title: Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas.
abstract: BACKGROUND
  In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gaisignaling, but it is not known how the biological function of the Gaipathway is controlled.
  
  
  OBJECTIVE
  To study GNAS and AIP mutation status, AIP and Gai-2protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010.
  
  
  RESULTS
  Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2staining. In regression modeling, AIP expression associated with Gai-2(P = 2.33 × 10-9) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 × 10-4), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 × 10-7).
  
  
  CONCLUSIONS
  We demonstrate, for the first time, that AIP protein expression associates with Gai-2protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long-term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population.
authors.affiliation: EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Ritvonen
authors.affiliation: Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.affiliation: Department of NeurosurgeryUniversity of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Atte
authors.initials: A
authors.lastname: Karppinen
authors.affiliation: EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Vehkavaara
authors.affiliation: Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Hande
authors.initials: H
authors.lastname: Demir
authors.affiliation: Department of PathologyHUSLAB and University of Helsinki, Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: EndocrinologyAbdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland camilla.schalin-jantti@hus.fi auli.karhu@helsinki.fi.
authors.forename: Camilla
authors.initials: C
authors.lastname: Schalin-Jäntti
authors.affiliation: Department of Medical and Clinical Genetics & Genome-Scale BiologyResearch Programs Unit, University of Helsinki, Helsinki, Finland camilla.schalin-jantti@hus.fi auli.karhu@helsinki.fi.
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
mesh_terms: D000328:Adult; D002864:Chromogranins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005387:Finland; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D007018:Hypopituitarism / Q000209:etiology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics
chemical_list: D002864:Chromogranins; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; C103265:aryl hydrocarbon receptor-interacting protein; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs