USP8 and TP53 drivers are associated with CNV in a corticotroph adenoma cohort enriched for aggressive tumors

Context: Pituitary corticotroph adenomas are rare tumors that can
be associated with excess adrenocorticotropic hormone (ACTH) and adrenal
cortisol production, resulting in the clinically debilitating endocrine
condition Cushing disease. A subset of corticotroph tumors behave
aggressively, and genomic drivers behind the development of these tumors
are largely unknown. Objective: To investigate genomic drivers of
corticotroph tumors at risk for aggressive behavior.
Design: Whole-exome sequencing of patient-matched corticotroph
tumor and normal DNA from a patient cohort enriched for tumors at risk for
aggressive behavior. Setting: Tertiary care center.
Patients: 27 corticotroph tumors from 22 patients analyzed. 12
tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were
Crooke’s cell tumors, and 1 was a corticotroph carcinoma.
Intervention: Whole-exome sequencing. Main outcome
measure: Somatic mutation genomic biomarkers.
Results: We found recurrent somatic mutations in USP8 and TP53
genes, both with higher allelic fractions than other somatic mutations.
These mutations were mutually exclusive, with TP53 mutations occurring
only in USP8-wildtype (WT) tumors, indicating they may be independent
driver genes. USP8-WT tumors were characterized by extensive somatic copy
number variation compared to USP8-mutated tumors. Independent of
molecular driver status, we found an association between invasiveness,
macroadenomas, and aneuploidy. Conclusions: Our data suggest that
corticotroph tumors may be categorized into a USP8-mutated, genome-stable
subtype versus a USP8-WT, genome-disrupted subtype, the latter of which
has a TP53-mutated subtype with high level of chromosome instability.
These findings could help identify high risk corticotroph tumors, namely
those with widespread CNV, that may need closer monitoring and more
aggressive treatment.