title: Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy.
abstract: Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.
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
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: Shintaro
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
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 Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsushita
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: Ayaka
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Tomiyama
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Niwa
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: 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.|Department of Neurosurgery, Yokohama City University Faculty of Medicine, Yokohama, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Suzuki
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 Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Fukuoka
authors.affiliation: Department of Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.|Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yanagisawa
authors.affiliation: Department of Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Department of Pathology, Hidaka Hospital, Takasaki, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibui
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Neurosurgery, The University of Tokyo Graduate School and Faculty of Medicine, Tokyo, Japan.
authors.forename: Akitake
authors.initials: A
authors.lastname: Mukasa
authors.affiliation: Department of Neurosurgery, The University of Tokyo Graduate School and Faculty of Medicine, Tokyo, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Department of Neurosurgery, Chiba Cancer Center, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iuchi
authors.affiliation: Department of Neurosurgery, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mizoguchi
authors.affiliation: Department of Neurosurgery, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimoto
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Department of Clinical Oncology and Neuro-oncology Program, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Neurosurgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.affiliation: Department of Neurosurgery, Shinshu Ueda Medical Center, Ueda, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Neurosurgery and Institute for Clinical Research, Osaka National Hospital, Osaka, Japan.
authors.forename: Yonehiro
authors.initials: Y
authors.lastname: Kanemura
authors.affiliation: Department of Neurosurgery and Institute for Clinical Research, Osaka National Hospital, Osaka, Japan.|Department of Neurosurgery, Kansai Medical University Hirakata Hospital, Hirakata, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: Department of Neurosurgery, Kansai Medical University Hirakata Hospital, Hirakata, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Asai
authors.affiliation: Department of Neurosurgery, University of Miyazaki Faculty of Medicine, Miyazaki, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yokogami
authors.affiliation: Department of Neurosurgery, University of Miyazaki Faculty of Medicine, Miyazaki, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: Department of Neurosurgery, Yokohama City University Faculty of Medicine, Yokohama, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kawahara
authors.affiliation: Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan.|Department of Urology, Jichi Medical University School of Medicine, Shimotsuke, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.affiliation: Department of Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsutani
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Neuro-oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
mesh_terms: D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012008:Recurrence; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000628:therapy
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: CNS germ cell tumors; Germinoma; MAPK; MTOR; NGGCT