8-hydroxyguanine and Head-and-Neck-Neoplasms

Reduced efficiency of DNA repair systems has long been a suspected factor in increasing the risk of cancer.. In this work we investigate influence of three selected polymorphisms of DNA repair gene XRCC1 and level of oxidative damage (measured as level of 8-oxo-guanine) on modulation of the risk of HNSCC.. In group of 359 patients with HNSCC (diagnosed with OSCC) the occurrence of polymorphic variants in Arg399Gln, Arg280His and Arg194Trp of XRCC1 were studied with TaqMan technique. In addition we determined level of 8-oxo-guanine with ELISA.. Arg399Gln polymorphism and Arg194Trp polymorphism of XRCC1 gene increases the risk of HNSCC. The coexistence of Arg399Gln and Arg194Trp simultaneously enhances this effect. At the same time, their coexistence with His280His raises the risk to a level higher than in the absence of such coexistence, although the His280His itself is not associated with an increased risk of HNSCC. Patients have higher levels of 8-oxo-guanine than control group, and His280His is polymorphism with highest mean value of 8-oxoG level among studied.. Patients with HNSCC not only have an increased level of 8-oxoguanine and the Arg399Gln and Arg/Trp of XRCC1 modulate risk of cancer, but there is also a relationship between these two phenomena, and it can be explained using intragenic combinations revealing that a high level of 8-oxoG could be a potential mechanism behind the modulation of HNSCC risk by the polymorphisms studied.

Topics: DNA Repair; Genetic Predisposition to Disease; Genotyping Techniques; Guanine; Head and Neck Neoplasms; Humans; Poland; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk Factors; X-ray Repair Cross Complementing Protein 1

Squamous cell carcinoma of head and neck (SCCHN), one of the leading cancers worldwide, is most prevalent in Indian sub-continent. The major risk factors involved are smoking and consumption of alcohol, since they provide high free radical generating environment. We studied 8-oxoguanine DNA-glycosylase (OGG1) Ser326Cys polymorphism in 278 SCCHN cases and 278 matched controls by PCR-RFLP and observed that the variant genotype Ser/Cys exhibited an enhanced risk of ∼1.7 folds (OR=1.71, 95% CI=1.20-2.93) and Cys/Cys ∼2.5 folds (OR=2.55, 95% CI=1.29-5.00). Furthermore, we found a significant increase in salivary cell 8-OHdG with respect to Ser/Cys and Cys/Cys genotypes of OGG1 in SCCHN cases, when compared to Ser/Ser and Ser/Cys genotypes of the control population. Our results demonstrate that Ser326Cys variant genotype is associated with an increased risk of SCCHN in north India. Ser326Cys variant genotype was found to accumulate more of 8-OHdG, which may serve as a biomarker for early diagnosis of SCCHN.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Case-Control Studies; DNA Adducts; DNA Damage; DNA Glycosylases; Female; Guanine; Head and Neck Neoplasms; Humans; India; Male; Middle Aged; Polymorphism, Genetic; Risk Assessment; Squamous Cell Carcinoma of Head and Neck

It is possible that oxidatively damaged DNA which arises as a result of radiotherapy may be involved in the therapeutic effect of the ionizing radiation and in the side effects. Therefore, for the first time, the broad spectrum of oxidatively damaged DNA biomarkers: urinary excretion of 8-oxodG (8-oxo-7,8-dihydro-2'-deoxyguanosine), 8-oxoGua (8-oxo-7,8-dihydroguanine) as well as the level of oxidatively damaged DNA in leukocytes, was analyzed in head and neck cancer patients (n = 27) undergoing fractionated radiotherapy using methodologies which involve HPLC (high-performance liquid chromatography) prepurification followed by gas chromatography with isotope dilution mass spectrometry detection and HPLC/EC. Of all the analyzed parameters in the majority of patients, only urinary excretion of the modified nucleoside significantly increased over the initial level in the samples collected 24 hr after the last fraction. However, for the distinct subpopulation of 10 patients, a significant increase in the level of 8-oxodG in cellular DNA and a simultaneous drop in urinary 8-oxoGua (the repair product of oxidative DNA damage) were detected after completion of the therapy. Because 8-oxoGua is a repair product of the DNA damage, there is a possibility that, at least in the case of some patients with the lowest activity of OGG1 (8-oxo-7,8-dihydroguanine glycosylase), the combination of lower OGG1 repair efficacy and irradiation was associated with increased background level of 8-oxoGua in cellular DNA. Apparently reduced DNA repair is unable to cope with the radiation-induced, and the extra amount of 8-oxoGua leading to an increase of potentially mutagenic/carcinogenic lesions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Damage; DNA, Neoplasm; Dose Fractionation, Radiation; Gas Chromatography-Mass Spectrometry; Guanine; Head and Neck Neoplasms; Humans; Leukocytes; Oxidative Stress; Radiation Injuries; Uric Acid

An increasing number of studies indicate that reduced DNA-repair capacity is associated with increased cancer risk. Using a functional assay for the removal of the oxidative DNA lesion 8-oxoguanine by the DNA-repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), we have previously shown that reduced OGG activity is a risk factor in lung cancer. Here, we report that OGG activity in peripheral blood mononuclear cells from 37 cases with squamous cell carcinoma of the head and neck (SCCHN) was significantly lower than in 93 control subjects, frequency matched for age and gender. Retesting of OGG activity 3 to 4 years after diagnosis and successful treatment of 18 individuals who recovered from the disease showed that OGG activity values were similar to those determined at diagnosis, suggesting that reduced OGG activity in case patients was not caused by the disease. Logistic regression analysis indicated that the adjusted odds ratio (OR) associated with a unit decrease in OGG activity was statistically significantly increased [OR, 2.3; 95% confidence interval (95% CI), 1.5-3.4]. Individuals in the lowest tertile of OGG activity exhibited an increased risk of SCCHN with an OR of 7.0 (95% CI, 2.0-24.5). The combination of smoking and low OGG was associated with a highly increased estimated relative risk for SCCHN. These results suggest that low OGG is associated with the risk of SCCHN, and if confirmed by additional epidemiologic studies, screening of smokers for low OGG activity might be used as a strategy for the prevention of lung cancer and SCCHN.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; DNA Damage; DNA Repair; Female; Guanine; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Staging; Oxidation-Reduction; Reference Values; Risk Factors; Surveys and Questionnaires