Olivera Casar-Borota1,2, Henning Bünsow Boldt3,4, Britt Edén Engström5,6, Marianne Skovsager Andersen7,8, Bertrand Baussart9, Daniel Bengtsson10,11, Katarina Berinder12,13, Bertil Ekman14,15, Ulla Feldt-Rasmussen16,17, Charlotte Höybye12,13, Jens Otto L Jørgensen18, Anders Jensen Kolnes19,20, Márta Korbonits21,22, Åse Krogh Rasmussen23, John R Lindsay24,25, Paul Benjamin Loughrey25,26, Dominique Maiter27, Emilija Manojlovic-Gacic28, Jens Pahnke29,30,31, Pietro Luigi Poliani32, Vera Popovic33, Oskar Ragnarsson34,35, Camilla Schalin-Jäntti36, David Scheie37, Miklós Tóth38, Chiara Villa39,40,41, Martin Wirenfeldt3,4, Jacek Kunicki42, Pia Burman43. 1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 2. Department of Clinical Pathology, Uppsala University Hospital, Uppsala, Sweden. 3. Department of Pathology, Odense University Hospital, Odense, Denmark. 4. Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 5. Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden. 6. Department of Endocrinology and Diabetology, Uppsala University Hospital, Uppsala, Sweden. 7. Department of Endocrinology, Odense University Hospital, Odense, Denmark. 8. Clinical Institute, University of Southern Denmark, Odense, Denmark. 9. Department of Neurosurgery, Foch Hospital, Suresnes, France. 10. Department of Internal Medicine, Kalmar, Region of Kalmar County, Sweden. 11. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. 12. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. 13. Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden. 14. Department of Endocrinology, University Hospital, Linköping, Sweden. 15. Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden. 16. Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen, Denmark. 17. Institute of Clinical Medicine, Faculty of Health Research Sciences, Copenhagen University, Copenhagen, Denmark. 18. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. 19. Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway. 20. Faculty of Medicine, University of Oslo, Oslo, Norway. 21. Centre for Endocrinology, William Harvey Research Institute, Barts, UK. 22. The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 23. Department of Endocrinology and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark. 24. Mater Infirmorum Hospital, Belfast Health & Social Care Trust (BHSCT), UK. 25. Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, UK. 26. Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK. 27. Department of Endocrinology and Nutrition, UCL Cliniques universitaires Saint-Luc, 1200 Brussels, Belgium. 28. Institute of Pathology, School of Medicine, University of Belgrade, Belgrade, Serbia. 29. University of Oslo (UiO) and Oslo University Hospital (OUS), Department of Pathology, Translational Neurodegeneration Research and Neuropathology Lab, Oslo, Norway. 30. LIED, University of Lübeck, Lübeck, Germany. 31. Department of Pharmacology, Medical Faculty, University of Latvia, Riga, Latvia. 32. Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy. 33. Medical Faculty, University of Belgrade, Serbia. 34. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 35. Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden. 36. Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. 37. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 38. Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 39. Department of Pathological Cytology and Anatomy, Foch Hospital, Suresnes, France. 40. INSERM U1016, Institut Cochin, Paris, France; Université Paris Descartes-Université de Paris, Paris, France. 41. Department of Endocrinology, Sart Tilman B35, 4000 Liège, Belgium. 42. Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 43. Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Sweden.
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.
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.
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