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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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.

OriginalsprogEngelsk
TidsskriftThe Journal of clinical endocrinology and metabolism
Vol/bind106
Udgave nummer4
Sider (fra-til)1183-1194
ISSN0021-972X
DOI
StatusUdgivet - apr. 2021

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