Corticotroph aggressive pituitary tumours and carcinomas frequently harbour ATRX mutations

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  • Olivera Casar-Borota, Uppsala University and Uppsala Clinical Research Center, Uppsala University, Sweden.
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  • Henning Bünsow Boldt, Department of Pathology, Odense University Hospital, Odense
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  • Britt Edén Engström, Uppsala University and Uppsala Clinical Research Center, Uppsala University, Sweden.
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  • Marianne Skovsager Andersen, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
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  • Bertrand Baussart, 5LPO-BirdLife France, France
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  • Daniel Bengtsson, Department of Infectious Diseases, Linköping University Hospital, Linköping, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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  • Katarina Berinder, Karolinska University Hospital og Karolinska Institute
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  • Bertil Ekman, Department of Endocrinology, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
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  • Ulla Feldt-Rasmussen, Department of Medical Endocrinology, Rigshospitalet, Copenhagen, Denmark
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  • Charlotte Höybye, Karolinska University Hospital og Karolinska Institute
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  • Jens Otto L Jørgensen
  • Anders Jensen Kolnes, Department of Gynaecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. Institute for Cancer Genetics and Informatics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. Faculty of Medicine, University of Oslo, Oslo, Norway.
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  • Márta Korbonits, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ UK.
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  • Åse Krogh Rasmussen, Københavns Universitet
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  • John R Lindsay, Belfast Health and Social Care Trust
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  • Paul Benjamin Loughrey, Queen's Cancer Research Institute, Queen's University
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  • Dominique Maiter, Royal observatory of Belgium, Ringlaan 3, B-1180 Brussel, Belgium
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  • Emilija Manojlovic-Gacic, University of Belgrade
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  • Jens Pahnke, University of Oslo (UiO) and Oslo University Hospital (OUS)
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  • Pietro Luigi Poliani, University of Brescia Medical School
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  • Vera Popovic, University of Belgrade
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  • Oskar Ragnarsson, Univ Gothenburg, University of Gothenburg, Gothenburg Global Biodivers Ctr
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  • Camilla Schalin-Jäntti, University of Helsinki and Helsinki University Hospital
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  • David Scheie, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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  • Miklós Tóth, Semmelweis Univ, Semmelweis University, Dept Psychiat & Psychoterapy
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  • Chiara Villa, Royal observatory of Belgium, Ringlaan 3, B-1180 Brussel, Belgium
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  • Martin Wirenfeldt, From the Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Odense, Denmark; Department of Cardiology, Odense University Hospital, Odense, Denmark.
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  • Jacek Kunicki, Maria Sklodowska-Curie National Research Institute of Oncology
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  • Pia Burman, Department of Nephrology in Lund, Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund, Sweden.

CONTEXT: Aggressive pituitary tumours (APTs) are characterised by unusually rapid growth and lack of response to standard treatment. About 1-2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumours are overrepresented amongst APTs and PCs. Mutations in the ATRX gene, regulating chromatin remodelling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumours.

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 tumours lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

RESULTS: Nine of the 48 tumours (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 tumours, 7/22 (32%), vs 2/24 (8%) in the tumours of the Pit-1 lineage. Loss-of-function ATRX mutations were found in all the nine ATRX immuno-negative cases: nonsense mutations (n=4), frameshift deletions (n=4) and large deletions affecting 22-28 of the 36 exons (n=3). More than one ATRX gene defect was identified in two PCs.

CONCLUSION: ATRX mutations occur in a subset of aggressive pituitary tumours and are more common in corticotroph tumours. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumours.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Endocrinology and Metabolism
Vol/bind106
Nummer4
Antal sider12
ISSN0021-972X
DOI
StatusUdgivet - mar. 2021

Bibliografisk note

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

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