AWARD NUMBER: W81XWH-15-1-0124 TITLE: Novel Therapeutic Development of NF1-Associated Malignant Peripheral Nerve Sheath Tumor (MPNST) PRINCIPAL INVESTIGATOR:

Most malignant peripheral nerve sheath tumors (MPNSTs) exhibit combined inactivation of NF1, CDKN2A, and polycomb repressive complex 2 component genes (Embryonic Ectoderm Development [EED] and Suppressor of Zeste 12 [SUZ12]). Mutations in EED and SUZ12 induce loss of trimethylation at lysine 27 of histone 3 (H3K27me3), with subsequent aberrant transcriptional activation of polycomb repressive complex 2–repressed homeobox master regulators. These findings prompted us to investigate the performance of an anti-H3K27me3 monoclonal antibody clone C36B11 as an immunohistochemical marker for MPNSTs. We assessed the C36B11 reactivity pattern in a pathologically and genetically well-characterized cohort of 68 MPNSTs, spanning various clinical presentations, such as type 1 neurofibromatosis (NF1), radiotherapy, and sporadic MPNSTs. We found that 69% (n=47) of all MPNSTs demonstrated loss of H3K27me3 expression, with 42 (61%) showing complete loss and 5 (7%) showing partial loss, whereas 31% (n = 21) retained H3K27me3 expression. Among the NF1related high-grade MPNSTs, 60% demonstrated loss of expression. In contrast, the majority of both sporadic (95%) and radiotherapy-related (91%) MPNSTs showed loss of H3K27me3 expression. Two of the 3 low-grade MPNSTs and all neurofibromas showed retained expression. Furthermore, all 5 epithelioid MPNSTs retained H3K27me3 labeling. The specificity of H3K27me3 loss as a marker for MPNSTs was studied by testing a large spectrum of lesions included in MPNST differential diagnosis, such as spindle/desmoplastic melanomas, synovial sarcomas, myoepithelial tumors, and other mesenchymal neoplasms, all of which retained expression of H3K27me3. We conclude that immunohistochemical analysis of H3K27me3 has Correspondence: Cristina R. Antonescu, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (; Email: [email protected]) Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.ajsp.com. HHS Public Access Author manuscript Am J Surg Pathol. Author manuscript; available in PMC 2016 May 26. Published in final edited form as: Am J Surg Pathol. 2016 April ; 40(4): 479–489. doi:10.1097/PAS.0000000000000564. A uhor M anscript