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We sought to better understand the underlying molecular pathogenesis of two distinct corticotroph adenomas in a 43-year-old female.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WES demonstrated a loss-of-function variant in the G-protein coupled receptor 162 [\n                      <jats:italic>GPR162<\/jats:italic>\n                      (R218*)] in the right corticotroph tumor, and a novel missense variant in ubiquitin specific peptidase 8 [\n                      <jats:italic>USP8<\/jats:italic>\n                      (P681Q)] in the left tumor. Compared to wild-type\n                      <jats:italic>GPR162<\/jats:italic>\n                      which potently suppressed POMC transcription, the stop-gain variant (R218*) exhibited reduced inhibitory effect. The novel\n                      <jats:italic>USP8<\/jats:italic>\n                      variant (P681Q) found in the contra-lateral tumor led to increased\n                      <jats:italic>POMC<\/jats:italic>\n                      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 (\n                      <jats:italic>CYP21A2<\/jats:italic>\n                      p.A392T) though without clinical features of congenital adrenal hyperplasia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11102-025-01549-6","type":"journal-article","created":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T10:25:14Z","timestamp":1750587914000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic profiling of synchronous pituitary corticotroph adenomas"],"prefix":"10.1007","volume":"28","author":[{"given":"Dongyun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Santana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keanu","family":"Javaherian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Bergsneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilene B.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry V.","family":"Vinters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3865-0810","authenticated-orcid":false,"given":"Anthony P.","family":"Heaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"issue":"4","key":"1549_CR1","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s12022-019-09587-0","volume":"30","author":"SMC De Sousa","year":"2019","unstructured":"De Sousa SMC, Wang PPS, Santoreneos S, Shen A, Yates CJ, Babic M et al (2019) The genomic landscape of sporadic prolactinomas. 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(\n                      A\n                      ) Visualization of somatic variant ZNF717 c.1797T\u2009>\u2009A (p.C599*) using IPA Gene View (Qiagen). (\n                      B\n                      ) The list of this variant in COSMIC dataset [\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ].","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig. 1"}},{"value":"Illustration of features of germline variant of CTBP2. (\n                      A\n                      ) Visualization of somatic variant CTBP2 c.308G\u2009>\u2009A p.R103Q using IPA Gene View (Qiagen). (\n                      B\n                      ) The list of this variant in COSMIC dataset [\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ].","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig. 2"}},{"value":"Illustration of features of germline variant of ANKRD36. (\n                      A\n                      ) Visualization of somatic variant ANKRD36 c.4145T\u2009>\u2009G (p.L1382*) using IPA Gene View (Qiagen). (\n                      B\n                      ) The list of this variant in COSMIC dataset [\n                      \n                      ,\n                      \n                      ,\n                      \n                      ].","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig. 3"}}],"article-number":"77"}}