Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents.
AffiliationDepartment of Gastrointestinal Surgery, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK.
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AbstractThere is increasing evidence to suggest that O(6)-alkyl guanine DNA-alkyltransferase (MGMT) activity provides protection against alkylating agent induced formation of GC-->AT transition mutations in the K-ras oncogene of colorectal tumours. As this mutagenic event occurs during the growth of adenomas, both biomarkers of exposure (N7-methylguanine levels in DNA) and susceptibility (MGMT activity) were measured in biopsy samples obtained from normal and adenomatous tissue from 34 patients with large adenomas (>10 mm in size). There was no correlation between MGMT activity in the adenoma and in matched normal tissue. However, MGMT activity was significantly lower in adenoma tissue than in adjacent normal mucosa (5.18 versus 7.05 fmol/microg DNA, P = 0.01), particularly in men and those whose age was greater than the median. Upon stratification by K-ras mutational status, MGMT activity was lower in adenomas bearing a K-ras GC-->AT transition mutation (mean 4.21 fmol/microg DNA) than in adjacent normal tissue (mean 7.7 fmol/microg DNA; P < 0.004). In contrast, there was no significant difference in MGMT activity in adenomas lacking a K-ras GC-->AT transition mutation and adjacent normal mucosa. N7-methylguanine levels however did not vary with age, gender, K-ras mutational status or MGMT activity. These results are consistent with the acquisition of K-ras GC-->AT transition mutations in adenomas with low MGMT activity as a result of unavoidable exposure to methylating agents.
CitationReduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents. 2004, 25 (7):1243-7 Carcinogenesis
- Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents.
- Authors: Lees NP, Harrison KL, Hall CN, Margison GP, Povey AC
- Issue date: 2007 Mar
- Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis.
- Authors: Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG
- Issue date: 2000 May 1
- DNA alkylation and repair in the large bowel: animal and human studies.
- Authors: Povey AC, Badawi AF, Cooper DP, Hall CN, Harrison KL, Jackson PE, Lees NP, O'Connor PJ, Margison GP
- Issue date: 2002 Nov
- 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.
- Authors: Jackson PE, Hall CN, O'Connor PJ, Cooper DP, Margison GP, Povey AC
- Issue date: 1997 Jul
- Reduced lung tumorigenesis in human methylguanine DNA--methyltransferase transgenic mice achieved by expression of transgene within the target cell.
- Authors: Liu L, Qin X, Gerson SL
- Issue date: 1999 Feb