ACTIVATING MUTATIONS OF THE GS ALPHA-GENE IN NONFUNCTIONING PITUITARY-TUMORS

The majority of pituitary tumors are of monoclonal origin; however, th e molecular basis for their formation is poorly understood. Somatic mu tations in the alpha-subunit of the GTP-binding protein, G(s)alpha (gs p oncogene) have been found in about one third of GH-secreting tumors. Mutations in another alpha-subunit of a GTP-binding protein, G(i2)alp ha (gip mutations) have been described in other endocrine tumors. In t his study, we examined 21 nonfunctioning pituitary tumors and 4 macrop rolactinomas for gsp mutations and 27 nonfunctioning tumors and 4 macr oprolactinomas for gip mutations. Using the polymerase chain reaction and denaturing gradient gel electrophoresis, 2 nonfunctioning pituitar y tumors displayed migration abnormalities when the G(s) alpha-gene wa s analyzed. Sequence analysis of these abnormally migrating polymerase chain reaction products revealed two previously known gsp mutations: arginine at codon 201 altered to cysteine, and glutamine at codon 227 changed to leucine. No gip mutations could be demonstrated. These find ings emphasize the monoclonal origin of nonfunctioning pituitary tumor s and suggest that cAMP may play a role in tumorigenesis of nonfunctio ning pituitary tumors.