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

Abstract

Background

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

Methods

We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies to 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 two 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 MEK inhibitor and resistant to EGFR 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 transform 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.