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

被引：82

作者：

Fukuoka, Kohei ^{[1
,2
]}

Kanemura, Yonehiro ^{[3
,4
]}

Shofuda, Tomoko ^{[3
]}

Fukushima, Shintaro ^{[1
]}

Yamashita, Satoshi ^{[5
]}

Narushima, Daichi ^{[6
]}

Kato, Mamoru ^{[6
]}

Honda-Kitahara, Mai ^{[1
]}

Ichikawa, Hitoshi ^{[7
]}

Kohno, Takashi ^{[8
]}

Sasaki, Atsushi ^{[9
]}

Hirato, Junko ^{[10
]}

Hirose, Takanori ^{[11
]}

Komori, Takashi ^{[12
]}

Satomi, Kaishi ^{[1
,13
,14
]}

Yoshida, Akihiko ^{[13
,14
]}

Yamasaki, Kai ^{[1
,15
]}

Nakano, Yoshiko ^{[1
,15
]}

Takada, Ai ^{[3
]}

Nakamura, Taishi ^{[1
,16
]}

Takami, Hirokazu ^{[1
,17
]}

Matsushita, Yuko ^{[1
,18
]}

Suzuki, Tomonari ^{[2
]}

Nakamura, Hideo ^{[19
]}

Makino, Keishi ^{[20
]}

Sonoda, Yukihiko ^{[21
,22
]}

Saito, Ryuta ^{[22
]}

Tominaga, Teiji ^{[22
]}

Matsusaka, Yasuhiro ^{[23
]}

Kobayashi, Keiichi ^{[24
]}

Nagane, Motoo ^{[24
]}

Furuta, Takuya ^{[25
,26
]}

Nakada, Mitsutoshi ^{[25
]}

Narita, Yoshitaka ^{[18
]}

Hirose, Yuichi ^{[27
]}

Ohba, Shigeo ^{[27
]}

Wada, Akira ^{[28
]}

Shimizu, Katsuyoshi ^{[28
]}

Kurozumi, Kazuhiko ^{[29
]}

Date, Isao ^{[29
]}

Fukai, Junya ^{[30
]}

Miyairi, Yousuke ^{[31
]}

Kagawa, Naoki ^{[32
]}

Kawamura, Atsufumi ^{[33
]}

Yoshida, Makiko ^{[34
]}

Nishida, Namiko ^{[35
,36
]}

Wataya, Takafumi ^{[37
]}

Yamaoka, Masayoshi ^{[38
]}

Tsuyuguchi, Naohiro ^{[32
]}

Uda, Takehiro ^{[32
]}

机构：

[1] Natl Canc Ctr, Res Inst, Div Brain Tumor Translat Res, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan

[2] Saitama Med Univ Int Med Ctr, Dept Neurooncol Neurosurg, Hidaka, Saitama, Japan

[3] Natl Hosp Org, Osaka Natl Hosp, Inst Clin Res, Dept Res & Innovat, Osaka, Japan

[4] Natl Hosp Org, Osaka Natl Hosp, Dept Neurosurg, Osaka, Japan

[5] Natl Canc Ctr, Res Inst, Div Epigenom, Tokyo, Japan

[6] Natl Canc Ctr, Res Inst, Dept Bioinformat, Tokyo, Japan

[7] Natl Canc Ctr, Res Inst, Dept Clin Genom, Tokyo, Japan

[8] Natl Canc Ctr, Res Inst, Div Genome Biol, Tokyo, Japan

[9] Saitama Med Univ, Dept Pathol, Saitama, Japan

[10] Gunma Univ Hosp, Dept Pathol, Maebashi, Gunma, Japan

[11] Hyogo Canc Ctr, Dept Diagnost Pathol, Kobe, Hyogo, Japan

[12] Tokyo Metropolitan Neurol Hosp, Dept Lab Med & Pathol Neuropathol, Tokyo, Japan

[13] Natl Canc Ctr, Dept Pathol, Tokyo, Japan

[14] Natl Canc Ctr, Clin Labs, Tokyo, Japan

[15] Osaka City Gen Hosp, Dept Pediat Hematol & Oncol, Osaka, Japan

[16] Yokohama City Univ, Grad Sch Med, Dept Neurosurg, Fukuura, Kanagawa, Japan

[17] Univ Tokyo, Fac Med, Dept Neurosurg, Tokyo, Japan

[18] Natl Canc Ctr, Dept Neurosurg & Neurooncol, Tokyo, Japan

[19] Kurume Univ, Sch Med, Dept Neurosurg, Kurume, Fukuoka, Japan

[20] Kumamoto Univ, Grad Sch, Fac Life Sci, Dept Neurosurg, Kumamoto, Japan

[21] Yamagata Univ, Sch Med, Dept Neurosurg, Yamagata, Japan

[22] Tohoku Univ, Grad Sch Med, Dept Neurosurg, Sendai, Miyagi, Japan

[23] Osaka City Gen Hosp, Dept Pediat Neurosurg, Osaka, Japan

[24] Kyorin Univ, Fac Med, Dept Neurosurg, Tokyo, Japan

[25] Kanazawa Univ, Grad Sch Med Sci, Dept Neurosurg, Kanazawa, Ishikawa, Japan

[26] Kurume Univ, Dept Pathol, Kurume, Fukuoka, Japan

[27] Fujita Hlth Univ, Dept Neurosurg, Toyoake, Aichi, Japan

[28] Showa Univ, Sch Med, Dept Neurosurg, Tokyo, Japan

[29] Okayama Univ, Grad Sch Med, Dept Neurol Surg Dent & Pharmaceut Sci, Okayama, Japan

[30] Wakayama Med Univ, Dept Neurol Surg, Wakayama, Japan

[31] Nagano Childrens Hosp, Dept Neurosurg, Nagano, Japan

[32] Osaka Univ, Grad Sch Med, Dept Neurosurg, Osaka, Japan

[33] Hyogo Prefectural Kobe Childrens Hosp, Dept Neurosurg, Kobe, Hyogo, Japan

[34] Hyogo Prefectural Kobe Childrens Hosp, Dept Pathol, Kobe, Hyogo, Japan

[35] Tazuke Kofukai Fdn, Med Res Inst, Dept Neurosurg, Osaka, Japan

[36] Kitano Hosp, Osaka, Japan

[37] Shizuoka Childrens Hosp, Dept Neurosurg, Shizuoka, Japan

[38] Jikei Univ, Sch Med, Dept Pediat, Tokyo, Japan

[39] Univ Occupat & Environm Hlth, Dept Neurosurg, Kitakyushu, Fukuoka, Japan

[40] Kanazawa Med Univ, Dept Neurosurg, Kanazawa, Ishikawa, Japan

[41] Toyama Univ Hosp, Dept Neurosurg, Toyama, Japan

[42] Kinki Univ, Fac Med, Dept Neurosurg, Osaka, Japan

[43] Kansai Med Univ, Dept Neurosurg, Hirakata, Osaka, Japan

[44] Hokkaido Med Ctr Child Hlth & Rehabil, Dept Neurosurg, Sapporo, Hokkaido, Japan

[45] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pathol & Appl Neurobiol, Kyoto, Japan

[46] Natl Hosp Org, Osaka Natl Hosp, Dept Pathol, Osaka, Japan

[47] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada

[48] Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada

[49] Teikyo Univ Hosp, Dept Neurosurg, Mizonokuchi, Kanagawa, Japan

[50] Takatsuki Gen Hosp, Dept Pediat Neurosurg, Takatsuki, Osaka, Japan

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2018年 / 6卷

基金：

日本学术振兴会;

关键词：

Ependymal tumors; Fusion gene; Gene rearrangement; Molecular classification; POSTERIOR-FOSSA EPENDYMOMA; INTRACRANIAL EPENDYMOMA; RISK STRATIFICATION; DNA METHYLATION; TERT PROMOTER; PROGRESSION; EXPRESSION; MUTATIONS; CHILDREN; SURVIVAL;

D O I：

10.1186/s40478-018-0630-1

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页数：18

共 37 条

[1] Development of a robust and sensitive pyrosequencing assay for the detection of IDH1/2 mutations in gliomas [J].

Arita, Hideyuki ;

Narita, Yoshitaka ;

Matsushita, Yuko ;

Fukushima, Shintaro ;

Yoshida, Akihiko ;

Takami, Hirokazu ;

Miyakita, Yasuji ;

Ohno, Makoto ;

Shibui, Soichiro ;

Ichimura, Koichi .

BRAIN TUMOR PATHOLOGY, 2015, 32 (01) :22-30

[2] Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss [J].

Arita, Hideyuki ;

Narita, Yoshitaka ;

Fukushima, Shintaro ;

Tateishi, Kensuke ;

Matsushita, Yuko ;

Yoshida, Akihiko ;

Miyakita, Yasuji ;

Ohno, Makoto ;

Collins, V. Peter ;

Kawahara, Nobutaka ;

Shibui, Soichiro ;

Ichimura, Koichi .

ACTA NEUROPATHOLOGICA, 2013, 126 (02) :267-276

[3] DNA methylation-based classification of central nervous system tumours [J].

Capper, David ;

Jones, David T. W. ;

Sill, Martin ;

Hovestadt, Volker ;

Schrimpf, Daniel ;

Sturm, Dominik ;

Koelsche, Christian ;

Sahm, Felix ;

Chavez, Lukas ;

Reuss, David E. ;

Kratz, Annekathrin ;

Wefers, Annika K. ;

Huang, Kristin ;

Pajtler, Kristian W. ;

Schweizer, Leonille ;

Stichel, Damian ;

Olar, Adriana ;

Engel, Nils W. ;

Lindenberg, Kerstin ;

Harter, Patrick N. ;

Braczynski, Anne K. ;

Plate, Karl H. ;

Dohmen, Hildegard ;

Garvalov, Boyan K. ;

Coras, Roland ;

Hoelsken, Annett ;

Hewer, Ekkehard ;

Bewerunge-Hudler, Melanie ;

Schick, Matthias ;

Fischer, Roger ;

Beschorner, Rudi ;

Schittenhelm, Jens ;

Staszewski, Ori ;

Wani, Khalida ;

Varlet, Pascale ;

Pages, Melanie ;

Temming, Petra ;

Lohmann, Dietmar ;

Selt, Florian ;

Witt, Hendrik ;

Milde, Till ;

Witt, Olaf ;

Aronica, Eleonora ;

Giangaspero, Felice ;

Rushing, Elisabeth ;

Scheurlen, Wolfram ;

Geisenberger, Christoph ;

Rodriguez, Fausto J. ;

Becker, Albert ;

Preusser, Matthias .

NATURE, 2018, 555 (7697) :469-+

[4] Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study [J].

Castelo-Branco, Pedro ;

Choufani, Sanaa ;

Mack, Stephen ;

Gallagher, Denis ;

Zhang, Cindy ;

Lipman, Tatiana ;

Zhukova, Nataliya ;

Walker, Erin J. ;

Martin, Dianna ;

Merino, Diana ;

Wasserman, Jonathan D. ;

Elizabeth, Cynthia ;

Alon, Noa ;

Zhang, Libo ;

Hovestadt, Volker ;

Kool, Marcel ;

Jones, David T. W. ;

Zadeh, Gelareh ;

Croul, Sidney ;

Hawkins, Cynthia ;

Hitzler, Johann ;

Wang, Jean C. Y. ;

Baruchel, Sylvain ;

Dirks, Peter B. ;

Malkin, David ;

Pfister, Stefan ;

Taylor, Michael D. ;

Weksberg, Rosanna ;

Tabori, Uri .

LANCET ONCOLOGY, 2013, 14 (06) :534-542

[5] Heterogeneity within the PF-EPN-B ependymoma subgroup [J].

Cavalli, Florence M. G. ;

Huebner, Jens-Martin ;

Sharma, Tanvi ;

Luu, Betty ;

Sill, Martin ;

Zapotocky, Michal ;

Mack, Stephen C. ;

Witt, Hendrik ;

Lin, Tong ;

Shih, David J. H. ;

Ho, Ben ;

Santi, Mariarita ;

Emery, Lyndsey ;

Hukin, Juliette ;

Dunham, Christopher ;

McLendon, Roger E. ;

Lipp, Eric S. ;

Gururangan, Sridharan ;

Grossbach, Andrew ;

French, Pim ;

Kros, Johan M. ;

van Veelen, Marie-Lise C. ;

Rao, Amulya A. Nageswara ;

Giannini, Caterina ;

Leary, Sarah ;

Jung, Shin ;

Faria, Claudia C. ;

Mora, Jaume ;

Schueller, Ulrich ;

Alonso, Marta M. ;

Chan, Jennifer A. ;

Klekner, Almos ;

Chambless, Lola B. ;

Hwang, Eugene I. ;

Massimino, Maura ;

Eberhart, Charles G. ;

Karajannis, Matthias A. ;

Lu, Benjamin ;

Liau, Linda M. ;

Zollo, Massimo ;

Ferrucci, Veronica ;

Carlotti, Carlos ;

Tirapelli, Daniela P. C. ;

Tabori, Uri ;

Bouffet, Eric ;

Ryzhova, Marina ;

Ellison, David W. ;

Merchant, Thomas E. ;

Gilbert, Mark R. ;

Armstrong, Terri S. .

ACTA NEUROPATHOLOGICA, 2018, 136 (02) :227-237

[6] Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts [J].

Ellison, David W. ;

Kocak, Mehmet ;

Figarella-Branger, Dominique ;

Felice, Giangaspero ;

Catherine, Godfraind ;

Pietsch, Torsten ;

Frappaz, Didier ;

Massimino, Maura ;

Grill, Jacques ;

Boyett, James M. ;

Grundy, Richard G. .

JOURNAL OF NEGATIVE RESULTS IN BIOMEDICINE, 2011, 10

[7]

Ellison DW, 2016, WHO CLASSIFICATION T, V4

[8] Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling [J].

Figarella-Branger, Dominique ;

Lechapt-Zalcman, Emmanuele ;

Tabouret, Emeline ;

Juenger, Stephanie ;

de Paula, Andre Maues ;

Bouvier, Corinne ;

Colin, Carole ;

Jouvet, Anne ;

Forest, Fabien ;

Andreiuolo, Felipe ;

Quintin-Roue, Isabelle ;

Machet, Marie-Christine ;

Heitzmann, Anne ;

Milin, Serge ;

Sevestre, Henri ;

Godfraind, Catherine ;

Labrousse, Francois ;

Metellus, Philippe ;

Scavarda, Didier ;

Pietsch, Torsten .

NEURO-ONCOLOGY, 2016, 18 (07) :919-927

[9] Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain [J].

Gojo, Johannes ;

Loetsch, Daniela ;

Spiegl-Kreinecker, Sabine ;

Pajtler, Kristian W. ;

Neumayer, Katharina ;

Korbel, Pia ;

Araki, Asuka ;

Brandstetter, Anita ;

Mohr, Thomas ;

Hovestadt, Volker ;

Chavez, Lukas ;

Kirchhofer, Dominik ;

Ricken, Gerda ;

Stefanits, Harald ;

Korshunov, Andrey ;

Pfister, Stefan M. ;

Dieckmann, Karin ;

Azizi, Amedeo A. ;

Czech, Thomas ;

Filipits, Martin ;

Kool, Marcel ;

Peyrl, Andreas ;

Slavc, Irene ;

Berger, Walter ;

Haberler, Christine .

NEURO-ONCOLOGY, 2017, 19 (09) :1183-1194

[10] Lack of efficacy of bevacizumab plus irinotecan in cases of pediatric recurrent ependymoma - a Pediatric Brain Tumor Consortium study [J].

Gururangan, Sridharan ;

Fangusaro, Jason ;

Poussaint, Tina Young ;

Onar-Thomas, Arzu ;

Gilbertson, Richard J. ;

Vajapeyam, Sridhar ;

Gajjar, Amar ;

Goldman, Stewart ;

Friedman, Henry S. ;

Packer, Roger J. ;

Boyett, James M. ;

Kun, Larry E. .

NEURO-ONCOLOGY, 2012, 14 (11) :1404-1412

← 1 2 3 4 →