1. Academic Validation
  2. Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

  • Acta Neuropathol Commun. 2023 Nov 27;11(1):186. doi: 10.1186/s40478-023-01683-x.
Kensuke Tateishi 1 2 3 Yohei Miyake 4 5 Taishi Nakamura 4 5 Hiromichi Iwashita 6 7 Takahiro Hayashi 4 5 Akito Oshima 4 5 Hirokuni Honma 4 5 Hiroaki Hayashi 5 8 Kyoka Sugino 4 9 5 Miyui Kato 9 5 Kaishi Satomi 10 Satoshi Fujii 7 11 Takashi Komori 12 Tetsuya Yamamoto 4 Daniel P Cahill 13 14 Hiroaki Wakimoto 13 14
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, 2360004, Japan. [email protected].
  • 2 Laboratory of Biopharmaceutical and Regenerative Science, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan. [email protected].
  • 3 Neurosurgical-Oncology Laboratory, Yokohama City University, Yokohama, Japan. [email protected].
  • 4 Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, 2360004, Japan.
  • 5 Neurosurgical-Oncology Laboratory, Yokohama City University, Yokohama, Japan.
  • 6 Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.
  • 7 Department of Diagnostic Pathology, Yokohama City University Hospital, Yokohama, Japan.
  • 8 Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
  • 9 Laboratory of Biopharmaceutical and Regenerative Science, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan.
  • 10 Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan.
  • 11 Department of Molecular Pathology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
  • 12 Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
  • 13 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
  • 14 Translational-Neurooncology Laboratory, Brain Tumor Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
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 IDH2R172K and TP53R248W 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 IDH2R172K and TP53R248W 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.

Keywords

Astrocytoma; IDH2 mutation; Malignant phenotype; PDX.

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