Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis

Christopher G. Smith; Hannah West; Rebecca Harris; Shelley Idziaszczyk; Timothy S. Maughan; Richard Kaplan; Susan Richman; Philip Quirke; Matthew Seymour; Valentina Moskvina; Verena Steinke; Peter Propping; Frederik J. Hes; Juul Wijnen; Jeremy P. Cheadle

doi:10.1093/jnci/djt183

Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis

Christopher G. Smith, Hannah West, Rebecca Harris, Shelley Idziaszczyk, Timothy S. Maughan, Richard Kaplan, Susan Richman, Philip Quirke, Matthew Seymour, Valentina Moskvina, Verena Steinke, Peter Propping, Frederik J. Hes, Juul Wijnen, Jeremy P. Cheadle

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20 Scopus citations

Abstract

Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10^-3; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10^-4; P = 1.4×10^-5 combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1^Gly308Glu carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1^Gly308Glu may act as a low-penetrance allele that contributes to colorectal tumorigenesis.

Original language	English
Pages (from-to)	1249-1253
Number of pages	5
Journal	Journal of the National Cancer Institute
Volume	105
Issue number	16
DOIs	https://doi.org/10.1093/jnci/djt183
State	Published - 21 Aug 2013
Externally published	Yes

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Smith, C. G., West, H., Harris, R., Idziaszczyk, S., Maughan, T. S., Kaplan, R., Richman, S., Quirke, P., Seymour, M., Moskvina, V., Steinke, V., Propping, P., Hes, F. J., Wijnen, J., & Cheadle, J. P. (2013). Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. Journal of the National Cancer Institute, 105(16), 1249-1253. https://doi.org/10.1093/jnci/djt183

@article{692898d0955740a2a03228fb2a53d04e,

title = "Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis",

abstract = "Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10-3; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10-4; P = 1.4×10-5 combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1Gly308Glu carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1Gly308Glu may act as a low-penetrance allele that contributes to colorectal tumorigenesis.",

author = "Smith, {Christopher G.} and Hannah West and Rebecca Harris and Shelley Idziaszczyk and Maughan, {Timothy S.} and Richard Kaplan and Susan Richman and Philip Quirke and Matthew Seymour and Valentina Moskvina and Verena Steinke and Peter Propping and Hes, {Frederik J.} and Juul Wijnen and Cheadle, {Jeremy P.}",

note = "Funding Information: This work was supported by Tenovus; the Kidani Trust; Cancer Research Wales; the Bobby Moore Fund from Cancer Research UK; the Wales Gene Park; and the Wales Assembly Government NISCHR Cancer Genetics BRU. Funding Information: We thank James Colley, Stefan Aretz, and the COIN and COIN-B management groups and members for their support or advice. We thank Alex White for molecular modeling. We acknowledge the use of DNA from blood samples collected in COIN, COIN-B, FOCUS2, FOCUS3, and PICCOLO funded by Cancer Research UK and the MRC. These trials were conducted with the support of the National Institute of Health Research Cancer Research Network. We acknowledge the use of DNA from the UK Blood Services collection, funded by the Wellcome Trust grant 076113/C/04/Z, by the Juvenile Diabetes Research Foundation grant WT061858, and by the National Institute of Health Research of England.",

year = "2013",

month = aug,

day = "21",

doi = "10.1093/jnci/djt183",

language = "English",

volume = "105",

pages = "1249--1253",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "16",

}

Smith, CG, West, H, Harris, R, Idziaszczyk, S, Maughan, TS, Kaplan, R, Richman, S, Quirke, P, Seymour, M, Moskvina, V, Steinke, V, Propping, P, Hes, FJ, Wijnen, J & Cheadle, JP 2013, 'Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis', Journal of the National Cancer Institute, vol. 105, no. 16, pp. 1249-1253. https://doi.org/10.1093/jnci/djt183

TY - JOUR

T1 - Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis

AU - Smith, Christopher G.

AU - West, Hannah

AU - Harris, Rebecca

AU - Idziaszczyk, Shelley

AU - Maughan, Timothy S.

AU - Kaplan, Richard

AU - Richman, Susan

AU - Quirke, Philip

AU - Seymour, Matthew

AU - Moskvina, Valentina

AU - Steinke, Verena

AU - Propping, Peter

AU - Hes, Frederik J.

AU - Wijnen, Juul

AU - Cheadle, Jeremy P.

N1 - Funding Information: This work was supported by Tenovus; the Kidani Trust; Cancer Research Wales; the Bobby Moore Fund from Cancer Research UK; the Wales Gene Park; and the Wales Assembly Government NISCHR Cancer Genetics BRU. Funding Information: We thank James Colley, Stefan Aretz, and the COIN and COIN-B management groups and members for their support or advice. We thank Alex White for molecular modeling. We acknowledge the use of DNA from blood samples collected in COIN, COIN-B, FOCUS2, FOCUS3, and PICCOLO funded by Cancer Research UK and the MRC. These trials were conducted with the support of the National Institute of Health Research Cancer Research Network. We acknowledge the use of DNA from the UK Blood Services collection, funded by the Wellcome Trust grant 076113/C/04/Z, by the Juvenile Diabetes Research Foundation grant WT061858, and by the National Institute of Health Research of England.

PY - 2013/8/21

Y1 - 2013/8/21

N2 - Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10-3; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10-4; P = 1.4×10-5 combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1Gly308Glu carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1Gly308Glu may act as a low-penetrance allele that contributes to colorectal tumorigenesis.

AB - Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10-3; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10-4; P = 1.4×10-5 combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1Gly308Glu carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1Gly308Glu may act as a low-penetrance allele that contributes to colorectal tumorigenesis.

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U2 - 10.1093/jnci/djt183

DO - 10.1093/jnci/djt183

M3 - Article

C2 - 23852950

AN - SCOPUS:84883185736

SN - 0027-8874

VL - 105

SP - 1249

EP - 1253

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

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ER -

Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis

Abstract

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