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.To study ATRX protein expression and mutational
status of the ATRX gene in APTs and PCs.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.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.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.
