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Purpose <p>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.</p> Methods <p>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.</p> Results <p>WES demonstrated a loss-of-function variant in the G-protein coupled receptor 162 [<i>GPR162</i> (R218*)] in the right corticotroph tumor, and a novel missense variant in ubiquitin specific peptidase 8 [<i>USP8</i> (P681Q)] in the left tumor. Compared to wild-type <i>GPR162</i> which potently suppressed POMC transcription, the stop-gain variant (R218*) exhibited reduced inhibitory effect. The novel <i>USP8</i> variant (P681Q) found in the contra-lateral tumor led to increased <i>POMC</i> 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 (<i>CYP21A2</i> p.A392T) though without clinical features of congenital adrenal hyperplasia.</p> Conclusion <p>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.</p>

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Genetic profiling of synchronous pituitary corticotroph adenomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月22日

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  • Dongyun Zhang,
  • Karen Tsai,
  • Cristian Santana,
  • Keanu Javaherian,
  • Matthew Lee,
  • Marvin Bergsneider,
  • Won Kim,
  • Marilene B. Wang,
  • Harry V. Vinters,
  • Weihong Yan,
  • Anthony P. Heaney

摘要

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.