Hirokazu Takami1,2, Asmaa Elzawahry3, Yasin Mamatjan4,5, Shintaro Fukushima1, Kohei Fukuoka1,6,7, Tomonari Suzuki8, Takaaki Yanagisawa6, Yuko Matsushita1,9, Taishi Nakamura1,10, Kaishi Satomi1,11, Shota Tanaka2, Akitake Mukasa12, Nobuhito Saito2, Masayuki Kanamori13, Toshihiro Kumabe13,14, Teiji Tominaga13, Keiichi Kobayashi15, Motoo Nagane15, Toshihiko Iuchi16, Kaoru Tamura17, Taketoshi Maehara17, Kazuhiko Sugiyama18, Koji Yoshimoto19,20, Keiichi Sakai21, Masahiro Nonaka22, Akio Asai22, Kiyotaka Yokogami23, Hideo Takeshima23, Yoshitaka Narita9, Soichiro Shibui9, Yoichi Nakazato24, Natsuko Hama3, Yasushi Totoki3, Mamoru Kato3, Tatsuhiro Shibata3, Ryo Nishikawa8, Masao Matsutani8, Koichi Ichimura1,25. 1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. 3. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. 4. MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 5. Faculty of Science, Thompson Rivers University, Kamloops, British Columbia, Canada. 6. Division of Pediatric Neuro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan. 7. Department of Pediatrics, Saitama Children's Medical Center, Saitama, Japan. 8. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan. 9. Department of Neurosurgery and Neuro-oncology, National Cancer Center Hospital, Tokyo, Japan. 10. Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan. 11. Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. 12. Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan. 13. Department of Neurosurgery, Tohoku University School of Medicine, Miyagi, Japan. 14. Department of Neurosurgery, Kitasato University, Kanagawa, Japan. 15. Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan. 16. Department of Neurosurgery, Chiba Cancer Center, Chiba, Japan. 17. Department of Neurosurgery, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan. 18. Department of Neurosurgery, Hiroshima University Faculty of Medicine, Hiroshima, Japan. 19. Department of Neurosurgery, Kyushu University Hospital, Fukuoka, Japan. 20. Department of Neurosurgery, Kagoshima University Hospital, Kagoshima, Japan. 21. Department of Neurosurgery, Shinshu Ueda Medical Center, Ueda, Japan. 22. Department of Neurosurgery, Kansai Medical University, Osaka, Japan. 23. Department of Neurosurgery, University of Miyazaki Faculty of Medicine, Miyazaki, Japan. 24. Department of Pathology, Hidaka Hospital, Gunma, Japan. 25. Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.
BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.
Authors: Sofia Gkountela; Kelvin X Zhang; Tiasha A Shafiq; Wen-Wei Liao; Joseph Hargan-Calvopiña; Pao-Yang Chen; Amander T Clark Journal: Cell Date: 2015-05-21 Impact factor: 41.582
Authors: Gabriela Bindea; Bernhard Mlecnik; Marie Tosolini; Amos Kirilovsky; Maximilian Waldner; Anna C Obenauf; Helen Angell; Tessa Fredriksen; Lucie Lafontaine; Anne Berger; Patrick Bruneval; Wolf Herman Fridman; Christoph Becker; Franck Pagès; Michael R Speicher; Zlatko Trajanoski; Jérôme Galon Journal: Immunity Date: 2013-10-17 Impact factor: 31.745
Authors: Jenny N Poynter; Jessica R B M Bestrashniy; Kevin A T Silverstein; Anthony J Hooten; Christopher Lees; Julie A Ross; Jakub Tolar Journal: BMC Cancer Date: 2015-10-23 Impact factor: 4.430
Authors: Hui Shen; Juliann Shih; Daniel P Hollern; Linghua Wang; Reanne Bowlby; Satish K Tickoo; Vésteinn Thorsson; Andrew J Mungall; Yulia Newton; Apurva M Hegde; Joshua Armenia; Francisco Sánchez-Vega; John Pluta; Louise C Pyle; Rohit Mehra; Victor E Reuter; Guilherme Godoy; Jeffrey Jones; Carl S Shelley; Darren R Feldman; Daniel O Vidal; Davor Lessel; Tomislav Kulis; Flavio M Cárcano; Kristen M Leraas; Tara M Lichtenberg; Denise Brooks; Andrew D Cherniack; Juok Cho; David I Heiman; Katayoon Kasaian; Minwei Liu; Michael S Noble; Liu Xi; Hailei Zhang; Wanding Zhou; Jean C ZenKlusen; Carolyn M Hutter; Ina Felau; Jiashan Zhang; Nikolaus Schultz; Gad Getz; Matthew Meyerson; Joshua M Stuart; Rehan Akbani; David A Wheeler; Peter W Laird; Katherine L Nathanson; Victoria K Cortessis; Katherine A Hoadley Journal: Cell Rep Date: 2018-06-12 Impact factor: 9.423