Non-recurrent mutations and copy number changes predominate pituitary adenoma genomes

Pituitary adenomas (PAs) are common neoplasms. Our current understanding of the molecular basis of PA formation is incomplete. Routine implementation of targeted genomics has enabled the discovery of rare, potentially clinically actionable events.

We used a cancer-focused gene panel to sequence a cohort of 171 PAs from patients who underwent surgery at Brigham and Women's Hospital from 2012 to 2020.

We identified known genetic variants enriched in specific PA subtypes: GNAS (somatotroph) and USP8 (Cushing's disease). Total mutational burden did not vary across adenoma subtypes; most adenomas possessed a few non-recurrent mutations in various established oncogenes and tumor suppressors. In contrast, the burden of copy number alterations varied widely across adenoma subtypes and was associated with higher MIB1 labeling index. We identified frequent deletions spanning MEN1 in prolactinomas and silent corticotroph adenomas, and subtype-specific copy number changes including 16p, 16q alterations in somatotroph adenomas without GNAS mutations. Within the corticotroph lineage, adenomas leading to Cushing's disease had few copy number alterations while silent corticotroph adenomas had numerous.

This study highlights a role for individualized genetic events in PA formation and suggests that divergent patterns of genomic instability may facilitate tumorigenesis even within the same lineage. Taken together, we demonstrate how gene panels may illuminate novel biology in endocrine tumors.