Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 4; pp. 1183 - 1194
• Main Authors: Casar-Borota, Olivera, Boldt, Henning Bünsow, Engström, Britt Edén, Andersen, Marianne Skovsager, Baussart, Bertrand, Bengtsson, Daniel, Berinder, Katarina, Ekman, Bertil, Feldt-Rasmussen, Ulla, Höybye, Charlotte, Jørgensen, Jens Otto L, Kolnes, Anders Jensen, Korbonits, Márta, Rasmussen, Åse Krogh, Lindsay, John R, Loughrey, Paul Benjamin, Maiter, Dominique, Manojlovic-Gacic, Emilija, Pahnke, Jens, Poliani, Pietro Luigi, Popovic, Vera, Ragnarsson, Oskar, Schalin-Jäntti, Camilla, Scheie, David, Tóth, Miklós, Villa, Chiara, Wirenfeldt, Martin, Kunicki, Jacek, Burman, Pia
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.04.2021; Copyright Oxford University Press; Williams & Wilkins Co
• Subjects: ACTH-Secreting Pituitary Adenoma - epidemiology; ACTH-Secreting Pituitary Adenoma - genetics; ACTH-Secreting Pituitary Adenoma - pathology; Adenoma - epidemiology; Adenoma - genetics; Adenoma - pathology; adenomas; Adolescent; Adult; Aged; aggressive PitNETs; amplification; ATRX (alpha thalassemia/mental retardation syndrome X-linked); ATRX protein; Brain cancer; Brain tumors; Cancer; Cancer and Oncology; Cancer och onkologi; Carcinoma; Carcinoma - epidemiology; Carcinoma - genetics; Carcinoma - pathology; Cell lineage; Chromatin; Chromatin remodeling; classification; Clinical Medicine; Clinical s; Cohort Studies; Corticotrophs - metabolism; Corticotrophs - pathology; Cushing's; Cushing's disease; daxx; Development and progression; disease; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Europe - epidemiology; european-society; Exons; expression; Female; Frameshift mutation; Gene Frequency; genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Humans; Immunohistochemistry; Intellectual disabilities; Klinisk medicin; Lanreotide; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Metastases; Middle Aged; Mutation; Neoplasm Invasiveness - genetics; Neuroendocrine tumors; Oncology, Experimental; Pathology; pathway; Patologi; Pit1 protein; Pituitary; pituitary adenoma; pituitary carcinoma; Pituitary gland; Pituitary gland tumors; Pituitary Neoplasms - epidemiology; Pituitary Neoplasms - genetics; Pituitary Neoplasms - pathology; Protein expression; Telomeres; Thalassemia; Tumors; X-linked Nuclear Protein - genetics; Young Adult; Europe; Denmark; United Kingdom; Sweden; France; Norway; pituitary carcinoma; pituitary adenoma; aggressive PitNETs; Cushing’s disease; ATRX (alpha thalassemia/mental retardation syndrome X-linked); Cushings disease
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa749

Abstract Context Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.