Stains & molecular markers
H3K27me3
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: H3K27me3 [title]
H3K27me3
Editor-in-Chief: Debra L. Zynger, M.D.
Topic Completed: 29 January 2019
Minor changes: 2 September 2020
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: H3K27me3 [title]
Table of Contents
Definition / general | Essential features | Pathophysiology | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining - normal | Negative staining - disease | Board review style question #1 | Board review style answer #1Cite this page: Nawar N, Dickson BC. H3K27me3. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsh3k27me3.html. Accessed January 20th, 2021.
Definition / general
- H3K27me3 (trimethylation at lysine 27 of histone H3) is a downstream target of the polycomb repressive complex 2 (PRC2), which has histone methlyltransferase activity (Nature 2011;469:343, Nat Genet 2014;46:1170); PRC2 contains evolutionarily conserved proteins essential for regulating gene expression (Sci Adv 2015;1:e1500737)
- As a gene transcription repressor, H3K27me3 has diverse roles in embryogenesis and neoplasia (Cell Res 2018;28:593, Epigenetics 2014;9:658)
Essential features
- Loss of H3K27me3 occurs in a significant subset of malignant peripheral nerve sheath tumors (Nat Genet 2014;46:1227, Mod Pathol 2016;29:4)
- Other neoplasms may show loss of H3K27me3 expression, such as meningioma (Pathol Res Pract 2018;214:417), radiation associated unclassified sarcoma (Mod Pathol 2016;29:4), radiation associated angiosarcoma (Virchows Arch 2018;472:361), dedifferentiated chondrosarcoma (Mod Pathol 2018 Oct 5 [Epub ahead of print]), melanoma (Mod Pathol 2017;30:1677) and Merkel cell carcinoma (Mod Pathol 2017;30:877), amongst others (Histopathology 2017;70:385)
- Some tumors may exhibit heterogeneous H3K27me3 expression (mosaic pattern)
Pathophysiology
- Polycomb repressive complex 2 (PRC2) has diverse roles in stem cell pluripotency, somatic differentiation and proliferation (Nature 2011;469:343, Sci Adv 2015;1:e1500737)
- Enzymatic subunits EZH1 and EZH2 of the PRC2 catalyze methylation of H3K27 (Nature 2011;469:343); trimethylation of H3K27 is associated with gene repression (Cell Rep 2016;17:1369)
- Alterations involving PRC2, accessory proteins or H3K27me3 may disrupt an epigenetic regulatory network, with complex and varied contributions in neoplasia (Mol Cancer Res 2014;12:639)
Interpretation
- H3K27me3 is constitutively expressed and intact expression is denoted by the presence of diffuse nuclear staining; loss of staining may be complete or heterogeneous (mosaic) (Mod Pathol 2016;29:4)
- Interpretation is context dependent
- For example, when presented with a peripheral nerve sheath tumor, loss of staining would favor malignant peripheral nerve sheath tumor over neurofibroma (Mod Pathol 2016;29:4, Mod Pathol 2016;29:582)
- An eccentric intranuclear dot reflects the inactivated X chromosome in normal tissues (Histopathology 2016;69:702)
Uses by pathologists
- Complete loss of H3K27me3 occurs in about 34 - 72% of malignant peripheral nerve sheath tumors (91 - 100% radiation associated, 41 - 71% neurofibromatosis type 1 associated, 32 - 90% sporadic and 0% epithelioid) (Mod Pathol 2016;29:4, Am J Surg Pathol 2016;40:479, Mod Pathol 2016;29:582, Mod Pathol 2017;30:1677)
- As a result, this may be used to differentiate from potential mimics (e.g., neurofibroma)
- It is important to note that H3K27me3 may be lost in a significant proportion of melanoma (Mod Pathol 2017;30:1677) and rarely other malignant and benign neoplasms (Mod Pathol 2016;29:582)
- H3K27me3 immunohistochemistry highlights the inactivated X chromosome in female tissues; as a result, this may be used to predict sex in nonneoplastic tissues (Histopathology 2016;69:702)
Prognostic factors
- Loss of H3K27me3 in malignant peripheral nerve sheath tumors appears to be associated with higher grade and aggressive behavior (Histopathology 2016;69:702, Mod Pathol 2016;29:582)
- Loss of H3K27me3 may portent aggressive behavior in meningioma (Acta Neuropathol 2018;135:955); conversely, increased expression has been associated with a worse prognosis in some tumors, such as oral squamous cell carcinoma (Cancer 2013;119:4259)
Microscopic (histologic) images
Contributed by Brendan Dickson, M.D.
Malignant peripheral nerve sheath tumor
Malignant triton tumor with rhabdomyoblastic differentiation
Schwannoma
Positive staining - normal
- Normal tissue contains intact nuclear H3K27me3 expression
- Presence of an eccentric intranuclear dot reflects the inactivated X chromosome in normal tissues (Histopathology 2016;69:702)
Positive staining - disease
- Most tumor tissues contain intact nuclear H3K27me3 expression
Negative staining - normal
- To date, no normal tissues have been reported to consistently lack H3K27me3 expression
Negative staining - disease
- Complete loss of H3K27me3 occurs in about 34 - 72% malignant peripheral nerve sheath tumors (91 - 100% radiation associated, 41 - 71% neurofibromatosis type 1 associated, 32 - 90% sporadic and 0% epithelioid) (Mod Pathol 2016;29:4, Am J Surg Pathol 2016;40:479, Mod Pathol 2016;29:582, Mod Pathol 2017;30:1677)
- Complete loss of H3K27me3 occurs in about 37% of melanomas (Mod Pathol 2017;30:1677)
- H3K27me3 is reported to rarely be lost in a subset of other tumors, such as meningioma (Pathol Res Pract 2018;214:417), radiation associated unclassified sarcoma (Mod Pathol 2016;29:4), radiation associated angiosarcoma (Virchows Arch 2018;472:361), undifferentiated pleomorphic sarcoma (Histopathology 2017;70:385), osteosarcoma (Histopathology 2017;70:385), dedifferentiated chondrosarcoma (Mod Pathol 2018 Oct 5 [Epub ahead of print]), melanoma (Mod Pathol 2017;30:1677) and Merkel cell carcinoma (Mod Pathol 2017;30:877)
Board review style question #1
- A tumor is biopsied in a patient with a remote history of cancer. It shows a cellular spindle cell neoplasm with a herringbone pattern. Which of the following neoplasms is most likely to exhibit loss of H3K27me3?
- Cellular schwannoma
- Epithelioid malignant peripheral nerve sheath tumor
- Neurofibroma
- Radiation associated malignant peripheral nerve sheath tumor
Board review style answer #1
D. Radiation associated malignant peripheral nerve sheath tumor. Complete loss of H3K27me3 occurs in > 90% of radiation associated malignant peripheral nerve sheath tumor. It is intact in the vast majority of cases of epithelioid malignant peripheral nerve sheath tumor, schwannoma and neurofibroma.
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