ArticleModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc2019
Histone H3K27 dimethyl loss is highly specific for malignant peripheral nerve sheath tumor and distinguishes true PRC2 loss from isolated H3K27 trimethyl loss.
Article in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 44 citations in OpenAlex.
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- Diagnostic Utility and Clinicopathologic Associations of Histone H3 Lysine 27 Trimethylation (H3K27me3) Immunohistochemistry for Merkel Cell Carcinoma.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2026Article
- Development of a High-Throughput Platform for Quantitation of Histone Modifications on a New QTOF Instrument.Molecular & cellular proteomics : MCP · 2025Article
- Merkel cell carcinoma: updates in tumor biology, emerging therapies, and preclinical models.Frontiers in oncology · 2024Review
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- H3K27me3 deficiency in dedifferentiated carcinoma and carcinosarcoma of the endometrium.Virchows Archiv : an international journal of pathology · 2023Article
- Molecular testing of soft tissue tumors.Diagnostic cytopathology · 2023Review
- PRAME expression in spindle cell melanoma, malignant peripheral nerve sheath tumour, and other cutaneous sarcomatoid neoplasms: a comparative analysis.Histopathology · 2022Article
- Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer.International journal of molecular sciences · 2022Review
- Global Level Quantification of Histone Post-Translational Modifications in a 3D Cell Culture Model of Hepatic Tissue.Journal of visualized experiments : JoVE · 2022Article
- Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2022Article
- The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma.Frontiers in oncology · 2022Review
- Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation.Virchows Archiv : an international journal of pathology · 2021Article
- Epigenetic Dysregulations in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma.International journal of molecular sciences · 2021Review
- Assessment of H3K27me3 immunohistochemistry and combination of NF1 and p16 deletions by fluorescence in situ hybridization in the differential diagnosis of malignant peripheral nerve sheath tumor and its histological mimics.Diagnostic pathology · 2021Article
- Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma.Genome medicine · 2021Article
- The roles of Polycomb repressive complexes in mammalian development and cancer.Nature reviews. Molecular cell biology · 2021Review
- Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations.Diagnostics (Basel, Switzerland) · 2021Review
- Trimethylacetic Anhydride-Based Derivatization Facilitates Quantification of Histone Marks at the MS1 Level.Molecular & cellular proteomics : MCP · 2021Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
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Abstract
Malignant peripheral nerve sheath tumors contain loss of histone H3K27 trimethylation (H3K27me3) due to driver mutations affecting the polycomb repressive complex 2 (PRC2). Consequently, loss of H3K27me3 staining has served as a diagnostic marker for this tumor type. However, recent reports demonstrate H3K27me3 loss in numerous other tumors, including some in the differential diagnosis of malignant peripheral nerve sheath tumor. Since these tumors lose H3K27me3 through mechanisms distinct from PRC2 loss, we set out to determine whether loss of dimethylation of H3K27, which is also catalyzed by PRC2, might be a more specific marker of PRC2 loss and malignant peripheral nerve sheath tumor. Using mass spectrometry, we identify a near complete loss of H3K27me2 in malignant peripheral nerve sheath tumors and cell lines. Immunohistochemical analysis of 72 malignant peripheral nerve sheath tumors, seven K27M-mutant gliomas, 43 ependymomas, and 10 Merkel cell carcinomas demonstrates that while H3K27me3 loss is common across these tumor types, H3K27me2 loss is limited to malignant peripheral nerve sheath tumors and is highly concordant with H3K27me3 loss (33/34 cases). Thus, increased specificity does not come at the cost of greatly reduced sensitivity. To further compare H3K27me2 and H3K27me3 immunohistochemistry, we investigated 42 melanomas and 54 synovial sarcomas, histologic mimics of malignant peripheral nerve sheath tumor with varying degrees of H3K27me3 loss in prior reports. While global H3K27me3 loss was not seen in these tumors, weak and limited H3K27me3 staining was common. By contrast, H3K27me2 staining was more clearly retained in all cases, making it a superior binary classifier. This was confirmed by digital image analysis of stained slides. Our findings indicate that H3K27me2 loss is highly specific for PRC2 loss and that PRC2 loss is a rarer phenomenon than H3K27me3 loss. Consequently, H3K27me2 loss is a superior diagnostic marker for malignant peripheral nerve sheath tumor.
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