8-hydroxyguanine and Esophageal-Neoplasms

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

To examine the effects of alcohol consumption on cancer risk, we measured oxidative DNA damage and its repair activity in the livers and esophagi of rats fed with ethanol. Using our previously designed protocol for feeding rats with a high concentration of ethanol, we examined the effects of ethanol consumption on 8-oxo-Gua generation and repair activity in the livers and esophagi of rats. We found that a high concentration of ethanol accompanied with a vitamin-depleted diet increased 8-oxo-Gua and its repair activity. 8-Oxo-Gua is known to induce point mutations, leading to carcinogenesis. Therefore, these results suggested that a high concentration of ethanol and an irregular diet increased liver and esophageal cancer risk. On the other hand, we showed that a low concentration of ethanol decreased 8-oxo-Gua and its repair activity in the livers of mice treated with a carcinogen. Taken together, the effects of ethanol consumption on cancer risk depend on the ethanol concentration and the diet pattern.

Topics: Alcohol Drinking; Animals; Carcinogens; Cell Transformation, Neoplastic; Diet; DNA Damage; Esophageal Neoplasms; Esophagus; Ethanol; Guanine; Liver; Liver Neoplasms; Mice; Oxidative Stress; Rats; Rats, Sprague-Dawley

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

Oxidative stress is involved in many types of DNA damage, e.g., resulting in 8-hydroxyguanine adducts. Since a human counterpart exists for the yeast gene OGG1 (hOGG1) encoding an enzyme that repairs 8-hydroxyguanine, its polymorphism, Ser(326)Cys, might have potential as a genetic marker for cancer susceptibility. To investigate its association with stomach cancer risk and possible interactions with environmental factors, we conducted a case-control study of 101 stomach cancer cases and 198 controls using PCR-single-strand conformation polymorphism and a questionnaire approach. The proportional distribution of the Cys/Cys alleles did not differ between stomach cancer cases and controls, but subgroup analyses revealed that a frequent drinking habit elevated the odds ratio (OR) for stomach cancer in Cys/Cys compared to Ser/Ser and Ser/Cys carriers. The ORs with frequent consumption of pickled vegetables and meat tended to be higher in Cys/Cys than in Ser/Ser and Ser/Cys carriers, these interactions being on the borderline of statistical significance. Our findings suggest that the hOGG1 Ser(326)Cys polymorphism may alter the impact of some environmental factors on stomach cancer development. For confirmation, an additional study with a larger number of subjects is now required.

Topics: Adult; Aged; Aged, 80 and over; Alcohol Drinking; Alleles; China; Cysteine; DNA-Formamidopyrimidine Glycosylase; Environment; Esophageal Neoplasms; Female; Guanine; Humans; Male; Middle Aged; N-Glycosyl Hydrolases; Odds Ratio; Oxidative Stress; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Serine; Smoking; Stomach Neoplasms