Abstract
Simple SummaryAcromegaly treatment consists of surgical, medical, and radiation therapy. First-generation somatostatin receptor ligands are the mainstay of medical therapy, with approximately 40% disease control rate. Several parameters have been evaluated as predictors of response to these drugs, including mutations in the stimulatory G-protein α subunit (gsp mutation), which is still controversial. In this study, we aimed to evaluate in a large series of patients whether gsp mutation predicts long-term response to medical treatment and to characterize the gsp mutated population. The ability to predict response to medical therapy would help to choose a therapy that presents higher odds of controlling the disease, which ultimately would reduce treatment costs and disease morbi-mortality.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.
Highlights
Is a disease caused by growth hormone (GH) hypersecretion, leading to increased production and secretion of insulin-like growth factor type I (IGF-I) due, in most cases, to a GH secreting pituitary adenoma
The present study confirmed the frequency of gsp+ mutations in approximately 40% of sporadic somatotropinomas
Whereas gsp+ tumors were significantly smaller than gsp- tumors, the phenotype did not differ with respect to sex, age, GH, and IGF-I levels at diagnosis or the association with biochemical control
Summary
Is a disease caused by growth hormone (GH) hypersecretion, leading to increased production and secretion of insulin-like growth factor type I (IGF-I) due, in most cases, to a GH secreting pituitary adenoma (somatotropinoma). First-generation somatostatin receptor ligands (fg-SRLs), namely, octreotide, and lanreotide, are the standard first-line medical treatment options for the majority of patients, with biochemical control rates varying from 19 to 60% [4]. GNAS1 activating mutations (gsp mutations) are found in approximately 40% of sporadic somatotropinomas [6], commonly found in codons 201 and. 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. We aimed to evaluate whether gsp mutation predicts longterm response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted
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