8-hydroxyguanine and Carcinoma--Squamous-Cell

We examined whether cigarette smoking affects the degrees of oxidative damage (8-hydroxyl-2'-deoxyguanosine [8-OHdG]) on mitochondrial DNA (mtDNA), whether the degree of 8-OHdG accumulation on mtDNA is related to the increased total mtDNA copy number, and whether human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys polymorphisms affect the degrees of 8-OHdG accumulation on mtDNA in thoracic esophageal squamous cell carcinoma (TESCC).. DNA extracted from microdissected tissues of paired noncancerous esophageal muscles, noncancerous esophageal mucosa, and cancerous TESCC nests (n = 74) along with metastatic lymph nodes (n = 38) of 74 TESCC patients was analyzed. Both the mtDNA copy number and mtDNA integrity were analyzed by quantitative real-time polymerase chain reaction (PCR). The hOGG1 Ser326Cys polymorphisms were identified by restriction fragment length polymorphism PCR and PCR-based direct sequencing.. Among noncancerous esophageal mucosa, cancerous TESCC nests, and metastatic lymph nodes, the mtDNA integrity decreased (95.2 to 47.9 to 18.6 %; P < 0.001) and the mtDNA copy number disproportionally increased (0.163 to 0.204 to 0.207; P = 0.026). In TESCC, higher indexes of cigarette smoking (0, 0-20, 20-40, and >40 pack-years) were related to an advanced pathologic N category (P = 0.038), elevated mtDNA copy number (P = 0.013), higher mtDNA copy ratio (P = 0.028), and increased mtDNA integrity (P = 0.069). The TESCC mtDNA integrity in patients with Ser/Ser, Ser/Cys, and Cys/Cys hOGG1 variants decreased stepwise from 65.2 to 52.1 to 41.3 % (P = 0.051).. Elevated 8-OHdG accumulations on mtDNA in TESCC were observed. Such accumulations were associated with a compensatory increase in total mtDNA copy number, indexes of cigarette smoking, and hOGG1 Ser326Cys polymorphisms.

Topics: Carcinoma, Squamous Cell; DNA Glycosylases; DNA, Mitochondrial; Esophageal Neoplasms; Esophagus; Female; Genotype; Guanine; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Polymorphism, Genetic; Prognosis; Real-Time Polymerase Chain Reaction; Smoking; Thoracic Neoplasms

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

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

Esophageal tissue often undergoes oxidative damage from exposure to cigarettes and alcohol. The OGG1 gene plays a major role in maintaining genetic integrity by removing 8-oxoguanine (8-oxoG) in cellular DNA by way of the base excision repair pathway. The OGG1 gene is located at 3p26.2 of the human chromosome. Although deletion in the 3p region is frequently found in cases of esophageal cancer, few reports have focused on the allelic loss of the OGG1 gene. Using 24 samples of surgically-resected esophageal cancer tissue, we assessed the allelic loss of the OGG1 gene with a set of three microsatellite markers that flank the OGG1 gene. We compared the loss of homozygosity status for the OGG1 gene with clinicopathologic factors, as well as OGG1 expression and accumulation of 8-oxoG, which was estimated in an immunohistochemical study. Of 24 cases, 20 were suitable for determining OGG1 allelic loss. Allelic loss of OGG1 was observed in 6 of 20 (30%) cases. An inverse correlation between OGG1 allelic loss and OGG1 expression was weakly observed (p=0.051). In contrast, OGG1 allelic loss showed a positive correlation with 8-oxoG accumulation, although the correlation was not statistically significant (0.095). OGG1 allelic loss was observed in 30% of patients in our study, a lower frequency than that reported in other malignancies, and correlated with reduced OGG1 expression and 8-oxoG accumulation. These findings suggest that attenuated OGG1 expression contributes to 8-oxoG accumulation under oxidative stress, resulting in cancer development in the esophagus. Thus, OGG1 allelic loss is related to carcinogenesis by oxidative stress rather than cancer progression in esophageal cancer.

Topics: Carcinoma, Squamous Cell; Cell Differentiation; DNA Damage; DNA Glycosylases; DNA Repair; Esophageal Neoplasms; Esophagus; Guanine; Homozygote; Humans; Immunoenzyme Techniques; Loss of Heterozygosity; Lymphatic Metastasis; Microsatellite Repeats; Neoplasm Invasiveness; Oxidative Stress

The human homologue of the yeast OGG1 gene, hOGG1, has been cloned, and its genetic structure has been determined. Several polymorphisms in the hOGG1 gene were detected in the Japanese populations, and among them, the Ser-Cys polymorphism at codon 326 has been shown to have a functional difference in complementation of mutant Escherichia coli that is defective in the repair of 8-hydroxyguanine. Activity in the repair of 8-hydroxyguanine is greater in hOGG1-Ser326 protein than in hOGG1(326) protein. Because many environmental carcinogens produce 8-hydroxyguanine residue and mismatching to this modified base potentially causes oncogenic mutations, the capacity to repair these lesions can be involved in cancer susceptibility in human beings. We, therefore, examined allele distributions of the Ser326Cys polymorphism in a case-control study of male lung cancer in Okinawa. The analyses based on 241 cases and 197 hospital controls disclosed the following findings. (a) Those with the Cys/Cys genotype were at an increased risk of squamous cell carcinoma and nonadenocarcinoma compared to those with the Ser/Cys and those with the Ser/Ser genotypes combined. The odds ratios adjusted for age and smoking history were 3.01 (95% confidence interval, 1.33-6.83) and 2.18 (95% confidence interval, 1.05-4.54), respectively. (b) The odds ratios for other histological subtypes of lung cancer or those in total were not significant. Those for Cys/Cys or Ser/Cys genotype against Ser/Ser did not reach statistical significance in any cell type. (c) The distributions of this polymorphism varied for different populations (Chinese, Japanese, Micronesians, Melanesians, Hungarians, and Australian Caucasians), with much less prevalence of Cys allele in the latter three populations. Although our sample size was limited, these results indicate that the Ser326Cys variant may be related to squamous cell lung cancer susceptibility. The Cys/Cys genotype appears to be more susceptible to squamous cell carcinoma, although the risk is less than that previously reported to be associated with the CYP1A1 gene. Further studies are needed to assess the importance of the interpopulation variation to cancer susceptibility.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Carcinoma, Squamous Cell; Case-Control Studies; Cysteine; DNA Damage; Genetic Predisposition to Disease; Guanine; Humans; Japan; Lung Neoplasms; Male; Middle Aged; N-Glycosyl Hydrolases; Polymorphism, Genetic; Risk Assessment; Serine