title: Low O6-alkylguanine DNA-alkyltransferase activity in normal colorectal tissue is associated with colorectal tumours containing a GC-->AT transition in the K-ras oncogene.
abstract: O6-alkylguanine DNA-alkyltransferase (ATase) provides protection against the toxic, mutagenic and carcinogenic effects of alkylating agents, principally by removing the promutagenic lesion O6-alkylguanine from DNA. Differences in ATase activity in human tissue may thus determine mutational susceptibility. As GC-->AT transitions, which can be induced by O6-alkylguanine in DNA, are commonly observed in the K-ras oncogene of alkylating agent induced animal tumours and in human colorectal tumours, we have examined whether differences in ATase activity may affect the risk of K-ras mutations in humans with colorectal tumours. NTase activity in normal tissue from individuals with a K-ras mutation in colorectal tissue and more specifically a GC-->AT transition (but not a transversion mutation) was significantly lower than that in individuals without a mutation (P < 0.01). Thus, individuals with low ATase activity in normal tissue (i.e. below the median) were at increased risk of having a transition (OR 10.1; 95% CI 1.9-99.0), but not a transversion mutation (OR 1.7; 95% CI 0.3-12.2). There were no significant differences in tumour ATase activity in individuals with or without a mutation. These results suggest that ATase can protect colorectal tissue against the mutagenic effects of alkylating agents and furthermore, that alkylating agent exposure plays a role in the aetiology of colorectal tumours containing a GC-->AT transition in the K-ras oncogene.
authors.affiliation: Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK.
authors.forename: P E
authors.initials: PE
authors.lastname: Jackson
authors.forename: C N
authors.initials: CN
authors.lastname: Hall
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connor
authors.forename: D P
authors.initials: DP
authors.lastname: Cooper
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
authors.forename: A C
authors.initials: AC
authors.lastname: Povey
mesh_terms: D003106:Colon / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012007:Rectum / Q000201:enzymology*
chemical_list: D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase