884
Number of pages	10
Journal	British journal of cancer
Volume	103
Issue number	12
DOIs	https://doi.org/10.1038/sj.bjc.6605966
State	Published - Dec 7 2010
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/sj.bjc.6605966

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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, N. A., Peterlongo, P., ... 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

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, NA, 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

@article{1bec81dc519a40ccb261bcdb1da91832,

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

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.",

keywords = "MUTYH, base excision repair, carrier risk estimates, colorectal cancer, meta-analysis",

author = "E. Theodoratou and H. Campbell and A. Tenesa and R. Houlston and E. Webb and S. Lubbe and P. Broderick and S. Gallinger and Croitoru, {E. M.} and Jenkins, {M. A.} and Win, {A. K.} and Cleary, {S. P.} and T. Koessler and Pharoah, {P. D.} and S. K{\"u}ry and S. B{\'e}zieau and B. Buecher and Ellis, {N. A.} and P. Peterlongo and K. Offit and Aaltonen, {L. A.} and S. Enholm and A. Lindblom and Zhou, {X. L.} and Tomlinson, {I. P.} and V. Moreno and I. Blanco and G. Capell{\`a} and R. Barnetson and Porteous, {M. E.} and Dunlop, {M. G.} and Farrington, {S. M.}",

note = "Funding Information: We thank all the study participants and the many colleagues world wide who contributed to recruitment. We are particularly grateful to Ruth Wilson, Rosa Bisset, Nicola Cartwright and Gisela Johnstone, and all those who contributed to recruitment, data collection and data curation for the Scottish COGS and SOCCS studies. This work was supported by grants from Cancer Research UK (C348/A3758, C348/A8896), Scottish Government Chief Scientist Office (K/OPR/2/2/D333, CZB/4/94, CZB/4/449); Medical Research Council (G0000657-53203); Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity. org.uk). ET is funded by a Cancer Research UK Fellowship C31250/ A10107. The work at the Institute of Cancer Research is supported grants from Cancer Research UK (supported by Bobby Moore), Steven Lubbe is supported by a Cancer Research UK PhD Studentship. The work in Canada was made possible through collaboration and cooperative agreements with the Colon Cancer",

year = "2010",

month = dec,

day = "7",

doi = "10.1038/sj.bjc.6605966",

language = "English (US)",

volume = "103",

pages = "1875--1884",

journal = "British journal of cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "12",

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TY - JOUR

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, N. A.

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.

N1 - Funding Information: We thank all the study participants and the many colleagues world wide who contributed to recruitment. We are particularly grateful to Ruth Wilson, Rosa Bisset, Nicola Cartwright and Gisela Johnstone, and all those who contributed to recruitment, data collection and data curation for the Scottish COGS and SOCCS studies. This work was supported by grants from Cancer Research UK (C348/A3758, C348/A8896), Scottish Government Chief Scientist Office (K/OPR/2/2/D333, CZB/4/94, CZB/4/449); Medical Research Council (G0000657-53203); Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity. org.uk). ET is funded by a Cancer Research UK Fellowship C31250/ A10107. The work at the Institute of Cancer Research is supported grants from Cancer Research UK (supported by Bobby Moore), Steven Lubbe is supported by a Cancer Research UK PhD Studentship. The work in Canada was made possible through collaboration and cooperative agreements with the Colon Cancer

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 - MUTYH

KW - base excision repair

KW - carrier risk estimates

KW - colorectal cancer

KW - meta-analysis

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JO - British journal of cancer

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

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