gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Abstract

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

Management of pasireotide-induced hyperglycemia in patients with acromegaly: An experts’ consensus statement

“…high AIP mutation status, low expression of E-cadherin and high expression of Ki-67 are considered good candidates to benefit from pasireotide treatment (12,18,(39)(40)(41)(42)(43)(44)(45). Despite the potential of these indicators, limited comprehensive studies and routine clinical practices make it challenging for clinicians to use these markers for patient selection, leading to a reliance on imaging and patient history.…”

“…While high SSTR2 density is a good predictor of (12,18,43,44). Additionally, GH-secreting adenomas with mutations in the stimulatory G-protein alpha subunit, showing higher SSTR5 expression, may be more responsive to pasireotide (45).…”

Current and Emerging Medical Therapies in Pituitary Tumors

“…At the pathological level, GHomas with high values of Ki67 and sparsely granulated (SG) pattern display a poorer response to SRLs [48], which is associated with a lower density of SST2 at the cell membrane of SG tumors, and a T2-hyperintensity signal on the MRI [49,50]. Recently, Wildemberg et al showed, in an elegant study, that somatic mutations of the gsp oncogene, identified in nearly 40% of GHomas, were not predictive of response to SRLs [51]. Familial predisposition to acromegaly has been known since the end of the 1990s [52], and germline mutations of the AIP (Arylhydrocarbon receptor interacting protein) gene are found in approximately 15% of FIPA (Familial Isolated Pituitary Adenoma) syndrome cases [53].…”

MicroRNA in Acromegaly: Involvement in the Pathogenesis and in the Response to First-Generation Somatostatin Receptor Ligands

“…Acromegaly is caused, in the vast majority of cases, by a sporadic GH-secreting pituitary adenoma [ 4 ]. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 ( GNAS1 ) gene [ 17 , 18 ]. Germline mutations in the aryl hydrocarbon receptor-interacting protein ( AIP ) gene can be found in approximately 4 to 12% of patients with apparently sporadic acromegaly, especially if they are young (age < 30 years old) and carry macroadenomas [ 19 , 20 , 21 , 22 ].…”