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Autor(en) / Beteiligte
Titel
Exome sequencing identifies frequent genomic loss of TET1 in IDH-wild-type glioblastoma12
Ist Teil von
  • Neoplasia (New York, N.Y.), 2020-11, Vol.22 (12), p.800-808
Ort / Verlag
Neoplasia Press
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
  • 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 TERT p (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.
Sprache
Englisch
Identifikatoren
ISSN: 1522-8002
eISSN: 1476-5586
DOI: 10.1016/j.neo.2020.10.010
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7642757
Format
Schlagworte
Original article

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