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Carcinogenesis Advance Access published online on February 12, 2004
Carcinogenesis, doi:10.1093/carcin/bgh111
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents

Nicholas P. Lees 1, Kathryn L. Harrison 2, C. Nick Hall 3, Geoffrey P. Margison 4, and Andrew C. Povey 5*

1 Department of Gastrointestinal Surgery, Wythenshawe Hospital, Southmoor Rd, Wythenshawe, Manchester, M23 9LT, UK; Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20, 4BX, UK
2 Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20, 4BX, UK; School of Epidemiology and Health Sciences, Medical School, The University of Manchester, Oxford Rd, M13 9PT, UK
3 Department of Gastrointestinal Surgery, Wythenshawe Hospital, Southmoor Rd, Wythenshawe, Manchester, M23 9LT, UK
4 Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20, 4BX, UK
5 School of Epidemiology and Health Sciences, Medical School, The University of Manchester, Oxford Rd, M13 9PT, UK

* Corresponding author. E-mail: a.povey{at}man.ac.uk.

Received 3 September 2003 ; revised 2 February 2004 ; accepted 3 February 2004

Abstract

There is increasing evidence to suggest that O6-alkyl guanine DNAalkyltransferase (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 (>10mm 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 vs 7.05 fmoles/µg 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 fmoles/µg DNA) than in adjacent normal tissue (mean 7.7 fmoles/µg 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.

O6-alkylguanine DNA-alkyltransferase, MGMT, K-ras, mutation, colorectal, adenoma
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