| Esophageal cancer (EC), one of the six most frequent malignancies in the world, characterizes by its unbalanced geographic distribution, with a difference in its incidence as big as 500 times between the high- and low- incidence region. A high-incidence zone for EC has been found from the east of Turkey to Iraq, Iran and Middle Asia, straightly extending to the North China. The incidence of esophageal cancer in male 31.66/100,000 is higher than in female 15.93/100,000. Linzhou (formerly Linxian) and nearby Anyang city have been well recognized as the highest incidence area for EC in the world, with an incidence of 161/100,000 for men and 103/100,000 for female. The dramatic differences in geographic distribution for EC raise many important scientific questions, e.g., what is the molecular basis for the high susceptibility to EC and what is the relationship between environment and genetic changes in high susceptibility to EC?Although the exact factors for EC still remain unclear, the research on EC in the high-incidence area in Henan Province showed that the environmental carcinogens, are the mainly risk factors. Such as the nitroamine and fungal toxins. The molecular studies further indicate that alteration of DNA repaired enzyme (polymorphism) may play an important role in human carcinogenesis. These alterated enzymes may be desirable biomarkers for identifying high-risk subjects.O6-Alkylguanine-DNA alkyltransferase (AGT) is one of important DNA repair enzyme in repairing O6-alkylguanine in DNA. O6-Alkylguanine is a one of importantly former mutations induced from alkylchemistry substances existing in environment and drugs. A large number of environmental carcinogens and mutagens, including N-nitroso compounds is alkylating agents. Many cancer chemotherapic drugs are alkylating agents. O6-Alkylguanine is a major premutagenetic lesion in DNA produced by these alkylating agents. If not repaired in time, the O6-alkylguaninepreferentially pairs with thymine rather than with cytosine during DNA replication, resulting in a GC to AT transition Formation and persistence of O6-alkylguanine in DNA is of major importance in mutagenesis and tumor initiation.Different activity for AGT in different populations has been observed. These differences root from methyl guanine-DNA methyltransferase (MGMT) genetic polymorphism. O6-alkylguanine-DNA alkyltransferase is coded by methylguanine-DNA methyltransferase (MGMT) gene in mammal animals, but coded by ada and ogt gene in bacterium. AGT can specifically repair O6-alkylguanine adducts in DNA by transferring the adducts from DNA to a cysteinel45 residue of its active site. The reaction is stoichiometric and there is no regeneration of the active site and no turnover of AGT. Thus AGT plays a critical role in protecting cells from mutagenetic or carcinogenetic action of alkylating agents. We hypothesized that, with the presence of high nitrite compound in Anyang, Henan, DNA repair mistake caused by existing of genetic polymorphisms of AGT may raise the risk of esophageal carcinogenesis. To test our hypothesis, a retrospective case-control study was conducted to characterize the changes of AGT polymorphism in subjects from high incidence area in Henan, China, and to provide informative evidence and useful methods for high-risk population screening. Materials and Methods:Two hundred and seventy-five cases with esophageal squmous cell carcinoma (ESCC) were recruited from Anyang Tumor Hospital, all the patients were histopathologically confirmed from 2000 to 2002. All the cases were from Anyang district and surrounding areas and were investigated to exclude other simultaneous malignancies. Three hundred and fifteen subjects with matched age and sex were randomly selected as control group from the same region in the field surveys between year 2000 and 2002. Genomic DNA was extracted from remnant liquid of blood clot using protocols provided by Gentra Puregene DNA purification kit. Polymerase Chain Reaction (PCR) and PCR based Restriction Fragment Length Polymorphisms (PCR-RFLP) and...
|
PDF Full Text Request