title: Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission.
abstract: Although the molecular mechanisms underlying GH secreting pituitary tumor formation are not well understood, mutations in the alpha-subunit of the stimulatory G gene, GNAS, have been identified in up to 40%. As these mutations could play a role in tumor growth, we screened 60 GH secreting tumors for GNAS mutations and assessed whether mutation status correlated with their clinical and pathological characteristics. Tumor specimens obtained at surgery were snap frozen. Tumor DNA was extracted, and PCR was used to amplify regions containing 2 sites of recurrent activating somatic mutations in codons 201 and 227 in GNAS. Amplicons were bi-directionally sequenced and analyzed. GNAS mutations were present in 24/60 (40%) of tumors; these were arg201cys(n = 15), arg201ser(n = 2), arg201his(n = 2), gln227leu(n = 4), gln227arg(n = 1). Preoperative IGF-I levels (age-adjusted) were higher (p = 0.01), but GH levels were slightly higher (p = 0.18) in mutation positive vs. negative groups. Mutation positive tumors were somewhat smaller than negative tumors (p = 0.07). The proportion of tumors >2 cm was somewhat less among positive (8.3%) vs. negative tumors (25%) (p = 0.10). Neither mib proliferation index, the proportion of invasive tumors nor surgical remission rates differed in the groups. IGF-I normalization rate with somatostatin analog therapy was similar in positive (3 of 6) vs. negative (3 of 7) patients. GH secreting tumors harboring GNAS mutations had higher preoperative IGF-I levels, somewhat higher preoperative GH levels and tended to be smaller than tumors without mutations. Presence of a GNAS mutation did not predict a difference in a proliferation marker, surgical remission or response to somatostatin analog therapy.
authors.affiliation: Department of Medicine, Columbia University College of Physicians & Surgeons, 650 West 168th Street, 9-905, New York, NY, USA. puf1@columbia.edu
authors.forename: Pamela U
authors.initials: PU
authors.lastname: Freda
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Jane E
authors.initials: JE
authors.lastname: Walsh
authors.forename: M Nabi
authors.initials: MN
authors.lastname: Kanibir
authors.forename: George
authors.initials: G
authors.lastname: Kleinman
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Kalmon D
authors.initials: KD
authors.lastname: Post
mesh_terms: D000172:Acromegaly / Q000209:etiology; D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D002864:Chromogranins; D015331:Cohort Studies; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D019382:Human Growth Hormone / Q000097:blood*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D012074:Remission Induction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D002864:Chromogranins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs