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

Luiz Eduardo Wildemberg; Daniel Henriques; Paula C L Elias; Carlos Henrique de A Lima; Nina R de Castro Musolino; Aline Helen Silva Camacho; Olivia Faria; Debora Nazato; Julio Abucham; Lucio Vilar; Jose Italo Mota; Martha Katherine P Huayllas; Leila Chimelli; Margaret de Castro; Leandro Kasuki; Mônica R Gadelha

doi:10.3390/cancers13194857

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

Cancers (Basel). 2021 Sep 28;13(19):4857. doi: 10.3390/cancers13194857.

Authors

Luiz Eduardo Wildemberg^{1

2}, Daniel Henriques¹, Paula C L Elias³, Carlos Henrique de A Lima⁴, Nina R de Castro Musolino⁵, Aline Helen Silva Camacho⁴, Olivia Faria¹, Debora Nazato⁶, Julio Abucham⁶, Lucio Vilar⁷, Jose Italo Mota⁸, Martha Katherine P Huayllas⁹, Leila Chimelli⁴, Margaret de Castro³, Leandro Kasuki^{1

2}, Mônica R Gadelha^{1

2

4}

Affiliations

¹ Endocrine Unit and Neuroendocrinology Research Center, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-617, Brazil.
² Neuroendocrine Unit, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde, Rio de Janeiro 20231-092, Brazil.
³ Division of Endocrinology, Department of Internal Medicine, Ribeirao Preto Medical School, Universidade de São Paulo, Ribeirão Preto 14049-900, Brazil.
⁴ Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde, Rio de Janeiro 20231-092, Brazil.
⁵ Neuroendocrine Unit, Division of Functional Neurosurgery, Hospital das Clínicas da Universidade de São Paulo, São Paulo 05403-000, Brazil.
⁶ Neuroendocrine Unit, Division of Endocrinology and Metabolism, Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo 04023-062, Brazil.
⁷ Division of Endocrinology, Hospital das Clínicas da Universidade Federal de Pernambuco, Recife 50670-901, Brazil.
⁸ Endocrinology and Metabolism Unit, Hospital Geral de Fortaleza, Secretaria Estadual de Saúde, Fortaleza 60150-160, Brazil.
⁹ Neuroendocrinology and Neurosurgery Unit, Hospital Brigadeiro, São Paulo 01401-000, Brazil.

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.

Keywords: acromegaly; gsp mutation; somatostatin receptor ligands; somatotropinoma.