Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma
Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive g...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01683-x |
| _version_ | 1797413685950414848 |
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| author | Kensuke Tateishi Yohei Miyake Taishi Nakamura Hiromichi Iwashita Takahiro Hayashi Akito Oshima Hirokuni Honma Hiroaki Hayashi Kyoka Sugino Miyui Kato Kaishi Satomi Satoshi Fujii Takashi Komori Tetsuya Yamamoto Daniel P. Cahill Hiroaki Wakimoto |
| author_facet | Kensuke Tateishi Yohei Miyake Taishi Nakamura Hiromichi Iwashita Takahiro Hayashi Akito Oshima Hirokuni Honma Hiroaki Hayashi Kyoka Sugino Miyui Kato Kaishi Satomi Satoshi Fujii Takashi Komori Tetsuya Yamamoto Daniel P. Cahill Hiroaki Wakimoto |
| author_sort | Kensuke Tateishi |
| collection | DOAJ |
| description | Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2 R172K and TP53 R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2 R172K and TP53 R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma. |
| first_indexed | 2024-03-09T05:22:29Z |
| format | Article |
| id | doaj.art-bbe8b7243e7e40e29827ce3987261302 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-09T05:22:29Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-bbe8b7243e7e40e29827ce39872613022023-12-03T12:39:53ZengBMCActa Neuropathologica Communications2051-59602023-11-0111111310.1186/s40478-023-01683-xGenetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytomaKensuke Tateishi0Yohei Miyake1Taishi Nakamura2Hiromichi Iwashita3Takahiro Hayashi4Akito Oshima5Hirokuni Honma6Hiroaki Hayashi7Kyoka Sugino8Miyui Kato9Kaishi Satomi10Satoshi Fujii11Takashi Komori12Tetsuya Yamamoto13Daniel P. Cahill14Hiroaki Wakimoto15Department of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Pathology, Yokohama City University HospitalDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityNeurosurgical-Oncology Laboratory, Yokohama City UniversityDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityLaboratory of Biopharmaceutical and Regenerative Science, Graduate School of Medical Science, Yokohama City UniversityDepartment of Pathology, Kyorin University School of MedicineDepartment of Diagnostic Pathology, Yokohama City University HospitalDepartment of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological HospitalDepartment of Neurosurgery, Graduate School of Medicine, Yokohama City UniversityDepartment of Neurosurgery, Massachusetts General HospitalDepartment of Neurosurgery, Massachusetts General HospitalAbstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2 R172K and TP53 R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2 R172K and TP53 R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.https://doi.org/10.1186/s40478-023-01683-xIDH2 mutationAstrocytomaMalignant phenotypePDX |
| spellingShingle | Kensuke Tateishi Yohei Miyake Taishi Nakamura Hiromichi Iwashita Takahiro Hayashi Akito Oshima Hirokuni Honma Hiroaki Hayashi Kyoka Sugino Miyui Kato Kaishi Satomi Satoshi Fujii Takashi Komori Tetsuya Yamamoto Daniel P. Cahill Hiroaki Wakimoto Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma Acta Neuropathologica Communications IDH2 mutation Astrocytoma Malignant phenotype PDX |
| title | Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma |
| title_full | Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma |
| title_fullStr | Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma |
| title_full_unstemmed | Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma |
| title_short | Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma |
| title_sort | genetic alterations that deregulate rb and pdgfra signaling pathways drive tumor progression in idh2 mutant astrocytoma |
| topic | IDH2 mutation Astrocytoma Malignant phenotype PDX |
| url | https://doi.org/10.1186/s40478-023-01683-x |
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