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PMID: 16891355 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents.

Gut ·Vol. 56 ·No. 3 ·2007-03-00 ·Pages 380-4

Lees NP, Harrison KL, Hall CN, Margison GP, Povey AC

Abstract

O(6)-alkylguanine DNA-alkyltransferase (MGMT) provides protection against alkylating agent-induced GC-->AT transition mutations. Such mutations are frequently seen in the KRAS oncogene of large colorectal adenomas, but whether adenoma or mutational risk in humans is influenced by MGMT activity and alkylating agent exposure is unclear. Hence, MGMT activity and, as an indicator of alkylating agent exposure, DNA-N7-methylguanine (N7-MeG) levels were determined in the normal tissue of patients with and without adenomas. Biopsy specimens of normal colorectal mucosa were collected during colonoscopy from 85 patients with histologically proved colorectal adenomas (cases) and from 85 patients free of gastrointestinal neoplasia (referents) matched by age, sex and biopsy location. MGMT activity and N7-MeG levels were measured in colorectal tissue extracts and DNA, respectively. MGMT activity was higher in the normal mucosa of cases than in referents (6.65+/-3.03 vs 5.61+/-2.74 fmol/micro g DNA, p = 0.01). On stratification of cases, MGMT activity was found to be considerably greater in the normal mucosa of cases with large adenomas (p = 0.003) and slightly higher in cases with a GC-->AT transition mutation in the K-ras gene (p = 0.03). Elevated MGMT levels were associated with an increased risk of adenoma (OR 1.17, 95% CI 1.03 to 1.33 per unit increase in activity). Detectable levels of N7-MeG were found in DNA from 89% of cases and 93% of referents, with levels ranging from <0.1 to 7.7 micro mol/mol dG. Cases and referents had similar DNA-N7-MeG levels. Human exposure to methylating agents is widespread. MGMT activity is increased in the normal mucosa of patients with adenomas.

MeSH Terms
Adenoma/genetics,metabolism Aged Aged, 80 and over Carrier Proteins/genetics,metabolism Case-Control Studies Colonic Polyps/genetics,metabolism Colonoscopy Colorectal Neoplasms/genetics,metabolism DNA Mutational Analysis/methods DNA Repair DNA, Neoplasm/genetics Female Guanine/analogs & derivatives,metabolism Humans Intestinal Mucosa/enzymology Male Membrane Proteins/genetics,metabolism Middle Aged Neoplasm Proteins/genetics,metabolism O(6)-Methylguanine-DNA Methyltransferase/metabolism
Chemicals
Carrier Proteins DNA, Neoplasm Membrane Proteins Neoplasm Proteins SSPN protein, human Guanine 7-methylguanine O(6)-Methylguanine-DNA Methyltransferase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lees N P
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK.
Harrison K L
Hall C N
Margison G P
Povey A C
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Article Info
Journal
Gut
Abbr.
Gut
ISSN
0017-5749
DOI
10.1136/gut.2006.097899
Published
2007-03-00
Epub
2006-00-04
Pages
380-4
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC1856833
Subset
IM
Corrections
CommentIn
PMID: 17339242
External Links
PubMed source DOI: 10.1136/gut.2006.097899 PMC Full Text View journal details
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