Genomic Features Associated with Clinical Heterogeneity in Corticotroph Adenomas

Abstract

Corticotroph adenomas are traditionally classified into Cushing disease (CD) and silent corticotroph adenomas (SCA). While SCAs are generally more invasive and associated with less favorable outcomes, and CD typically shows better postoperative prognosis, substantial clinical heterogeneity exists within both subtypes. This thesis investigates the genomic basis underlying this heterogeneity. The first study focuses on prognostic variability within Cushing disease. In a large international, multicenter cohort of patients who achieved postoperative remission, we evaluated the association between USP8 genotype, tumor size, and recurrence risk. We demonstrate that USP8 status alone does not fully explain outcome variability; rather, the combination of USP8 genotype and tumor size identifies distinct risk groups. In particular, USP8 wild-type macroadenomas are associated with a significantly higher risk of recurrence. The second study extends this analysis to both CD and SCA using integrated genomic and transcriptomic profiling, including whole-exome sequencing, copy-number analysis, and RNA sequencing. We identify molecular subgroups characterized by differential genomic alterations and varying levels of chromosomal instability. USP8-mutant tumors form a relatively homogeneous subgroup, whereas USP8 wild-type tumors display greater molecular diversity. SCA is enriched for alterations involving TP53, ATRX, and DAXX, and increased copy number burden is associated with invasive clinical features. Collectively, these findings support a model in which corticotroph adenomas represent a genomically stratified disease spectrum. Integrating genomic features with clinical parameters provides improved characterization of tumor heterogeneity and may inform future risk stratification and management strategies.