Andrew V Uzilov1,2, Patricia Taik2, Khadeen C Cheesman3, Pedram Javanmard3, Kai Ying2, Alessia Roehnelt3, Huan Wang2, Marc Y Fink1,2, Chun Yee Lau1, Aye S Moe2, Joaquin Villar2, Joshua B Bederson4, Andrew F Stewart5, Michael J Donovan6, Milind Mahajan1,2, Robert Sebra1,2, Kalmon D Post4, Rong Chen1,2, Eliza B Geer7. 1. Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Sema4, Stamford, Connecticut. 3. Division of Endocrinology, Diabetes, and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Diabetes, Obesity, and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. 6. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Multidisciplinary Pituitary and Skull Base Tumor Center, Departments of Medicine and Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract
CONTEXT: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. OBJECTIVE: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. DESIGN: Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. SETTING: Tertiary care center. PATIENTS: Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. INTERVENTION: Whole-exome sequencing. MAIN OUTCOME MEASURE: Somatic mutation genomic biomarkers. RESULTS: We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. CONCLUSIONS: Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.
CONTEXT: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. OBJECTIVE: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. DESIGN: Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. SETTING: Tertiary care center. PATIENTS: Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTHtumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. INTERVENTION: Whole-exome sequencing. MAIN OUTCOME MEASURE: Somatic mutation genomic biomarkers. RESULTS: We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. CONCLUSIONS: Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.
Authors: Pietro Locantore; Rosa Maria Paragliola; Gianluca Cera; Roberto Novizio; Ettore Maggio; Vittoria Ramunno; Andrea Corsello; Salvatore Maria Corsello Journal: Int J Mol Sci Date: 2022-06-19 Impact factor: 6.208
Authors: Luis Gustavo Perez-Rivas; Julia Simon; Adriana Albani; Sicheng Tang; Sigrun Roeber; Guillaume Assié; Timo Deutschbein; Martin Fassnacht; Monica R Gadelha; Ad R Hermus; Günter K Stalla; Maria A Tichomirowa; Roman Rotermund; Jörg Flitsch; Michael Buchfelder; Isabella Nasi-Kordhishti; Jürgen Honegger; Jun Thorsteinsdottir; Wolfgang Saeger; Jochen Herms; Martin Reincke; Marily Theodoropoulou Journal: Acta Neuropathol Commun Date: 2022-09-19 Impact factor: 7.578
Authors: Pia Burman; Jacqueline Trouillas; Marco Losa; Ann McCormack; Stephan Petersenn; Vera Popovic; Marily Theodoropoulou; Gerald Raverot; Olaf M Dekkers Journal: Eur J Endocrinol Date: 2022-09-19 Impact factor: 6.558