Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

Olivera Casar-Borota, Henning Bünsow Boldt, Britt Edén Engström, Marianne Skovsager Andersen, Bertrand Baussart, Daniel Bengtsson, Katarina Berinder, Bertil Ekman, Ulla Feldt-Rasmussen, Charlotte Höybye, Jens Otto L Jørgensen, Anders Jensen Kolnes, Márta Korbonits, Åse Krogh Rasmussen, John R Lindsay, Paul Benjamin Loughrey, Dominique Maiter, Emilija Manojlovic-Gacic, Jens Pahnke, Pietro Luigi PolianiVera Popovic, Oskar Ragnarsson, Camilla Schalin-Jäntti, David Scheie, Miklós Tóth, Chiara Villa, Martin Wirenfeldt, Jacek Kunicki, Pia Burman

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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.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume106
Issue number4
Pages (from-to)1183-1194
ISSN0021-972X
DOIs
Publication statusPublished - Apr 2021

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