Atypical teratoid rhabdoid tumors (AT/RT) are rare pediatric embryonal brain tumors. AT/RT are genomically characterized by a very simple genomic landscape caused by inactivation of the SMARCB1 tumor suppressor, chromatin remodelling, gene. Adult AT/RT is a super-rare disease with only 33 cases previously reported. For the first time, we report an adult pituitary AT/RT which has undergone whole-exome sequencing (WES) from a patient who subsequently died of intrachemotherapy leptomeningeal progression.


In combination, the detection of both somatic biallelic SMARCB1 mutations and the loss of INI-1 protein expression confirmed the diagnosis of AT/RT. Trisomy 8 was detected in a minority of AT/RT cells. The overall somatic mutation rate was 1.9 Mb. A total of 98 somatic mutations were detected of which 20/49 non-synonymous coding mutations were predicted to be potentially damaging to protein function. These 20 genes were stratified into 4 functionally discrete groups: Group 1). tubulin / actin dynamics; Group 2). cell adhesion; Group 3). metabolism; Group 4). cytotoxic resistance mechanisms.

Molecular pathway analysis predicted that loss of NOTCH1 signalling could be an important cellular node that was perturbed by a combination of LNX1 and POFUT1 mutations.

AT/RT cells did not express any endocrine differentiation markers. Furthermore, 90% of AT/RT cells demonstrated intense nuclear p53 expression despite no TP53 mutations or HDM2 amplification being detected.


This is the first adult AT/RT to have undergone next-generation sequencing using WES. We have shown that the genomic landscape can be relatively complex in comparison to pediatric primary AT/RT(Lee RS et al 2012. J Clin Invest; 122(8):2983-2988). First, we detected a somatic mutation rate which was four times higher (1.9 Mb versus <0.5 Mb) than pediatric primary AT/RT, but which was comparable to the mutation rate of pediatric metastatic AT/RT. Second, we detected a Chr8 CNV in a minority of cells. Given that Chr8 harbors the loci for a variety of pro-metastatic genes, including C-MYC, MT3-MMP and BNIP3, we hypothesize that the intra-chemotherapy tumor progression was possibly caused by a clonal population of trisomy 8 cells which over-expressed the respective proteins of these specific genes.

Given the dedifferentiated phenotype of AT/RT cells and that NOTCH1 signalling is known to be essential for maintaining the pituitary stem cell pool, we hypothesize that the combined effects of LNX1 and POFUT1 mutations could have been important events in the generation of an AT/RT cancer-initiating cell, through loss of NOTCH1 signalling. In this regard, we are currently investigating the expression of NOTCH1 signalling proteins, as well as elucidating the cause of the high levels of nuclear p53 expression within this AT/RT, which we also hypothesize was related to perturbations in NOTCH1 signalling.

Note: This abstract was not presented at the meeting.

Citation Format: Swethajit Biswas, Madeleine Wood, Abhijit Joshi, Nick Bown, Lisa Strain, Philip Kane, Tommy Martinsson, Javier Garrido, James Campbell, Amanda Swain, Alan Ashworth. Whole-exome sequencing of an adult pituitary atypical teratoid rhabdoid tumor (AT/RT) - A not so simple genome as pediatric AT/RT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5082. doi:10.1158/1538-7445.AM2014-5082