Transcriptome and Methylome Analysis of CNS Germ Cell Tumor Finds its Cell-of-Origin in Embryogenesis and Reveals Shared Similarities with Testicular Counterparts.

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.

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.

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 non-germinomatous 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 non-germinoma/non-seminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance.

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.

Neuro-oncology. 2022 Feb 08 [Epub ahead of print]

Hirokazu Takami, Asmaa Elzawahry, Yasin Mamatjan, Shintaro Fukushima, Kohei Fukuoka, Tomonari Suzuki, Takaaki Yanagisawa, Yuko Matsushita, Taishi Nakamura, Kaishi Satomi, Shota Tanaka, Akitake Mukasa, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Keiichi Kobayashi, Motoo Nagane, Toshihiko Iuchi, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Koji Yoshimoto, Keiichi Sakai, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Yoshitaka Narita, Soichiro Shibui, Yoichi Nakazato, Natsuko Hama, Yasushi Totoki, Mamoru Kato, Tatsuhiro Shibata, Ryo Nishikawa, Masao Matsutani, Koichi Ichimura, Intracranial Germ Cell Tumor Genome Analysis Consortium (the iGCT Consortium)

Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan., Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan., MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan., Division of Pediatric Neuro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan., Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan., Department of Neurosurgery, Tohoku University School of Medicine, Miyagi, Japan., Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan., Department of Neurosurgery, Chiba Cancer Center, Chiba, Japan., Department of Neurosurgery, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan., Department of Neurosurgery, Hiroshima University Faculty of Medicine, Hiroshima, Japan., Department of Neurosurgery, Kyushu University Hospital, Fukuoka, Japan., Department of Neurosurgery, Shinshu Ueda Medical Center, Ueda, Japan., Department of Neurosurgery, Kansai Medical University, Osaka, Japan., Department of Neurosurgery, University of Miyazaki Faculty of Medicine, Miyazaki, Japan., Department of Neurosurgery and Neuro-oncology, National Cancer Center Hospital, Tokyo, Japan., Department of Pathology, Hidaka Hospital, Gunma, Japan.