Endocrine Abstracts

Corticotroph tumours, comprising around 15% of pituitary tumours, express ACTH and other peptides originating from TPIT-lineage adenohypophyseal cells. Their tumorigenesis involves a complex interplay of genetic and epigenetic factors and hormonal and growth factor stimulation. Silent corticotroph tumours (SCT) share immunopositivity for ACTH and TPIT with functioning corticotroph tumours (FCT) but do not exhibit evidence of hypercortisolism. Despite their aggressive growth and high recurrence rates, the reasons for their failure to induce hypercortisolism remain speculative, focusing on factors like cell origin, sensitivity to hypothalamic stimulants, POMC cleavage, and cell cycle regulation. This study delves into the role of USP8 mutations in the pathogenesis of corticotroph tumours. USP8 is involved in the regulation of the epidermal growth factor receptor (EGFR) signalling pathway. USP8, when mutated, cannot properly regulate the ubiquitination and degradation of EGFR, and prolonged activation of EGFR due to impaired degradation can lead to sustained signalling, promoting increased POMC expression and subsequent ACTH secretion. Sanger sequencing was performed on 10 SCTs and 13 FCTs from a unique centre. Comprehensive analysis encompassed demographic, clinical, radiological, and genetic variables, including genes associated with ACTH processing, secretion, glucocorticoid receptor (GR) pathway, and the immune microenvironment. The results unveiled somatic USP8 mutations in 70% of SCTs and 30.8% of FCTs, all heterozygous and located in exon 14. Mutated tumours were more prevalent in younger individuals and women, smaller, less invasive, and exhibited heightened expression of ACTH-related genes (POMC, CHRH, AVPR1, TBX19, PCSK1/3, USB, CABLES1, EGFR). No significant changes were observed in genes related to ACTH degradation (PCSK2, PAM, CPE) or the GR pathway. In SCTs, mutated tumours displayed increased immune activity, as indicated by elevated PDL-1 expression. We also explored the expression of somatostatin receptor levels as potential therapeutic targets on these tumours. Both mutated SCTs and FCTs expressed higher levels of SSTR5 than non-mutated ones, and FCTs additionally expressed more SSTR2. In conclusion, USP8 mutations are prevalent in corticotroph lineage pituitary tumours, encompassing both silent and functioning variants. Mutated tumours exhibit a more differentiated profile, suggesting potential implications for diagnosis and targeted therapies.