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Supplement: International Research Conference on Food, Nutrition & Cancer

DNA Alkylation and Repair in the Large Bowel: Animal and Human Studies^{1 ,2}

Andrew C. Povey³, Alaa F. Badawi^*,4, Donald P. Cooper^*,5, C. Nicholas Hall, Kathryn L. Harrison, Peta E. Jackson^*,6, Nicholas P. Lees, Peter J. O’Connor^*,7 and Geoffrey P. Margison^*

Centre for Occupational and Environmental Health, School of Epidemiology and Health Sciences, University of Manchester, Manchester, M13 9PL, ^* Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, M20 9BX and Department of General Surgery, Wythenshawe Hospital, Manchester M23 9LT, England

³To whom correspondence should be addressed. E-mail: apovey{at}man.ac.uk.

O⁶-Methylguanine (O⁶-MeG), a procarcinogenic DNA adduct that arises from exposure to methylating agents, has been detected in human colorectal DNA at levels comparable to those that cause adverse effects in model systems. O⁶-MeG levels vary within the colon, being higher in the cancer-prone regions of the large bowel. In rats and mice, O⁶-MeG persistence in colon DNA is associated with the induction of colon tumors after treatment with methylating agents. These tumors frequently contain K-ras GCAT transition mutations, which is consistent with the mutagenic properties of O⁶-MeG: such mutations are also commonly found in human colorectal cancers. O⁶-Alkylguanine adducts are removed by the DNA repair protein, O⁶-alkylguanine DNA-alkyltransferase (MGMT). MGMT overexpression in transgenic mice reduces the formation of K-ras GCAT mutations and tumors induced by methylating agents. Interindividual variations in human colon MGMT activity are large and large bowel tumors can occur in regions of low activity. Low MGMT activity in normal mucosa has been associated with the occurrence of K-ras GCAT mutations, whereas reduced MGMT expression and an increased frequency of K-ras GCAT mutations in colorectal cancers have been linked to MGMT promoter methylation. MGMT activity is also lower in adenomas than in adjacent normal tissue but only in those adenomas with this specific mutation. These results are entirely consistent with the hypothesis that GCAT mutations in the K-ras oncogene result from the formation and persistence of O⁶-alkylguanine lesions in colorectal DNA. Human exposure to endogenous or exogenous alkylating agents may thus be an environmental determinant of colorectal cancer risk.

KEY WORDS: • O⁶-methylguanine • O⁶-alkylguanine DNA-alkyltransferase • MGMT • K-ras • colorectal cancer

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