Loss of PRC2 Function Promotes MPNST Pathogenesis

Malignant peripheral nerve sheath tumors (MPNST) are a highly aggressive subtype of soft-tissue sarcoma that can be classified into three categories: sporadic, neurofibromatosis type 1 (NF1)–associated, and radiotherapy-associated. Although loss of the wild-type NF1 allele has been implicated in malignant tumor progression in patients with NF1, it remains unclear whether additional genetic factors contribute to MPNST pathogenesis. To gain insight into the molecular origins of MPNSTs, Lee, Teckie, Wiesner, Ran, and colleagues characterized the genomic landscape of MPNST tumor samples and matched normal tissue from two independent cohorts of patients. This integrative analysis revealed that 80% of all MPNSTs harbored somatic loss-of-function mutations in embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), which encode core components of the Polycomb repressive complex 2 (PRC2); these mutations occurred in a mutually exclusive manner and were frequently accompanied by loss or structural variation of the corresponding wild-type allele. Loss of NF1 and cyclin-dependent kinase inhibitor 2A (CDKN2A) were also detected in the majority of MPNSTs and were associated with PRC2 mutations. Gene expression analysis revealed the upregulation of classical PRC2 target genes involved in development and morphogenesis in MPNSTs harboring EED mutations or homozygous SUZ12 loss. In line with the role of PRC2 in promoting trimethylation of lysine 27 of histone H3 (H3K27me3), loss of H3K27me3 staining correlated with homozygous PRC2 inactivation and was associated with malignant progression from benign plexiform neurofibroma to MPNST in clinical samples. Importantly, reintroduction of exogenous SUZ12 in an SUZ12-deficient MPNST cell line restored H3K27me3 levels, reduced the transcription of PRC2-regulated genes, and inhibited cell growth, but had little effect on cells with wild-type SUZ12 expression. Together, these results highlight the important and potentially cooperative role of inactivation of PRC2, NF1, and CDKN2A in MPNST tumorigenesis.

Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumours. Nat Genet 2014 Sep 21 [Epub ahead of print].