Levels of the DNA adduct, N7-methyldeoxyguanosine, are associated with increased risk of failure of treatment of cervical intraepithelial neoplasia

• Published in: Gynecologic oncology Vol. 93; no. 3; pp. 605 - 609
• Main Authors: Acladious, N.N, Harrison, K.L, Sutton, C.J, Povey, A.C, Mandal, D, Kitchener, H
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2004
• Subjects: Adult; Alkylating Agents - adverse effects; Biopsy; Cervical intraepithelial neoplasia; Cervical Intraepithelial Neoplasia - chemically induced; Cervical Intraepithelial Neoplasia - genetics; Cervical Intraepithelial Neoplasia - metabolism; Cervical Intraepithelial Neoplasia - pathology; Cohort Studies; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA Adducts - metabolism; DNA, Neoplasm - drug effects; DNA, Neoplasm - metabolism; Female; Humans; Methylating agent; N7-methyldeoxyguanosine; Prospective Studies; Risk Factors; Smoking - adverse effects; Treatment Outcome; Uterine Cervical Neoplasms - chemically induced; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Methylating agent; Cervical intraepithelial neoplasia; N7-methyldeoxyguanosine
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2004.03.005

Objective. To determine whether exposure to methylating agents was a risk factor for treatment failure in women undergoing colposcopic examination. Methods. Nine hundred fifty-eight women attending for colposcopic examination after abnormal cervical smear test results were recruited into the study cohort. Information on demographic factors, smoking and other risk factors was obtained and a pre-treatment biopsy was taken and stored at −70°C. After follow-up, cases who had treatment failure of cervical intraepithelial neoplasia (CIN) within 2 years following treatment were identified ( n = 77) and matched to women with no treatment failure of CIN in this time period (controls, n = 154). DNA was extracted from the pre-treatment biopsies and levels of N7-methyl-deoxyguanosine (N7-MedG), a marker of exposure to methylating agents, were quantified as the ring-opened form of the base damage by a validated immunoslotblot assay. Results. Sufficient DNA for N7-MedG analysis was extracted from 61 subjects corresponding to 20 matched case control pairs. N7-MedG was detected in cervical DNA with levels ranging from non-detected (<0.1 μmol/mol dG) to 4.83 μmol/mol dG. N7-MedG levels were significantly higher in cases (geometric mean 0.99 μmol/mol dG) than controls (0.33 μmol/mol dG; P = 0.01). There were no associations between N7-MedG levels and HPV or smoking status. Log N7-MedG content, after adjustment for HPV status at time of treatment, was found to be significantly associated with increased risk of treatment failure (OR 5.74, 95% CI 1.05–31.23). Conclusions. The association between pre-treatment levels of DNA damage induced by methylating agents and subsequent treatment failure implicates methylating agent exposure as a causative factor in treatment failure.