Pituitary · 2025
Genetic profiling of synchronous pituitary corticotroph adenomas.
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Zhang Dongyun, Tsai Karen, Santana Cristian, Javaherian Keanu, Lee Matthew, Bergsneider Marvin, Kim Won, Wang Marilene B, Vinters Harry V, Yan Weihong, Heaney Anthony P
Аннотация
PURPOSE: 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 two distinct corticotroph adenomas in a 43-year-old female.
METHODS: Two histopathologically confirmed corticotroph adenomas were submitted for whole-exome sequencing along with a matched blood sample. The functional effects of identified variants of uncertain significance on corticotroph tumor pro-opiomelanocortin transcription and proliferation were characterized.
RESULTS: 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 tumor. Compared to wild-type GPR162 which potently suppressed POMC transcription, the stop-gain variant (R218*) exhibited reduced inhibitory effect. The novel USP8 variant (P681Q) found in the contra-lateral tumor led to increased POMC transcription although weaker than the well characterized hotspot variant S718P, and did not affect EGFR ubiquitin. Interestingly, the patient also had a germline variant in the 21-alpha-hydroxylase gene (CYP21A2 p.A392T) though without clinical features of congenital adrenal hyperplasia.
CONCLUSION: We report, for the first time, the genetic profiles of a patient with dual pituitary corticotroph tumors, identifying a stop-gain variant in GPR162 in one tumor and a novel USP8 variant (S718P) in the other. While both somatic variants increased POMC expression, only GPR162 R218* affected proliferation. We hypothesize that alterations in adrenal steroidogenesis due to the CYP21A1 mutation may have reduced negative feedback on corticotroph cells and acted in a permissive way to facilitate corticotroph tumorigenesis.
METHODS: Two histopathologically confirmed corticotroph adenomas were submitted for whole-exome sequencing along with a matched blood sample. The functional effects of identified variants of uncertain significance on corticotroph tumor pro-opiomelanocortin transcription and proliferation were characterized.
RESULTS: 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 tumor. Compared to wild-type GPR162 which potently suppressed POMC transcription, the stop-gain variant (R218*) exhibited reduced inhibitory effect. The novel USP8 variant (P681Q) found in the contra-lateral tumor led to increased POMC transcription although weaker than the well characterized hotspot variant S718P, and did not affect EGFR ubiquitin. Interestingly, the patient also had a germline variant in the 21-alpha-hydroxylase gene (CYP21A2 p.A392T) though without clinical features of congenital adrenal hyperplasia.
CONCLUSION: We report, for the first time, the genetic profiles of a patient with dual pituitary corticotroph tumors, identifying a stop-gain variant in GPR162 in one tumor and a novel USP8 variant (S718P) in the other. While both somatic variants increased POMC expression, only GPR162 R218* affected proliferation. We hypothesize that alterations in adrenal steroidogenesis due to the CYP21A1 mutation may have reduced negative feedback on corticotroph cells and acted in a permissive way to facilitate corticotroph tumorigenesis.