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

Smith, Chris, West, Hannah, Harris, Rebecca, Idziaszczyk, Shelley Alexis, Maughan, Timothy Stanley, Kaplan, Richard, Richman, Susan, Quirke, Philip, Seymour, Matthew, Escott-Price, Valentina, Steinke, Verena, Propping, Peter, Hes, Frederik J., Wijnen, Juul and Cheadle, Jeremy P. 2013. Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. Journal of the National Cancer Institute 105 (16) , pp. 1249-1253. 10.1093/jnci/djt183

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Oxford University Press
ISSN: 0027-8874
Last Modified: 13 Apr 2019 21:44
URI: http://orca-mwe.cf.ac.uk/id/eprint/49303

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