{"doi":"10.1007/s11102-025-01549-6","title":"Genetic profiling of synchronous pituitary corticotroph adenomas","abstract":"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.","journal":"Pituitary","year":2025,"id":544906,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1435369,"name":"Karen Tsai","orcid":"0000-0003-2848-832X","position":1,"is_corresponding":false},{"id":1435370,"name":"C. Santana","orcid":"0000-0001-6323-7716","position":2,"is_corresponding":false},{"id":1435789,"name":"Keanu Javaherian","orcid":null,"position":3,"is_corresponding":false},{"id":1435371,"name":"Matthew Lee","orcid":"0009-0007-8106-0935","position":4,"is_corresponding":false},{"id":498559,"name":"Marvin Bergsneider","orcid":null,"position":5,"is_corresponding":false},{"id":582227,"name":"Won Kim","orcid":"0000-0003-3423-3825","position":6,"is_corresponding":false},{"id":497849,"name":"Marilene B. Wang","orcid":"0000-0002-2799-6325","position":7,"is_corresponding":false},{"id":244990,"name":"Harry V. Vinters","orcid":"0000-0002-2965-1240","position":8,"is_corresponding":false},{"id":1435790,"name":"Weihong Yan","orcid":null,"position":9,"is_corresponding":false},{"id":241815,"name":"Anthony P. Heaney","orcid":"0000-0003-3865-0810","position":10,"is_corresponding":false},{"id":497848,"name":"Dongyun Zhang","orcid":"0000-0002-0751-7809","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:53:17.418915Z","pmid":"40544420","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}