Exome sequencing identifies frequent genomic loss of TET1 in IDH-wild-type glioblastoma

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Genomic and epigenomic alterations of multiple cancer-driving genes are frequent in GBM. To identify molecular alterations associated with epigenetic aberrations, we performed whole exome sequencing-based analysis of DNA copy number variations in 55 adult patients with IDH-wild-type GBM. Beside mutations in common GBM driver genes such as TERTp (76%), TP53 (22%) and PTEN (20%), 67% of patients were affected by amplifications of genes associated with RTK/Rb/p53 cell signaling, including EGFR (45%), CDK4 (13%), and MDM2/4 (both 7%). The minimal deleted region at chromosome 10 was detected at the DNA demethylase TET1 (93%), mainly due to a loss-of-heterozygosity of complete chromosome 10 (53%) or by a mono-allelic microdeletion at 10q21.3 (7%). In addition, bi-allelic TET1 deletions, detected in 18 patients (33%), frequently co-occurred with EGFR amplification and were associated with low levels of TET1 mRNA expression, pointing at loss of TET1 activity. Bi-allelic TET1 loss was not associated with global concentrations of 5-hydroxymethylcytosine, indicating a site-specific effect of TET1 for DNA (de)methylation. Focal amplification of EGFR positively correlated with overall mutational burden, tumor size, and poor long-term survival. Bi-allelic TET1 loss was not an independent prognostic factor, but significantly associated with poor survival in patients with concomitant EGFR amplification. Rates of genomic TET1 deletion were significantly lower in a cohort of IDH1-mutated patients. Despite the relevance of TET1 for DNA demethylation and as potential therapeutic target, a frequent genomic loss of TET1 has not previously been reported in GBM.

Details

Original languageEnglish
Pages (from-to)800-808
Number of pages9
JournalNeoplasia
Volume22
Issue number12
Publication statusPublished - Dec 2020
Peer-reviewedYes

External IDs

Scopus 85094809694
ORCID /0000-0001-9599-8632/work/142241738
PubMed 33142244

Keywords

Keywords

  • Copy number variation (CNV), EGFR amplification, Glioblastoma (GBM), IDH, Next-generation sequencing (NGS), TET1 deletion

Library keywords