Molecular studies support a primary pituitary origin for pituitary adenomas. The most specific abnormality identified to date is a mutation of the G-protein, G/s, in some adenomas. G proteins are guanine- nucleotide-binding proteins that mediate signal transduction in pituitary cells. It has been postulated that other mutant G proteins may account for tumorigenesis in pituitary adenomas. One candidate is the recently discovered G-protein, Gq, which is linked to the thyrotropin/gonadotropin releasing hormone, phospholipase C (PLC) -inositol phosphate pathway and has transforming potential. This proposal seeks to determine molecular events in pituitary tumorigenesis, with the following specific aims: 1. To determine if pituitary adenomas carry mutations of G alphaq. a) To detect Galphaq mutations we will use PCR amplification and DNA sequencing to identify candidate Galphaq mutations in tumor specimens. b) To determine if mutations of Galphaq activate PLC we will assay tumor specimens for IPs. 2. To clinically characterize patients with pituitary adenomas carrying mutations of the G protein a chain Galphaq. a) To determine their epidemiological characteristics, we will establish a database for patients with pituitary adenomas and statistically analyze their epidemiological variables. b) To determine if these tumors are larger than those without the mutation, we will measure tumor size by magnetic resonance imaging. c) To determine the endocrinologic activity of pituitary adenomas with Galphaq mutations, we will perform hormonal assays, immunohistochemistry and in situ hybridization. d) To determine if pituitary adenomas with Galphaq mutations are somatostatin-receptor- positive we will study these tumors with in-vivo somatostatin receptor imaging techniques to determine if they are likely to respond to preoperative treatment with somatostatin analogue. e) To determine if preoperative octreotide treatment improves the results of surgery in patients with Galphaq mutations we will use an approved clinical protocol to determine if preoperative octreotide treatment improves surgical resection.
