Corticotroph aggressive pituitary tumours and carcinomas frequently harbour ATRX mutations.

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.