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Neuro Oncol. 2019 Jan 1;21(1):47-58. doi: 10.1093/neuonc/noy123.

Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma.

Author information

1
Institute for Refractory Cancer Research, Seoul, Korea.
2
Research Institute for Future Medicine, Seoul, Korea.
3
Department of Systems Biology, Columbia University, New York, New York, USA.
4
Department of Biomedical Informatics, Columbia University, New York, New York, USA.
5
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
6
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
7
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
8
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
9
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
10
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
11
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.

Abstract

Background:

Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features.

Methods:

We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs.

Results:

Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target.

Conclusions:

Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients.

Key Points:

1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.

PMID:
30085274
PMCID:
PMC6303467
[Available on 2020-01-01]
DOI:
10.1093/neuonc/noy123

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