New molecular aspects in gastric cancer: Possible clinical implications

The investigation of molecular and genetic changes in tumor cells has brought new insights into the evolution of human malignancies. We have focused on the identification and characterization of genetic alterations in gastric tumors. Tight cell-cell adhesion is critical for the maintenance of epithelial differentiation, while destabilization of adhesion favors invasiveness of epithelial cells and thus carcinoma progression. The E-cadherin cell adhesion complex, composed of E-cadherin itself, α-, β-, and γ-catenin, has been shown to play a major role in establishing and maintaining tight cell-cell junctions. E-cadherin and α-catenin expression are downregulated in various human carcinomas. We found E-cadherin mutations in 50% of diffuse-type gastric carcinomas. Loss of the wild-type allele of E-cadherin was detected in the majority of the tumors exhibiting E-cadherin mutations, but was also found in some intestinal-type carcinomas. No mutations in α- and β-catenin cDNA were identified in gastric tumors of both types. An accumulation of mutations based on genetic instability is thought to contribute to tumor development. Microsatellite instability reflects an elevated mutation rate and was shown to be a characteristic feature of tumors in the majority of patients affected with the hereditary nonpolyposis colorectal cancer syndrome. These alterations have also been identified at a lower frequency in sporadic tumors of various organs including gastric carcinomas. Interestingly, we found microsatellite instability at multiple loci in two synchronous tumors of one patient, who in addition also showed a clustering of gastric tumors in his family. This may be indicative for a familial gastric carcinoma syndrome associated with a germline mutation in one of the genes involved in DNA replication accuracy. The clinical implications of all of these findings for therapy, prognosis, diagnosis, and cancer risk assessment are discussed.