부산대학교 도서관

Biallelic inherited mutations in the oxidative DNA damage repair gone 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 x [10.sup.-3]; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P= 4.8 x [10.sup.-4]; P= 1.4 x [10.sup.-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.sup.Gly308Glu] carriers, nor did we find any associated somatic mutator phenotype. These data suggest that [OGG1.sup.Gly308Glu] may act as a low-penetrance allele that contributes to colorectal tumorigenesis. DOI: 10.1093/jnci/djt183