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

Japan Pediatric Molecular Neuro-Oncology Group (JPMNG)

研究成果: Article

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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.

元の言語English
ページ数1
ジャーナルActa neuropathologica communications
6
発行部数1
DOI
出版物ステータスPublished - 04-12-2018

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Ependymoma
Neoplasms
Methylation
RNA Sequence Analysis
Gene Fusion
Japan
Multivariate Analysis
Genome

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

これを引用

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title = "Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors",
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.",
author = "{Japan Pediatric Molecular Neuro-Oncology Group (JPMNG)} and Kohei Fukuoka and Yonehiro Kanemura and Tomoko Shofuda and Shintaro Fukushima and Satoshi Yamashita and Daichi Narushima and Mamoru Kato and Mai Honda-Kitahara and Hitoshi Ichikawa and Takashi Kohno and Atsushi Sasaki and Junko Hirato and Takanori Hirose and Takashi Komori and Kaishi Satomi and Akihiko Yoshida and Kai Yamasaki and Yoshiko Nakano and Ai Takada and Taishi Nakamura and Hirokazu Takami and Yuko Matsushita and Tomonari Suzuki and Hideo Nakamura and Keishi Makino and Yukihiko Sonoda and Ryuta Saito and Teiji Tominaga and Yasuhiro Matsusaka and Keiichi Kobayashi and Motoo Nagane and Takuya Furuta and Mitsutoshi Nakada and Yoshitaka Narita and Yuichi Hirose and Shigeo Ohba and Akira Wada and Katsuyoshi Shimizu and Kazuhiko Kurozumi and Isao Date and Junya Fukai and Yousuke Miyairi and Naoki Kagawa and Atsufumi Kawamura and Makiko Yoshida and Namiko Nishida and Takafumi Wataya and Masayoshi Yamaoka and Naohiro Tsuyuguchi and Takehiro Uda",
year = "2018",
month = "12",
day = "4",
doi = "10.1186/s40478-018-0630-1",
language = "English",
volume = "6",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

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TY - JOUR

T1 - Significance of molecular classification of ependymomas

T2 - C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors

AU - Japan Pediatric Molecular Neuro-Oncology Group (JPMNG)

AU - Fukuoka, Kohei

AU - Kanemura, Yonehiro

AU - Shofuda, Tomoko

AU - Fukushima, Shintaro

AU - Yamashita, Satoshi

AU - Narushima, Daichi

AU - Kato, Mamoru

AU - Honda-Kitahara, Mai

AU - Ichikawa, Hitoshi

AU - Kohno, Takashi

AU - Sasaki, Atsushi

AU - Hirato, Junko

AU - Hirose, Takanori

AU - Komori, Takashi

AU - Satomi, Kaishi

AU - Yoshida, Akihiko

AU - Yamasaki, Kai

AU - Nakano, Yoshiko

AU - Takada, Ai

AU - Nakamura, Taishi

AU - Takami, Hirokazu

AU - Matsushita, Yuko

AU - Suzuki, Tomonari

AU - Nakamura, Hideo

AU - Makino, Keishi

AU - Sonoda, Yukihiko

AU - Saito, Ryuta

AU - Tominaga, Teiji

AU - Matsusaka, Yasuhiro

AU - Kobayashi, Keiichi

AU - Nagane, Motoo

AU - Furuta, Takuya

AU - Nakada, Mitsutoshi

AU - Narita, Yoshitaka

AU - Hirose, Yuichi

AU - Ohba, Shigeo

AU - Wada, Akira

AU - Shimizu, Katsuyoshi

AU - Kurozumi, Kazuhiko

AU - Date, Isao

AU - Fukai, Junya

AU - Miyairi, Yousuke

AU - Kagawa, Naoki

AU - Kawamura, Atsufumi

AU - Yoshida, Makiko

AU - Nishida, Namiko

AU - Wataya, Takafumi

AU - Yamaoka, Masayoshi

AU - Tsuyuguchi, Naohiro

AU - Uda, Takehiro

PY - 2018/12/4

Y1 - 2018/12/4

N2 - 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.

AB - 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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