title: Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas.
abstract: Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Pathology Division, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: NODAI Genome Research Center, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takami
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Fukuoka
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery, Kansai Medical University Hirakata Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery and Neurooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.|Division of Paediatric Neuro-Oncology, Department of Neurosurgery, Jikei University School of Medicine, Nishi-shinbashi 3-25-8, Minato-ku, Tokyo, 105-8461, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yanagisawa
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Akitake
authors.initials: A
authors.lastname: Mukasa
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.|Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: Department of Neurosurgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Department of Neurosurgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iuchi
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences Kyusyu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimoto
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences Kyusyu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mizoguchi
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Neurosurgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.|Department of Neurosurgery, Shinshu Ueda Medical Center, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Clinical Oncology and Neuro-oncology Program, Cancer Treatment Center, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Neurosurgery, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yokogami
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan.
authors.forename: Yonehiro
authors.initials: Y
authors.lastname: Kanemura
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsumura
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kurozumi
authors.affiliation: Department of Neurosurgery, Dokkyo University School of Medicine, Kitakobayashi 880, Mibu, Tochighi, 321-0293, Japan.
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authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Neurosurgery, Kansai Medical University Hirakata Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: Department of Neurosurgery, Kansai Medical University Hirakata Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Asai
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
authors.forename: Nobutaka
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authors.lastname: Kawahara
authors.affiliation: Department of Neurosurgery, School of Medicine, Fujita Health University, 1-98, Kutsugake Dengakugakubo, Toyoake, Aichi, 470-1192, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Higashi-ku, Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Tatusya
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Pathology, Hidaka Hospital, 886 Nakao-machi, Takasaki, Gunma, 370-0001, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.affiliation: Department of Neurosurgery and Neurooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Tatsuhiro
authors.initials: T
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authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Masao
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authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Toshikazu
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authors.lastname: Ushijima
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kichimur@ncc.go.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D005854:Germ Cells; D018237:Germinoma / Q000235:genetics*; D006801:Humans; D007223:Infant; D007564:Japan; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Germinoma; Global low DNA methylation; LINE1 hypomethylation; Primordial germ cell; iGCT