PO-340 Dysregulation of the TP53 network and PRC2 activity are independent poor prognostic factors in patients with malignant peripheral nerve sheath tumours

Introduction Malignant peripheral nerve sheath tumours (MPNSTs) are rare and aggressive tumours with neuroectodermal origin, mainly affecting adolescents and young adults. Genetic aberrations in the EED and SUZ12 genes, encoding core components of the Polycomb repressive complex 2 (PRC2), have been found in up to 80% of MPNSTs. Homozygous losses of PRC2 components have been shown to result in complete loss of trimethylation of lysine 27 (H2K27m3) and this has been found to be an indicator of poor prognosis for MPNST patients. Furthermore, TP53 is one of few recurrently mutated genes, but the clinical relevance of the TP53 network in MPNSTs remains inconclusive. Here, we have analysed the prognostic impact of dysregulated PRC2 and TP53 activity on the gene expression-level in an aggregated series of MPNSTs. Material and methods Frozen samples from 60 MPNSTs and 15 neurofibromas from patients treated at specialised sarcoma centres in Norway, Sweden, and Italy were subjected to gene expression analyses (Genome-Wide GeneChip Human Transcriptome Array 2.0, Affymetrix). Single-sample gene set enrichment analysis was performed for a gene set upregulated in breast tumours with TP53 mutation [Miller et al. Proc Natl Acad Sci U S A. 2005;102(38:13550–5)] and a gene set upregulated in MPNSTs with PRC2 inactivation [Lee et al. Nat Genet. 2014;46(11:1227–32)]. Results and discussions Both the TP53 network and PRC2 activity were down-regulated in MPNSTs compared with the benign neurofibromas, as determined by a significantly higher gene set score (p=3 × 10–10 and p=0.0009, respectively). Furthermore, down-regulation of both processes were associated with inferior survival for MPNST patients (HR=4.1 [95% CI, 1.73–9.79], p=0.001 and HR=4.9 [95% CI, 1.65–14.69], p=0.004, respectively). In multivariable analyses, including the clinical variables NF1 status, sex, age at diagnosis, tumour location, tumour size, and remission status, both gene sets were independent prognostic markers, however the TP53 gene set signature had the strongest prognostic impact. Patients with down-regulation of both processes (n=25, 42%) had a particularly poor survival (HR=9.1, CI:2.1–39.9, p=0.003). Conclusion Dysregulation of the TP53 network and PRC2 function distinguish MPNSTs from benign neurofibromas and are independently associated with inferior patient survival.