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

E. Theodoratou; Harry 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. Kuery; S. Bezieau; 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. Capella; 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, Harry 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. Kuery, S. Bezieau, 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. Capella, R. Barnetson, M. E. Porteous, M. G. Dunlop, S. M. Farrington

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Abstract / Description of output

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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR = 1.16, 95% CI: 1.00-1.34) and Y179C alone (OR = 1.34, 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. British Journal of Cancer (2010) 103, 1875-1884. doi:10.1038/sj.bjc.6605966 www.bjcancer.com Published online 9 November 2010 (C) 2010 Cancer Research UK

Original language	English
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
Publication status	Published - 7 Dec 2010

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10.1038/sj.bjc.6605966

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants
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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., Kuery, S., Bezieau, 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

@article{3d308bdd33bf45ccaac8e96edb5d4223,

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 (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR = 1.16, 95% CI: 1.00-1.34) and Y179C alone (OR = 1.34, 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. British Journal of Cancer (2010) 103, 1875-1884. doi:10.1038/sj.bjc.6605966 www.bjcancer.com Published online 9 November 2010 (C) 2010 Cancer Research UK",

author = "E. Theodoratou and Harry 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. Kuery and S. Bezieau and B. Buecher and Ellis, {N. A.} and P. Peterlongo and K. Offit and Aaltonen, {L. A.} and S. Enholm and A. Lindblom and X-L Zhou and Tomlinson, {I. P.} and V. Moreno and I. Blanco and G. Capella and R. Barnetson and Porteous, {M. E.} and Dunlop, {M. G.} and Farrington, {S. M.}",

year = "2010",

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

language = "English",

volume = "103",

pages = "1875--1884",

journal = "British Journal of Cancer",

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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, Kuery, S, Bezieau, S, Buecher, B, Ellis, NA, Peterlongo, P, Offit, K, Aaltonen, LA, Enholm, S, Lindblom, A, Zhou, X-L, Tomlinson, IP, Moreno, V, Blanco, I, Capella, 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

TY - JOUR

T1 - A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

AU - Theodoratou, E.

AU - Campbell, Harry

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 - Kuery, S.

AU - Bezieau, 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 - Capella, 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 (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR = 1.16, 95% CI: 1.00-1.34) and Y179C alone (OR = 1.34, 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. British Journal of Cancer (2010) 103, 1875-1884. doi:10.1038/sj.bjc.6605966 www.bjcancer.com Published online 9 November 2010 (C) 2010 Cancer Research UK

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 (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR = 1.16, 95% CI: 1.00-1.34) and Y179C alone (OR = 1.34, 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. British Journal of Cancer (2010) 103, 1875-1884. doi:10.1038/sj.bjc.6605966 www.bjcancer.com Published online 9 November 2010 (C) 2010 Cancer Research UK

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DO - 10.1038/sj.bjc.6605966

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EP - 1884

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 12

ER -

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

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