The cell types of the anterior pituitary gland may each give rise to adenomas which hypersecrete specific hormones leading to infertility, growth disorders of metabolic dysfunctions. The local pituitary mass may also impinge on surrounding vital structures causing visual defects, cranial nerve palsies or sinus invasion. Although several mechanisms have been proposed for the etiology of pituitary adenomas, including hypothalamic dysfunction, peripheral hormone (e.g., estrogen) action and pituitary vascular abnormalities, no direct pathogenetic mechanism for pituitary tumorigenesis is known. This proposal aims to study the molecular pathogenesis of these tumors. Firstly, the clonal origin of the various pituitary adenomas will be determined by X-chromosome inactivation analysis in female patients using the X-chromosome genes, HPRT and PGK as probes. DNA extracted from tumor and lymphocyte DNA will be tested to determine whether these adenomas are of monoclonal origin.
The second aim of this proposal is to identify transforming genes isolated from specific pituitary adenomas. DNA extracted from pituitary tumor tissue obtained at surgery will be used to transfect mouse NIH-3T3 cells in order to test for the presence of transforming genes. After enrichment of the transforming DNA sequences by repeated transfectional cycles, DNA derived from tertiary transfectants will be cloned into a phage library, and sequenced. We show preliminary data depicting successful transformation induced by DNA extracted from 7 pituitary adenomas. Evidence will be provided suggesting that the putative transforming gene is not a member of the ras gene family. The transforming gene(s) will be sought and characterized in each of the pituitary tumor cell types, including PRL-cell, GH-cell, Cushing's, alpha subunit and non-functioning tumors. The clonal origin of these tumor types is also presented. The PI has access to a large pool of pituitary tumor patients and has already collected over 120 tumors for DNA analyses. The availability of this tissue bank will greatly facilitate these studies and is a valuable resource for future genetic studies of pituitary tumors. These studies will provide further insight into the pathogenesis of the cell-specific anterior pituitary adenomas.
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