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Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation

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Abstract

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

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Acknowledgements

Technical support for the experimental trials was provided by the following laboratory assistants: Motoko Tomita, Mami Nakamizo, Juri Godo, Kozue Ueno-Matsuda, Miwako Ishii, Jumi Yahiro-Matsumoto, and Haruka Inoue. We also appreciate the technical assistance from The Research Support Center, Kyushu University Graduate School of Medical Sciences. The English used in this manuscript was revised by Scientific Language (https://www.scientific-language.co.jp).

Funding

This study was supported by JSPS KAKENHI Grant Numbers 21K06887 and 19H03444.

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Authors and Affiliations

  1. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Yoshihiro Ito, Kenichi Kohashi, Shin Ishihara, Yu Toda, Yosuke Susuki, Kengo Kawaguchi, Hiroshi Furukawa, Yuki Tateishi, Yuichi Yamada, Izumi Kinoshita, Taro Mori, Hidetaka Yamamoto & Yoshinao Oda

  2. Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Yoshihiro Ito, Makoto Endo, Masato Yoshimoto, Shin Ishihara, Yosuke Susuki, Kengo Kawaguchi, Hiroshi Furukawa & Yasuharu Nakashima

  3. Division of Orthopaedic Oncology, Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka, 811-1395, Japan

    Masato Yoshimoto

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  1. Yoshihiro Ito
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Contributions

Y. Ito performed the research and wrote the paper. K. Kohashi, M. Endo, M. Yoshimoto, S. Ishihara, Y. Toda, Y. Susuki, K. Kawaguchi, H. Furukawa, Y. Tateishi, Y. Yamada, I. Kinoshita, T. Mori, and H. Yamamoto contributed to the research design and slide review. Y. Nakashima and Y. Oda designed the research and gave final approval of the manuscript. All authors critically reviewed and approved the manuscript.

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Correspondence to Yoshinao Oda.

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Ito, Y., Kohashi, K., Endo, M. et al. Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation. Virchows Arch 479, 1233–1244 (2021). https://doi.org/10.1007/s00428-021-03189-0

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