H3K27me3 deficiency defines a subset of dedifferentiated chondrosarcomas with characteristic clinicopathological features View Full Text


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Article Info

DATE

2018-10-05

AUTHORS

Naohiro Makise, Masaya Sekimizu, Eiichi Konishi, Toru Motoi, Takashi Kubo, Hisashi Ikoma, Shun-ichi Watanabe, Tomotake Okuma, Nobuyoshi Hiraoka, Masashi Fukayama, Akira Kawai, Hitoshi Ichikawa, Akihiko Yoshida

ABSTRACT

Dedifferentiated chondrosarcoma is a rare bone sarcoma, whose genetic background remains incompletely understood. Mutations in SUZ12 or EED, which encode polycomb repressive complex 2 (PRC2) components, and resulting deficiency in H3K27me3 are characteristic features of the majority of malignant peripheral nerve sheath tumors. Here, we investigated H3K27me3 and PRC2 status in dedifferentiated chondrosarcoma. Among 19 evaluable dedifferentiated chondrosarcoma cases, six (32%) showed immunohistochemical loss of H3K27me3 only in the dedifferentiated component, whereas the well-differentiated component retained H3K27me3. H3K27me3-deficient dedifferentiated chondrosarcoma occurred in two men and four women with a median age of 66. All of these tumors affected bones of the upper half of the body, with the ribs being preferentially involved, which represented a significantly different distribution compared to that in the 13 H3K27me3-intact dedifferentiated chondrosarcomas. H3K27me3-deficient dedifferentiated chondrosarcomas were histologically different from H3K27me3-intact dedifferentiated chondrosarcomas, as the former invariably demonstrated dedifferentiated histology with a striking similarity to classic malignant peripheral nerve sheath tumor, comprising sweeping to swirling fascicles of relatively uniform spindle cells. Heterologous rhabdomyoblastic differentiation, the focal presence of grade 3 chondrosarcoma histology, and a cartilaginous component in the metastatic sites were exclusively seen in some cases of H3K27me3-deficient dedifferentiated chondrosarcoma. In all three H3K27me3-deficient dedifferentiated chondrosarcomas that contained focal grade 3 histology, dedifferentiated components did not juxtapose to the grade 3 areas but transitioned abruptly from the grade 1–2 components. Targeted next generation sequencing, which was successfully performed on four H3K27me3-deficient dedifferentiated chondrosarcomas, identified an IDH2 mutation in one case and COL2A1 truncations in three cases. The dedifferentiated areas of three cases harbored SUZ12 or EED alterations, which were absent in the well-differentiated component, suggesting a role for PRC2 aberrations in dedifferentiation. H3K27me3 deficiency defines a novel subset of dedifferentiated chondrosarcoma that requires recognition because of its diagnostic and potential clinical implications. More... »

PAGES

435-445

References to SciGraph publications

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  • 2012-12-10. Clinical outcome for patients with dedifferentiated chondrosarcoma: a report of 9 cases at a single institute in JOURNAL OF ORTHOPAEDIC SURGERY AND RESEARCH
  • 2014-08-13. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies in NATURE
  • 2014-10-12. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors in NATURE GENETICS
  • 2001-04-01. H-ras Oncogene Mutation in Dedifferentiated Chondrosarcoma: Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Analysis in MODERN PATHOLOGY
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    http://scigraph.springernature.com/pub.10.1038/s41379-018-0140-5

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    http://dx.doi.org/10.1038/s41379-018-0140-5

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30291346


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