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Intra-Tumor DNA Methylation Heterogeneity in Glioblastoma; Implications for DNA Methylation-Based Classification.

Artikel i vetenskaplig tidskrift
Författare Anna Wenger
Sandra Ferreyra Vega
Teresia Kling
Thomas Olsson
Asgeir Store Jakola
Helena Carén
Publicerad i Neuro-oncology
Volym 21
Nummer/häfte 5
Sidor 616-27
ISSN 1523-5866
Publiceringsår 2019
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Sahlgrenska Cancer Center
Institutionen för biomedicin, avdelningen för patologi
Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap
Sidor 616-27
Språk en
Länkar dx.doi.org/10.1093/neuonc/noz011
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Cancer och onkologi, Cell- och molekylärbiologi

Sammanfattning

A feature of glioblastoma (GBM) is cellular and molecular heterogeneity, both within and between tumors. This variability causes a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous intra-tumor gene expression in GBM is well documented, but little is known regarding the epigenetic heterogeneity. Variability in DNA methylation within tumors would have implications for diagnostics, as methylation can be used for tumor classification, subtyping and determination of the clinically used biomarker MGMT promoter methylation. We therefore aimed to profile the intra-tumor DNA methylation heterogeneity in GBM and its effect on diagnostic properties.Three to four spatially separated biopsies per tumor were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis and investigated intra-tumor variation.All samples were classified as GBM IDH wild type (wt)/mutated by methylation profiling, but the subclass differed within five tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many CpG sites (mean: 17,000) had different methylation levels within the tumors. MGMT methylation status differed in IDH mutated patients (1/1).We demonstrated that intra-tumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by methylation analysis, the assigned subclass differed in samples from the same patient. The observed heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.

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