MICROSATELLITE INSTABILITY AND MUTATIONS OF P53 AND TGF-BETA RII GENES IN GASTRIC-CANCER

To investigate the molecular mechanism of gastric carcinogenesis, we a nalyzed genetic instability and p53 gene mutations in 40 primary gastr ic carcinomas. Tumor samples were from untreated patients with no fami ly history suggestive of genetic predisposition to cancer. We screened six microsatellite loci by the polymerase chain reaction (PCR) method , and exons 5-8 of the p53 gene by the PCR-based denaturing gradient g el electrophoresis and sequencing techniques. Microsatellite instabili ty was detected in 32.5% (13/40), and gene mutations in 40% (16/40), o f the tumors analyzed. No statistically significant associations were found between genetic alterations and clinico-pathological variables ( with the exception of diffusion of lymph node metastases, which was in versely associated with the presence of microsatellite alterations; P < 0.01). Interestingly, a negative association was found between genet ic instability and p53 gene mutations: 11 out of 13 tumors showing ins tability proved to carry a nonmutated p53 gene versus 2/13 carrying a mutated gene (P = 0.03). These observations suggest that genetic insta bility and p53 gene mutations play a crucial role in the gastric carci nogenic process, but likely act through distinct pathways during cance r development. However, genetic instability is not in and of itself ne oplastic. Therefore, we investigated whether insertion/deletion mutati ons of the polyadenine tract within the transforming growth factor-bet a type Il receptor gene (TGF-beta RII) were frequently present in gast ric tumors with an RER+ (replication error) phenotype. We found RII mu tations in 8/40 (20%) samples: mutations were present in 7/13 (54%) RE R+ tumors versus 1/27 (4%) RER- cases (P < 0.001).