# Genetic Profiling of Synchronous Pituitary Corticotroph Adenomas

## TL;DR

This study investigates the genetic causes of two separate pituitary tumors in a single patient, identifying specific mutations that may contribute to tumor development.

## Contribution

The study identifies novel somatic and germline genetic variants in corticotroph tumors and explores their functional impact on POMC transcription.

## Key findings

- A loss-of-function variant in GPR162 was found in one tumor, reducing its ability to suppress POMC transcription.
- A novel USP8 missense variant in the other tumor increased POMC transcription, similar to a known hotspot variant.
- A germline CYP21A2 variant was present but did not cause adrenal hyperplasia, and CYP21A2 was absent in both tumors.

## Abstract

Double or multiple pituitary adenomas account for only 1.6–3.3% of all corticotroph tumors. We sought to better understand the underlying molecular pathogenesis of 2 distinct corticotroph adenomas that were encountered in a 43-year-old female.

Two distinct histopathologically confirmed corticotroph adenomas were submitted for whole exome sequencing (WES) together with blood sample. The functional effects of identified pathogenic variants on murine corticotroph tumor pro-opio-melanocortin (POMC) transcription and proliferation were characterized.

WES demonstrated a loss-of-function variant in the G-protein coupled receptor 162 [GPR162 (R218*)] in the right corticotroph tumor, and a novel missense variant in ubiquitin specific peptidase 8 [USP8 (P681Q)] in the left corticotroph tumor. Compared to wild-type GPR162 which potently suppressed POMC transcription, the premature stop-gain GPR162 variant (R218*) found in our patient exhibited a reduced POMC transcription inhibitory effect. The novel USP8 variant (P681Q) found in the contra-lateral tumor led to increased POMC transcription similar to the well characterized USP8 hotspot variant S718P. Interestingly, the patient also had a germline variant in the 21-alpha-hydroxylase gene (CYP21A2 p.A392T) although she did not exhibit a phenotype consistent with congenital adrenal hyperplasia. The CYP21A2 transcript and protein were absent in both corticotroph tumors from the index case whereas the protein expression was demonstrated in a series of 9 corticotroph adenomas.

We hypothesize that the germline CYP21A2 variant by increasing corticotroph cell stimulation may have acted in a permissive way to facilitate the additional somatic mutations which led to development of the 2 distinct corticotroph tumors.