Levels of the DNA adduct, N7-methyldeoxyguanosine, are associated with increased risk of failure of treatment of cervical intraepithelial neoplasia.
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 degrees 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 micromol/mol dG) to 4.83 micromol/mol dG. N7-MedG levels were significantly higher in cases (geometric mean 0.99 micromol/mol dG) than controls (0.33 micromol/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.
Acladious
N N
NN
Department of Genito-Urinary Medicine, Manchester Royal Infirmary, Manchester, UK.
Harrison
K L
KL
Sutton
C J
CJ
Povey
A C
AC
Mandal
D
D
Kitchener
H
H
D000328:Adult; D000477:Alkylating Agents / Q000009:adverse effects*; D001706:Biopsy; D015331:Cohort Studies; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D006801:Humans; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D000477:Alkylating Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; C048746:7-methyl-2-deoxyguanosine; D003849:Deoxyguanosine