Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.
(2021) Journal of Clinical Endocrinology and Metabolism — Vol. 106, n° 4, p. 1183-1194 (2021)
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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.
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Casar-Borota, O., Boldt, H. B., Engström, B. E., Andersen, M. S., Baussart, B., Bengtsson, D., Berinder, K., Ekman, B., Feldt-Rasmussen, U., Höybye, C., Jørgensen, J. O. L., Kolnes, A. J., Korbonits, M., Rasmussen, Å. K., Lindsay, J. R., Loughrey, P. B., Maiter, D., Manojlovic-Gacic, E., Pahnke, J., et al. (2021). Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations. Journal of Clinical Endocrinology and Metabolism, 106(4), 1183-1194. https://doi.org/10.1210/clinem/dgaa749 (Original work published 2021)