Clinical Exome Sequencing Study in a Cohort of Growth Hormone-Secreting Pituitary Adenomas

Introduction: Genetic mutations have been reported in patients with acromegaly, potentially influencing clinical phenotype, tumor invasiveness, and prognosis. The genetic and molecular landscape of patients with acromegaly has been partially explored. Therefore, this study aimed to investigate germline genetic variants in patients with acromegaly through clinical exome sequencing (CES) analysis and to explore a possible correlation with the molecular and histological characteristics of somatotropinomas and the clinical features of acromegaly. Methods: A retrospective observational study was conducted to investigate the genetic profile of 46 patients with sporadic acromegaly through CES analysis, in comparison with 39 controls. Results: CES analysis identified 5759 unique variants in patients with acromegaly, without revealing predominant variants. However, a missense variant of uncertain significance (VUS) in the KCNJ12 gene (c.1289 A>G, p.Glu430Gly, rs5021699) was more frequent in patients with invasive tumors (P = 0.017) and in those with a higher Ki-67% (P = 0.033). Discussion: This study performed an extensive exploration of germline variants using CES analysis in patients with sporadic acromegaly. No predominant variants were identified in this cohort of somatotropinomas, but a VUS in the KCNJ12 gene was significantly associated with tumor invasiveness and a higher proliferative index, suggesting increased proliferation of tumor cells in patients carrying this genetic alteration. Conclusion: These findings may contribute to understanding the genetic landscape of acromegaly, and the gene identified may be of interest for further research on gene regulation of invasiveness and proliferation in somatotropinomas.