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Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3

Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3
Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3
Background: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.
Objectives: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.
Methods: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in ~300 population controls.
Results: Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p?=?0.0009; exact test for trends in proportions) and presented earlier (p?=?0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases.
Conclusion: Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.
1468-3288
1252-1255
Dallosso, A.R.
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Dolwani, S.
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Jones, N.
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Jones, S.
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Colley, J.
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Maynard, J.
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Idziaszczyk, S.
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Humphreys, V.
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Arnold, J.
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Donaldson, A.
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Eccles, D.
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Ellis, A.
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Evans, D.G.
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Frayling, I.M.
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Hes, F.J.
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Houlston, R.S.
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Meyer, E.R.
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Nielsen, M.
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Parry, S.
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Tyler, E.
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Moskvina, V.
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Cheadle, J.P.
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Sampson, J.R.
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Dallosso, A.R.
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Dolwani, S.
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Jones, N.
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Jones, S.
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Colley, J.
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Maynard, J.
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Idziaszczyk, S.
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Humphreys, V.
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Arnold, J.
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Donaldson, A.
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Eccles, D.
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Ellis, A.
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Evans, D.G.
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Frayling, I.M.
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Hes, F.J.
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Houlston, R.S.
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Meyer, E.R.
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Nielsen, M.
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Parry, S.
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Tyler, E.
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Moskvina, V.
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Cheadle, J.P.
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Sampson, J.R.
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Dallosso, A.R., Dolwani, S., Jones, N., Jones, S., Colley, J., Maynard, J., Idziaszczyk, S., Humphreys, V., Arnold, J., Donaldson, A., Eccles, D., Ellis, A., Evans, D.G., Frayling, I.M., Hes, F.J., Houlston, R.S., Meyer, E.R., Nielsen, M., Parry, S., Tyler, E., Moskvina, V., Cheadle, J.P. and Sampson, J.R. (2008) Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut, 57 (9), 1252-1255. (doi:10.1136/gut.2007.145748).

Record type: Article

Abstract

Background: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.
Objectives: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.
Methods: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in ~300 population controls.
Results: Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p?=?0.0009; exact test for trends in proportions) and presented earlier (p?=?0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases.
Conclusion: Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.

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Published date: 2008

Identifiers

Local EPrints ID: 69931
URI: http://eprints.soton.ac.uk/id/eprint/69931
ISSN: 1468-3288
PURE UUID: e8cf5363-8acb-40c8-84de-da4053954293
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 06 Jan 2010
Last modified: 14 Mar 2024 02:34

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Contributors

Author: A.R. Dallosso
Author: S. Dolwani
Author: N. Jones
Author: S. Jones
Author: J. Colley
Author: J. Maynard
Author: S. Idziaszczyk
Author: V. Humphreys
Author: J. Arnold
Author: A. Donaldson
Author: D. Eccles ORCID iD
Author: A. Ellis
Author: D.G. Evans
Author: I.M. Frayling
Author: F.J. Hes
Author: R.S. Houlston
Author: E.R. Meyer
Author: M. Nielsen
Author: S. Parry
Author: E. Tyler
Author: V. Moskvina
Author: J.P. Cheadle
Author: J.R. Sampson

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