Numerous recent studies demonstrate gastrinomas, similar to carcinoid tumors and all other pancreatic endocrine tumors (PETs) except insulinomas, usually (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 PETs. 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. In collaboration with the Metabolic Diseases Branch (Drs. Marx, Burns, Spiegel), the possible role of the calcium-sensing receptor and the frequency and prognostic value of alterations in gastrinomas in the gene for Multiple Endocrine Neoplasia-type 1 (MEN1) are being investigated. Our study of MEN-1 gene mutations shows it occurs in 31% of sporadic gastrinomas (n=54), however, at presence of absence did not correlate with tumor growth, location or biologic behavior (J. Clin. Endocrinol. Met., in press). With Dr. I. Lubensky Dept. of Pathology, NCI, alterations in the tumor suppressor gene, p16, are being investigated, as well as the importance of overexpression of growth factors and their receptors in gastrinomas, the predictive value of proliferating cell antigens (Ki-67, etc.) and the possible identification of important other alterations in determining prognosis using genomic-wide allelotyping. - gastrinoma, islet cell tumor, MEN1, prognosis, molecular pathogenesis
