Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. Issue 2 (February 2017)

• Record Type: Journal Article
• Authors: Ritvonen, Elina; Pitkänen, Esa; Karppinen, Atte; Vehkavaara, Satu; Demir, Hande; Paetau, Anders; Schalin-Jäntti, Camilla; Karhu, Auli
• Is Part Of: European journal of endocrinology. Volume 176:Issue 2(2017)
• Page Start: 243
• Page End: 252
• Publication Date: 2017-02
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/EJE-16-0620
• Languages: English
• ISSNs: 0804-4643

Abstract

Abstract : Introduction: 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 Gai signaling, but it is not known how the biological function of the Gai pathway is controlled. Aim: To study GNAS and AIP mutation status, AIP and Gai-2 protein 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-2 staining. 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-2 protein 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.