Elevated levels of the pro-carcinogenic adduct, O-6-methylguanine, in normal DNA from the cancer prone regions of the large bowel

Background-The pro-mutagenic lesion O-6-methyldeoxyguanosine (O-6-MedG), a marker of exposure to many N-nitroso compounds (NOC), can be detected in no rmal and tumour DNA isolated from colorectal tissue. The biological signifi cance of this exposure is, as yet, unknown but in situ NOC formation is bac terially catalysed suggesting that NOC formation and potentially DNA alkyla tion will vary throughout the large bowel. Aims-To determine if O-6-MedG levels in colorectal DNA vary within the larg e bowel. Patients-We studied 62 men and women undergoing surgery for colorectal tumo urs in the north west of England. Methods-O-6-MedG levels were measured in paired normal and tumour DNA sampl es. DNA was digested to nucleosides, fractionated by HPLC, and purified O-6 -MedG quantified by a radioimmunoassay. Results-O-6-MedG was detected in 27 out of a total of 62 (43%) normal DNA s amples and in 30 of 58 (52%) tumour DNA samples: it was present at concentr ations of <0.01-0.94 and <0.01-0.151 pmol O-6-MedG/mol deoxyguanosine for n ormal and tumour DNA, respectively. Levels of O-6-MedG in normal, but not t umour, DNA from the proximal colon were lower than those found in DNA from either the sigmoid colon (p=0.03) or rectum (p=0.05). When the analysis was restricted to samples that contained O-6-MedG, similar results were obtain ed in that O-6-MedG levels in normal DNA were lower in the proximal colon t han in the sigmoid colon (p=0.04) or rectum (p=0.03). Conclusions-DNA alkylation varied within the large bowel possibly due to in situ NOC formation and was highest in areas of the colon and rectum where the highest incidence of large bowel tumours occurs, suggesting that DNA al kylation may play a role in the aetiology of colorectal cancer.