Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas

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 Ga_i signaling, but it is not known how the biological function of the Ga_i pathway is controlled.

Aim: To study GNAS and AIP mutation status, AIP and Ga_i-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 Ga_i-2 staining. In regression modeling, AIP expression associated with Ga_i-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 Ga_i-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.