Pathogenic Factors And Determinants Of Prognosis In Pati

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Recent studies demonstrate gastrinomas, similar to carcinoid tumors and all other pancreatic endocrine tumors (PET's) except insulinomas, frequently (60-90%) are malignant and some may have an aggressive course. The molecular pathogenesis, not only for the tumors themselves, but also for determining their growth behavior is almost completely unknown. Recent studies demonstrate that in contrast to many other more common cancers neither oncogenes nor common tumor suppressor genes (p53, retinoblastoma, VHL gene, etc.) are generally altered in gastrinomas, carcinoids or other PET's. Recent analyses at NIH have identified a cohort of 25% of patients in whom gastrinomas pursued an aggressive clinical course. Both clinical and laboratory characteristics that distinguish patients with an aggressive course are being sought by statistical analysis as well as correlations with possible molecular changes in the gastrinoma that may correlate with prognosis and tumor growth. Our recent studies demonstrate that the tumor suppressor gene, p16, which is involved in maintaining cell cycle control, is frequently (50%) altered in gastrinomas, entirely due to methylation of CG-rich islands in the promoter region. Furthermore, alterations are found in the MEN1 gene in 40%. However, alterations in neither of these genes is predictive of aggressive gastrinoma growth. This last year we have investigated the importance of overexpression of growth factors (EGFR, HGFR)in gastrinomas and alterations in the HER-2/neu oncogene. Studies of LOH in chromosome one and chromosome X are also being carried out in PET's because alterations in each of these correlate with aggressive growth in a number of nonendocrine tumors. HER2/neu and EGFR were found to be overexpressed in a subset of gastrinomas and the expression level correlated with aggressiveness. The identification of such molecular alterations that correlate with tumor growth, will allow identification of patients with tumors that warrant more aggressive treatment.