Acta Neuropathologica Communications (Dec 2018)

Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors

  • Kohei Fukuoka,
  • Yonehiro Kanemura,
  • Tomoko Shofuda,
  • Shintaro Fukushima,
  • Satoshi Yamashita,
  • Daichi Narushima,
  • Mamoru Kato,
  • Mai Honda-Kitahara,
  • Hitoshi Ichikawa,
  • Takashi Kohno,
  • Atsushi Sasaki,
  • Junko Hirato,
  • Takanori Hirose,
  • Takashi Komori,
  • Kaishi Satomi,
  • Akihiko Yoshida,
  • Kai Yamasaki,
  • Yoshiko Nakano,
  • Ai Takada,
  • Taishi Nakamura,
  • Hirokazu Takami,
  • Yuko Matsushita,
  • Tomonari Suzuki,
  • Hideo Nakamura,
  • Keishi Makino,
  • Yukihiko Sonoda,
  • Ryuta Saito,
  • Teiji Tominaga,
  • Yasuhiro Matsusaka,
  • Keiichi Kobayashi,
  • Motoo Nagane,
  • Takuya Furuta,
  • Mitsutoshi Nakada,
  • Yoshitaka Narita,
  • Yuichi Hirose,
  • Shigeo Ohba,
  • Akira Wada,
  • Katsuyoshi Shimizu,
  • Kazuhiko Kurozumi,
  • Isao Date,
  • Junya Fukai,
  • Yousuke Miyairi,
  • Naoki Kagawa,
  • Atsufumi Kawamura,
  • Makiko Yoshida,
  • Namiko Nishida,
  • Takafumi Wataya,
  • Masayoshi Yamaoka,
  • Naohiro Tsuyuguchi,
  • Takehiro Uda,
  • Mayu Takahashi,
  • Yoshiteru Nakano,
  • Takuya Akai,
  • Shuichi Izumoto,
  • Masahiro Nonaka,
  • Kazuhisa Yoshifuji,
  • Yoshinori Kodama,
  • Masayuki Mano,
  • Tatsuya Ozawa,
  • Vijay Ramaswamy,
  • Michael D. Taylor,
  • Toshikazu Ushijima,
  • Soichiro Shibui,
  • Mami Yamasaki,
  • Hajime Arai,
  • Hiroaki Sakamoto,
  • Ryo Nishikawa,
  • Koichi Ichimura,
  • on behalf of the Japan Pediatric Molecular Neuro-Oncology Group (JPMNG)

DOI
https://doi.org/10.1186/s40478-018-0630-1
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 18

Abstract

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Abstract Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

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