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

Hee Jin Cho, Junfei Zhao, Sang Won Jung, Erik Ladewig, Doo Sik Kong, Yeon Lim Suh, Yeri Lee, Donggeon Kim, Sun Hee Ahn, Mykola Bordyuh, Hyun Ju Kang, Jason K. Sa, Yun Jee Seo, Sung Tae Kim, Do Hoon Lim, Yun Sik Dho, Jung Il Lee, Ho Jun Seol, Jung Won Choi, Woong Yang ParkChul Kee Park, Raul Rabadan, Do Hyun Nam

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)47-58
Number of pages12
JournalNeuro-Oncology
Volume21
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1
Externally publishedYes

Keywords

  • brain location
  • cancer genomics
  • cerebellar glioblastoma
  • glioblastoma subclassification

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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