Annual Report 2020
Division of Brain Tumor Translational Research
Koichi Ichimura, Tatsuya Ozawa, Arata Tomiyama, Yoshiko Nakano, Yuko Matsushita, Mai Kitahara, Yuko Hibiya, Sanae Matsuzaki, Yuki Yomoda, Kaishi Satomi, Masamichi Takahashi, Tomoyuki Nakano, Yuki Yamagishi, Yui Kimura, Daisuke Kawauchi, Takaki Omura
Introduction
Our laboratory focuses on translational research on various types of malignant brain tumors to improve diagnostic accuracy, identify novel molecular markers and develop new treatments. In order to meet the molecular criteria defined by the WHO classification published in 2016 and the forthcoming new WHO classification, we develop robust molecular tests and perform molecular diagnostics for brain tumors through a number of nationwide multi-center collaboration initiatives. We also develop novel targeted therapies, perform preclinical studies and conduct clinical trials in collaboration with clinicians.
The Team and What We Do
We are a team of neurosurgeons, pediatric neuro-oncologists, postgraduate students and laboratory technicians who are dedicated to researching brain tumors. We provide molecular analysis for patients operated on at the Department of Neurosurgery and Neuro-Oncology at the National Cancer Center Hospital as well as from a number of external collaborators. We also perform molecular tests for the Japan Children’s Cancer Group (JCCG) central diagnostic service. In 2020, we received 264 pediatric brain tumors for molecular testing. The JCCG central diagnostic service covers approximately half of all newly diagnosed pediatric brain tumors in Japan.
Research activities
1. Molecular diagnosis of pediatric brain tumors
Among the various pediatric brain tumors collected through the JCCG and Intracranial Germ Cell Tumor Consortium (iGCT) as well as through other collaborations, we conduct targeted hot-spot mutation screening and other known recurrent fusions depending on the tumor types. For tumors that do not have characteristic mutations/fusions, targeted sequencing, genome-wide DNA methylation analysis and RNA sequencing are performed to investigate their molecular pathogenesis, and the results are published as molecular case reports. We are particularly interested in refining the genome-wide DNA methylation profiling-based molecular diagnosis of pediatric brain tumors.
2. Molecular analysis for brain tumors
We have developed a novel digital PCR-based liquid biopsy to diagnose primary central nervous system lymphoma using patients’ cerebral spinal fluid.
3. Development of a novel therapy for glioblastoma
We also carried out a series of preclinical studies for other molecular targeted drugs or anticancer agents using multi-kinase inhibitors or CCNU to develop a novel therapy against glioblastomas which acquired resistance to temozolomide.
4. Genomic analysis of central nervous system germ cell tumors (CNS GCTs)
We are building up a large cohort of CNS GCTs with frozen tumor tissues through the iGCT Consortium and JCCG. We are developing a novel targeted therapy against CNS GCTs using a patient-derived yolk sac tumor cell line, which we established at the National Cancer Center. A single cell transcriptomic study and a whole genome sequencing in CNS GCTs are also being conducted.
Clinical trials
We conduct molecular analysis of the tumors enrolled in several clinical trials such as ENIGMA or JCOG1910. The results of the molecular analysis in JCOG1910 are used to stratify patients in the clinical trial real time.
Education
Six postgraduate students (PhD) did research work between April 2020 and March 2021 at the Division of Brain Tumor Translational Research. One of them successfully finished and obtained the PhD degree. The results were presented at the Japan Society for Neuro-Oncology Annual Meeting. We successfully organized the 19th International Symposium on Pediatric Neuro-Oncology in December 2020 in Karuizawa as a hybrid meeting.
Future Prospects
We continue to organize nationwide and international collaborations and conduct research on all types of malignant brain tumors as the leading translational research center for malignant brain tumors in Japan. We will continue to offer a molecular diagnostic service for brain tumors, including the central diagnostic system provided through JCCG. Novel targeted therapies are being developed, and we will continue to perform a thorough genomic analysis to investigate the molecular pathogenesis of brain tumors. Our laboratory acts as a hub for young dedicated clinician investigators to meet, collaborate and collectively push neuro-oncological research forward. Our goal is to improve the diagnosis and treatment of brain tumor patients in Japan, and make significant scientific contributions to the international neuro-oncological community through publication and international collaboration.
List of papers published in 2020
Journal
1. Tomomasa R, Arai Y, Kawabata-Iwakawa R, Fukuoka K, Nakano Y, Hama N, Nakata S, Suzuki N, Ishi Y, Tanaka S, Takahashi JA, Yuba Y, Shiota M, Natsume A, Kurimoto M, Shiba Y, Aoki M, Nabeshima K, Enomoto T, Inoue T, Fujimura J, Kondo A, Yao T, Okura N, Hirose T, Sasaki A, Nishiyama M, Ichimura K, Shibata T, Hirato J, Yokoo H, Nobusawa S. Ependymoma-like tumor with mesenchymal differentiation harboring C11orf95-NCOA1/2 or -RELA fusion: A hitherto unclassified tumor related to ependymoma. Brain Pathol, 31:e12943, 2021
2. Tamai S, Nakano Y, Kinoshita M, Sabit H, Nobusawa S, Arai Y, Hama N, Totoki Y, Shibata T, Ichimura K, Nakada M. Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features. Brain Tumor Pathol, 38:64-70, 2021
3. Takahashi S, Takahashi M, Kinoshita M, Miyake M, Kawaguchi R, Shinojima N, Mukasa A, Saito K, Nagane M, Otani R, Higuchi F, Tanaka S, Hata N, Tamura K, Tateishi K, Nishikawa R, Arita H, Nonaka M, Uda T, Fukai J, Okita Y, Tsuyuguchi N, Kanemura Y, Kobayashi K, Sese J, Ichimura K, Narita Y, Hamamoto R. Fine-Tuning Approach for Segmentation of Gliomas in Brain Magnetic Resonance Images with a Machine Learning Method to Normalize Image Differences among Facilities. Cancers (Basel), 13:2021
4. Kawauchi D, Takahashi M, Satomi K, Yamamuro S, Kobayashi T, Uchida E, Honda-Kitahara M, Narita Y, Iwadate Y, Ichimura K, Tomiyama A. The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death. Cancer Sci, 112:2442-2453, 2021
5. Ozawa T, Kaneko S, Szulzewsky F, Qiao Z, Takadera M, Narita Y, Kondo T, Holland EC, Hamamoto R, Ichimura K. C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation. Acta Neuropathol Commun, 9:36, 2021
6. Miyake Y, Fujii K, Nakamaura T, Ikegaya N, Matsushita Y, Gobayashi Y, Iwashita H, Udaka N, Kumagai J, Murata H, Takemoto Y, Yamanaka S, Ichimura K, Tateishi K, Yamamoto T. IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology. J Neuropathol Exp Neurol, 80:247-253, 2021
7. Mitani Y, Fukuoka K, Mori M, Arakawa Y, Matsushita Y, Hibiya Y, Honda S, Kobayashi M, Tanami Y, Kanemura Y, Ichimura K, Nakazawa A, Kurihara J, Koh K. Clinical Aggressiveness of TP53-Wild Type Sonic Hedgehog Medulloblastoma With MYCN Amplification, Chromosome 17p Loss, and Chromothripsis. J Neuropathol Exp Neurol, 80:205-207, 2021
8. Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Narita Y, Ichimura K, Yoshida A. Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2A homozygous deletion in the assessment of adult-type infiltrating astrocytoma. Mod Pathol, 34:688-700, 2021
9. Nakano Y, Takadera M, Miyazaki M, Qiao Z, Nakajima K, Noguchi R, Oyama R, Kimura Y, Okuhiro Y, Yamasaki K, Kunihiro N, Fukushima H, Inoue T, Hara J, Ozawa T, Kondo T, Ichimura K. Drug screening with a novel tumor-derived cell line identified alternative therapeutic options for patients with atypical teratoid/rhabdoid tumor. Hum Cell, 34:271-278, 2021
10. Kanamori M, Takami H, Yamaguchi S, Sasayama T, Yoshimoto K, Tominaga T, Inoue A, Ikeda N, Kambe A, Kumabe T, Matsuda M, Tanaka S, Natsumeda M, Matsuda KI, Nonaka M, Kurihara J, Yamaoka M, Kagawa N, Shinojima N, Negoto T, Nakahara Y, Arakawa Y, Hatazaki S, Shimizu H, Yoshino A, Abe H, Akimoto J, Kawanishi Y, Suzuki T, Natsume A, Nagane M, Akiyama Y, Keino D, Fukami T, Tomita T, Kanaya K, Tokuyama T, Izumoto S, Nakada M, Kuga D, Yamamoto S, Anei R, Uzuka T, Fukai J, Kijima N, Terashima K, Ichimura K, Nishikawa R. So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma? Neuro Oncol, 23:295-303, 2021
11. Arita H, Matsushita Y, Machida R, Yamasaki K, Hata N, Ohno M, Yamaguchi S, Sasayama T, Tanaka S, Higuchi F, Iuchi T, Saito K, Kanamori M, Matsuda KI, Miyake Y, Tamura K, Tamai S, Nakamura T, Uda T, Okita Y, Fukai J, Sakamoto D, Hattori Y, Pareira ES, Hatae R, Ishi Y, Miyakita Y, Tanaka K, Takayanagi S, Otani R, Sakaida T, Kobayashi K, Saito R, Kurozumi K, Shofuda T, Nonaka M, Suzuki H, Shibuya M, Komori T, Sasaki H, Mizoguchi M, Kishima H, Nakada M, Sonoda Y, Tominaga T, Nagane M, Nishikawa R, Kanemura Y, Kuchiba A, Narita Y, Ichimura K. TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations. Acta Neuropathol Commun, 8:201, 2020
12. Tateishi K, Miyake Y, Kawazu M, Sasaki N, Nakamura T, Sasame J, Yoshii Y, Ueno T, Miyake A, Watanabe J, Matsushita Y, Shiba N, Udaka N, Ohki K, Fink AL, Tummala SS, Natsumeda M, Ikegaya N, Nishi M, Ohtake M, Miyazaki R, Suenaga J, Murata H, Aoki I, Miller JJ, Fujii Y, Ryo A, Yamanaka S, Mano H, Cahill DP, Wakimoto H, Chi AS, Batchelor TT, Nagane M, Ichimura K, Yamamoto T. A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma. Cancer Res, 80:5330-5343, 2020
13. Yamada S, Muto J, De Leon JCA, Kumai T, Ito K, Murayama K, Hama N, Nakano Y, Satomi K, Arai Y, Shibata T, Inoue T, Nobusawa S, Ichimura K, Hirose Y, Abe M. Primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation: a similar cytological appearance as its soft tissue counterpart but no lobulation in association with desmoplastic stroma. Brain Tumor Pathol, 37:111-117, 2020
14. Kinoshita M, Arita H, Takahashi M, Uda T, Fukai J, Ishibashi K, Kijima N, Hirayama R, Sakai M, Arisawa A, Takahashi H, Nakanishi K, Kagawa N, Ichimura K, Kanemura Y, Narita Y, Kishima H. Impact of Inversion Time for FLAIR Acquisition on the T2-FLAIR Mismatch Detectability for IDH-Mutant, Non-CODEL Astrocytomas. Front Oncol, 10:596448, 2020
15. Kobayashi T, Miyazaki M, Sasaki N, Yamamuro S, Uchida E, Kawauchi D, Takahashi M, Otsuka Y, Kumagai K, Takeuchi S, Toyooka T, Otani N, Wada K, Narita Y, Yamaguchi H, Muragaki Y, Kawamata T, Mori K, Ichimura K, Tomiyama A. Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation. Cancers (Basel), 12:2020
16. Takadera M, Satomi K, Szulzewsky F, Cimino PJ, Holland EC, Yamamoto T, Ichimura K, Ozawa T. Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes. Acta Neuropathol Commun, 8:203, 2020
17. Nobusawa S, Nakata S, Nakano Y, Kawamura A, Yoshida M, Tamura A, Hasegawa D, Kosaka Y, Ito I, Watanabe R, Oishi T, Hayashi N, Ishikawa E, Sakamoto N, Okura N, Murakami C, Ichimura K, Hirato J, Yokoo H. CNS Low-grade Diffusely Infiltrative Tumors With INI1 Deficiency, Possessing a High Propensity to Progress to Secondary INI1-deficient Rhabdoid Tumors. Am J Surg Pathol, 44:1459-1468, 2020
18. Nakano Y, Yamasaki K, Satomi K, Fukushima H, Okuhiro Y, Okada K, Osugi Y, Sakamoto H, Inoue T, Yoshida A, Ichimura K, Hara J. A case of pediatric gliomatosis cerebri harboring H3F3A K27 mutation. Pediatr Blood Cancer, 67:e28270, 2020
19. Fujimoto K, Shinojima N, Hayashi M, Nakano T, Ichimura K, Mukasa A. Histone deacetylase inhibition enhances the therapeutic effects of methotrexate on primary central nervous system lymphoma. Neurooncol Adv, 2:vdaa084, 2020
20. Nakano Y, Watanabe Y, Honda-Kitahara M, Yamagishi Y, Niizuma H, Niihori T, Sasahara Y, Sonoda Y, Narita Y, Nagane M, Kure S, Ichimura K. Utility of a bridged nucleic acid clamp for liquid biopsy: Detecting BRAF V600E in the cerebrospinal fluid of a patient with brain tumor. Pediatr Blood Cancer, 67:e28651, 2020
21. Miki S, Satomi K, Ohno M, Matsushita Y, Kitahara M, Miyakita Y, Takahashi M, Matsuda M, Ishikawa E, Matsumura A, Yoshida A, Narita Y, Ichimura K. Highly sensitive detection of TERT promoter mutations in recurrent glioblastomas using digital PCR. Brain Tumor Pathol, 37:154-158, 2020
22. Ito J, Nakano Y, Shima H, Miwa T, Kogure Y, Isshiki K, Yamazaki F, Oishi Y, Morimoto Y, Kataoka K, Okita H, Hirato J, Ichimura K, Shimada H. Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. Brain Tumor Pathol, 37:105-110, 2020
23. Takami H, Perry A, Graffeo CS, Giannini C, Narita Y, Nakazato Y, Saito N, Nishikawa R, Matsutani M, Ichimura K, Daniels DJ. Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo Clinic and Japanese consortium cohorts. J Neurosurg, 1-11, 2020
24. Yamasaki K, Nakano Y, Nobusawa S, Okuhiro Y, Fukushima H, Inoue T, Murakami C, Hirato J, Kunihiro N, Matsusaka Y, Honda-Kitahara M, Ozawa T, Shiraishi K, Kohno T, Ichimura K, Hara J. Spinal cord astroblastoma with an EWSR1-BEND2 fusion classified as a high-grade neuroepithelial tumour with MN1 alteration. Neuropathol Appl Neurobiol, 46:190-193, 2020