Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas

Abstract

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

“…3 ). GNAS -mutated tumors are smaller ( 145–149 ), less likely to be locally invasive ( 149 ), and more likely to respond to SSAs ( 149 , 150 ), although a Brazilian cohort showed no differences in tumor extension or response to SSAs between mutated and nonmutated tumors ( 151 ). Dopamine receptor 2 expression is increased in GNAS -mutated tumors, potentially allowing for GNAS mutation status in predicting the response to dopamine agonists in GH-PTs ( 17 ).…”

Prognostic Models in Growth-Hormone- and Prolactin-Secreting Pituitary Neuroendocrine Tumors: A Systematic Review

“…Knosp grade, Knosp modification and Hardy–Wilson classifications are widely used and offer a good orientation. The Knosp grade offers the greatest diagnostic accuracy for the prediction of a surgical cure [ 40 , 41 , 42 ]. In addition, the degrees of ICA contact and Knosp score are associated with postoperative endocrine outcomes [ 43 ].…”

Pituitary Tumorigenesis—Implications for Management

“…Moreover, recent a multiomic analysis of a GNAS locus in two independent somatotroph tumor cohorts revealed that 43% of gsp-negative tumors showed a GNAS imprinting relaxation, which corresponded to a lower GNAS, SSTR2 and AIP expression, and a lower sensitivity to SSAs and potentially aggressive behavior [42]. However, the Oxford cohort showed that the granulation pattern in a tumor subtype, not the gsp mutation, predicts the tumor response to the SSAs while a Brazilian cohort showed no difference between the tumors with or without a GNAS mutation [39,43]. To conclude, even though the prevailing opinion is that the GNAS mutation is an indicator of a better response to the treatment, there are studies with controversial results.…”