Gastric carcinoma is one of the most frequent and lethal cancers in the world. Hence, its contribution to the public health burden is apparent and quite substantial. Yet, present clinical practices have little impact on the natural history of this progressive neoplasm. Generally, the diagnosis of gastric cancer is made in advanced stages; consequently, only a small number of patients survive beyond five years from the initial diagnosis. Therefore, advances in the currently limited armamentarium to combat this deadly cancer are eagerly awaited. These molecular genetic studies of gastric carcinoma are thus proposed to increase the understanding of its pathogenesis which may lead to new opportunities to decrease the mortality of this lethal cancer. The important genetic alterations which drive the neoplastic process of gastric tumorigenesis are largely unknown or uncharacterized. Recent advances in molecular biological techniques can now help us to identify the important genetic changes that occur during the development of this cancer. Thus, the investigators propose collection of quality samples to begin a comprehensive search for those genetic alterations which underlie gastric tumorigenesis. Microdissected primary gastric adenocarcinomas at various stages of malignancy will be collected from patients within the United States and around the world for accurate analyses. Xenografting of freshly resected tumors will also be initiated at our institution. APC's role in the development of gastric carcinoma will be clarified by conducting thorough analyses to determine the true prevalence, nature, and timing of APC mutations in gastric tumorigenesis. The p53 gene has been reported to be frequently altered in gastric carcinomas. It will be fully characterized in these gastric carcinomas for incorporation into the overall picture of important changes. Other tumor suppressor genes contributing to gastric cancer development will also be sought through a systematic allelic loss survey of the entire genome. The presence and cause of microsatellite instability which is characteristic of an inherited predisposition for colon cancer will be fully evaluated in these samples. Finally, the frequency and nature of genetic changes will be statistically correlated with demographic, clinical, and environmental data (including various geographic and anatomic locations, Helicobacter pylori infection, and histopathologic type) with the objective of gaining insight into the etiology of gastric cancer and its different phenotypes. The investigators anticipate that these and extended studies will lead to a composite molecular picture of gastric carcinomas which ultimately should delineate a useful working model of gastric tumorigenesis. These molecular genetic studies of gastric carcinomas are expected to have important biological as well as practical implications. The investigators anticipate that these research endeavors eventually will generate clinically significant genetic markers for improved diagnostic screening tests, the rational design of preventive strategies, and more effective therapeutic agents and/or modalities similar to those becoming apparent for colorectal cancer.
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| Powell, S M; Harper, J C; Hamilton, S R et al. (1997) Inactivation of Smad4 in gastric carcinomas. Cancer Res 57:4221-4 |
