TGF-β RⅡ,IGFⅡR,Bax Gene Mutations And Microsatellite Instability In Gastric Cancer And Precanerous Lesions And Hyperplastic Polyps

Background: Gastric cancer(GC) is still one of the most frequent malignant tumor in the world and contributes to the first leading cause of cancer death, particularly in Asia. But the mechanism of gastric carcinogenesia is unknown. Microsatellite instability (MSI), a form of genomic instability associated with defective DNA mismatch repair, was first describled in hereditary nonpolyposis colorectal cancer. Since then, MSI and frameshift mutations in several target genes containing nucleotide repeats have been reported in a variety of familial and sporadic human cancers including GC and gastric adenoma. Dysplasia(DYS) and intestinal metaplasia(IM) are generally believed to be preneoplastic lesions of the stomach. Several hyperplastic polyps(HP) have been detected transforming into carcinomas. Studies about these precancerous conditions are as a whole scarcity.Objective: To investigate mutations of TGF- receptor typeII gene (R II), IGF IIR gene , Bax gene, and the changeable pattern of MSI in GCs and precancerous lesions and HPs in order to explore a potential role of MSI in the development of GC.Methods: To characterize the genetic events during gastriccarcinogenesis, we analyzed DNA from GCs, DYSs, IMs and HPs for MSI using five microsatellite markers and for frameshift mutations at coding nucleotide repeats of RII, IGFIIR and Bax genes. Genomic DNA from thirty-six GC and twenty-three HP specimens biopsied by endoscopy and forty-one DYS and fifty-one IM sections cut from paraffin-embedded material was respectively extracted by phenol-chlorform and xylene-proteinase K. Single stand conformation polymorphism polymerize chain reaction (PCR-SSCP) was used to analyze gene mutations and MSI.Results: The mutations of RII gene, IGFIIR gene and Bax gene was respectively detected in7, 6 and 6 cases of GC. MSI was identified in 58. 3%(21/36), 26. 8%(11/41),17. 6% (9/51) and 21. 7%(5/23)out of GC, DYS, IM and HP respectively. Among MSI positive tumors 7(19.2%) show MSI-H pattern. All gene mutations were found in MSI+ GCs, especially in MSI-H GCs. Bax gene mutation was observed in 2 DYSs with MSI-L. One case of HP with BAT-26 loci instability showing RII gene mutation was detected.Conclusions: MSI and mutations of RII, IGFIIR, Bax gene can be detected in GC. The frequency of them are almost the same when compared with previously reported date. Significant associative relationship between gene mutations and MSI implying that MSI might be of importance in the development of GC, probably by inducingmutations of target genes such as RII.IGFIIR and Bax genes. MSI occurs not only in GCs and gastric adnomas, but also in DYSs, IMs without carcinoma and HPs, suggesting that genetic instability might be an early somatic event of multistep gastrc carcinogenesis. However, mutations of RII, IGFIIR and Bax genes are relatively late event.