Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas. Additional diagnostic markers are needed to aid in this often challenging differential diagnosis. Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED, were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases. Furthermore, both SUZ12 and EED mutations in MPNSTs were associated with loss of H3K27 tri-methylation, a downstream target of PRC2. Therefore we tested whether H3K27me3 immunohistochemistry is useful as a diagnostic and prognostic marker for MPNSTs. We performed H3K27me3 immunohistochemistry in 162 primary MPNSTs, 97 neurofibromas and 341 other tumors using tissue microarray. We observed loss of H3K27me3 in 34% (55/162) of all MPNSTs while expression was retained in all neurofibromas including atypical (n=8) and plexiform subtypes (n=24). Within other tumors we detected loss of H3K27me3 in only 7% (24/341). Surprisingly, 60% (9/15) of synovial sarcomas and 38% (3/8) of fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) showed loss of H3K27 trimethylation. Only 1 out of 44 schwannomas showed loss of H3K27me3 and all 4 perineuriomas showed intact H3K27me3. Furthermore, MPNSTs with loss of H3K27 tri-methylation showed inferior survival compared to MPNSTs with intact H3K27 tri-methylation, which was validated in two independent cohorts. Our results indicate that H3K27me3 immunohistochemistry is useful as a diagnostic marker in which loss of H3K27me3 favours MPNST above neurofibroma. However H3K27me3 immunohistochemistry is not suitable to distinguish MPNST from its morphological mimicker synovial sarcoma or fibrosarcomatous DFSP. Since loss of H3K27 tri-methylation was related to poorer survival in MPNST, chromatin modification mediated by this specific histone seems to orchestrate more aggressive tumour biology.

NF1+/− Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response

“…To examine the significance of the mast cell enrichment phenotype in human MPNST samples, we analyzed a tissue microarray of primary and locally recurrent MPNSTs with known NF1 status for c-Kit staining, a commonly used clinical marker of mast cells (31, 33). Mast cells were enriched in NF1-associated MPNSTs compared to sporadic MPNSTs (Figure 4F).…”

“…A human MPNST tissue microarray (TMA) was built using patient samples obtained under approval of the Institutional Review Board of The University of Texas MD Anderson Cancer Center as previously described (13, 31). An anonymized, full clinical database, including the neurofibromatosis status of each patient, was constructed.…”

Association between EZH2 expression, silencing of tumor suppressors and disease outcome in solid tumors

“…In contrast, complete PRC2 inactivation occurs in malignant peripheral nerve sheath tumors through mutation of SUZ12 or EED 35–37 . It is likely that inactivation of PRC2 also occurs in other sarcomas in view of frequent H3K27me3 loss 38 . In pediatric high-grade gliomas (pHGG), point mutation of the K27 residue of H3.3 or H3.1 histone variants into methionine (H3K27M) lead to a global reduction of H3K27me3 39–41 .…”

Epigenetic Alterations in Bone and Soft Tissue Tumors

“…At least four large studies have reported on the specificity and sensitivity of H3K27me3 loss in the diagnosis of MPNST. 35–38 Most studies have found good specificity, with rare examples of H3K27me3 loss in other sarcomas. However, one large series noted H3K27me3 loss in a subsets of synovial sarcomas and fibrosarcomatous dermatofibrosarcoma protuberans (9/15 and 3/8, respectively), two close histologic mimics of MPNST.…”

“…However, one large series noted H3K27me3 loss in a subsets of synovial sarcomas and fibrosarcomatous dermatofibrosarcoma protuberans (9/15 and 3/8, respectively), two close histologic mimics of MPNST. 35 The reported sensitivity values of H3K27me3 loss have been both more variable and less impressive (34—61%). In addition to its utility as a diagnostic marker, several series also found loss of H3K27me3 to have prognostic significance, as it was associated with aggressive disease.…”