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

Acladious, N. N.; Harrison, Kathryn; Sutton, Chris J; Povey, Andrew C.; Mandal, Debashis; Kitchener, Henry C

doi:10.1016/j.ygyno.2004.03.005

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…N7-MedGp levels have been associated with increased risk of treatment failure in cervical cancer (27) and the presence of N7-MedGp in bladder DNA is then consistent with the hypothesis that exposure to methylating agents may play an etiologic role in the development of this cancer. In contrast to previous studies which have reported lower DNA adduct levels in tumor DNA compared with DNA from adjacent normal tissue (28,29), in this study, N7-MedGp levels were much higher in tumor than normal DNA.…”

Section: Discussionsupporting

confidence: 73%

Bladder Tumor Contains Higher N7-Methylguanine Levels in DNA than Adjacent Normal Bladder Epithelium

Saad

O’Connor²,

Mostafa³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Schistosoma haematobium -infected patients are more likely to develop bladder cancer and be more exposed to carcinogenic N-nitroso compounds than uninfected patients. As N7-methylguanine is a marker of exposure to methylating agents of this type, we have measured N7-methyldeoxyguanosine 3V-monophosphate (N7-MedGp) by 32 P postlabeling. DNA was isolated from 42 paired normal and tumor tissue of Egyptians with bladder cancer. N7-MedGp was detected in DNA from 93% of the tumors and 74% of the normal bladder tissue samples. Adduct levels were highly variable and ranged from 0.04 to 6.4 and from 0.02 to 0.72 Mmol/mol deoxyguanosine 3V-monophosphate (dGp) in tumor and normal DNA, respectively. N7-MedGp levels in normal and tumor DNA were highly correlated with one another (P = 0.007). The mean difference (95% confidence interval) in adduct levels between tumor and normal DNA was 0.21 (0.13-0.32) Mmol/mol dGp and this was statistically significant (P < 0.001). The adduct ratio (tumor DNA/normal DNA) varied between 0.2 and 136 (median, 4.6). N7-MedGp levels were not associated with gender, age, or the presence of schistosomiasis. However, lower N7-MedGp levels were found in normal DNA from individuals lacking the GSTM1 gene (P = 0.03) but not the GSTT1 gene or in subjects with the Ile105Val GSTP1 polymorphism. These results show that exposure to methylating agents is widespread and suggest that such exposure may play a role both in tumor initiation and progression. (Cancer Epidemiol Biomarkers Prev 2006; 15(4):740 -3)

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Section: Discussionsupporting

confidence: 73%

Bladder Tumor Contains Higher N7-Methylguanine Levels in DNA than Adjacent Normal Bladder Epithelium

Saad

O’Connor²,

Mostafa³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…This is the first study to report the measurement of alkylation damage in DNA obtained from cervical cytology samples and only the second report of specific alkylation damage measurement in cervical tissues. 28 In our previous study of N7-MedG levels and treatment failure for CIN, we also found that smokers had higher levels compared to nonsmokers, but this association was not statistically significant and there was no association with number of cigarettes smoked. However, the sample size in this prior study was small.…”

Section: Discussionmentioning

confidence: 59%

“…However, other DNA adducts, in particular alkylation-induced lesions, may also be present, but would not have been detected by the procedures used. Our recent report that N7-MedG is a marker for treatment failure in cervical intraepithelial neoplasia (CIN) patients 28 has led us to investigate further the relationship between smoking and DNA alkylation in a series of cervical cytology samples in women with high and low grade CIN.…”

mentioning

confidence: 99%

N7‐methyldeoxyguanosine levels in DNA isolated from cervical cytology samples are associated with smoking

Harrison

Khan

Dey

et al. 2006

Intl Journal of Cancer

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Smoking has been associated, in epidemiological studies, with an increased risk of cervical neoplasia. This may be in part due to the presence of tobacco-specific nitrosamines in cervical mucous of smokers, which may result in carcinogenic DNA damage. We have thus examined whether cervical DNA contains alkylation damage arising from exposure to methylating agents (N7-methyldeoxyguanosine, N7-MedG). DNA was extracted from cervical cytology samples and N7-MedG levels were measured using an immunoslotblot assay. Ninety percentage of the DNA samples were alkylated and N7-MedG levels (mean, 95% CI) in ever-smokers (1.27, 0.90-1.81 lmol/mol dG) were significantly higher than those in nonsmokers (0.42, 0.20-0.91 lmol/mol dG: p 5 0.005). N7-MedG adduct levels were significantly correlated with number of cigarettes smoked per day and pack years of cigarette smoking in current smokers. There was no association with N7-MedG levels and cervical intraepithelial neoplasia status, age, parity or contraception use. Our study suggests that cervical DNA contains alkylation damage that can arise from exposure to cigarette smoke. ' 2006 Wiley-Liss, Inc.Key words: alkylation; smoking; cervical cancer; N7-methylguanine Cervical cancer is one of the most common neoplastic diseases affecting women with a combined worldwide incidence of almost half a million new cases annually.1 Laboratory and epidemiological research has provided overwhelming evidence that some subtypes of human papillomavirus (HPV) are a ''necessary but insufficient cause'' for cervical cancer.2-5 Therefore, other risk factors are also needed for the initiation and promotion of cervical carcinogenesis.A number of epidemiological studies suggest that cigarette smoking may be an aetiological risk factor for cervical cancer. 6-10The risk for neoplasia appears to increase with longer duration and intensity of smoking. 11,12 The cervix is known to contain enzymes that can metabolise the carcinogens that are present in cigarette smoke, 13,14 and expression of these enzymes may be modified by HPV infection. 14,15 Cigarette-derived chemicals, nicotine and its major metabolite cotinine, have been found in cervical mucus at levels higher than those present in blood serum, [16][17][18][19] and the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) is more prevalent in cervical mucus samples from smokers than those from nonsmokers.20 NNK alkylates DNA forming a range of DNA adducts including N7-methyldeoxyguanosine (N7-MedG), a poorly repaired adduct that can act as a biomarker of exposure to alkylating agents. 21 DNA adducts have been detected in human cervical tissues. [22][23][24][25][26][27] In most, but not all, of these studies, adduct levels were higher in smokers with the detected adducts, probably arising from exposure to polycyclic aromatic hydrocarbons present in cigarette smoke. However, other DNA adducts, in particular alkylation-induced lesions, may also be present, but would not have been detected by the procedures used. Our recent r...

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“…N7-meG levels are commonly measured, because this adduct is formed in the highest amounts after methylating agent exposure and they persist for longer than other adducts as they are poorly repaired [Bianchini and Wild, 1994]. N7-meG in human lung tissue DNA has been associated with smoking [Lewis et al, 2004;Mustonen et al, 1993] and in human cervical tissue with increased risk of failure of cervical intraepithelial neoplasia treatment [Acladious et al, 2004]. The earliest reported lesion to be found in human tissue DNA, O 6 -meG [Umbenhauer et al, 1985], has also been detected in human lung [Wilson et al, 1989] but no systematic studies in humans on the association between the levels of this adduct and cancer risk have been published.…”

Section: Dna Alkylation Adducts In Human Tissuesmentioning

confidence: 99%

Genetic Variation at the Human MGMT Locus and its Biological Consequences

Gp¹,

Povey²,

Santibanez-Koref³

2006

CPG

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O 6 -alkylguanine-DNA alkyltransferase (MGMT) repairs DNA adducts that result from alkylation at the O 6 position of guanine. These lesions are mutagenic and toxic and can be produced by a variety of agents ranging from carcinogens present in cigarette smoke to drugs used in cancer chemotherapy. There is a considerable amount of interindividual variation of MGMT activity and recent work has uncovered a series of polymorphisms that affect protein activity or are associated with differences in expression levels. On the other hand, current evidence for an association with cancer risk is tenuous: while some studies find such associations, others fail to support them. However, all published studies are based on small sample numbers. Not yet addressed are issues such as the relationship between sequence variation and the extent of the side effects of chemotherapy involving O 6 -alkylating agents. This review summarises the current state of knowledge in these areas.

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

Cited by 6 publications

References 29 publications

Bladder Tumor Contains Higher N7-Methylguanine Levels in DNA than Adjacent Normal Bladder Epithelium

Bladder Tumor Contains Higher N7-Methylguanine Levels in DNA than Adjacent Normal Bladder Epithelium

N7‐methyldeoxyguanosine levels in DNA isolated from cervical cytology samples are associated with smoking

Genetic Variation at the Human MGMT Locus and its Biological Consequences

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