Skip to main content

October 2019 - Johanna Klughammer and Barbara Kiesel

Johanna Klughammer, PhD and Dr. Barbara Kiesel

MedUni Wien RESEARCHER OF THE MONTH October 2019

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practic

Selected Literature

  1. Stupp R, Mason WP, Van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330.
  2. Wang Q, Hu B, Hu X, et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32(1):42-56.e46. doi:10.1016/j.ccell.2017.06.003.
  3. Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396-1401. doi:10.1126/science.1254257.
  4. Lee J-K, Wang J, Sa JK, et al. Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet. 2017;49(4):594-599. doi:10.1038/ng.3806.
  5. Wang J, Cazzato E, Ladewig E, et al. Clonal evolution of glioblastoma under therapy. Nat Genet. 2016;48(7):768-776. doi:10.1038/ng.3590.
  6. Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-474. doi:10.1038/nature26000.
  7. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709-722. doi:10.1056/NEJMoa1308345.
  8. Klughammer J, Kiesel B, Roetzer T, et al. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nat Med. 2018;24(10):1611-1624. doi:10.1038/s41591-018-0156-x.
  9. Klughammer J, Datlinger P, Printz D, et al. Differential DNA Methylation Analysis without a Reference Genome. Cell Rep. 2015;13(11):2621-2633. doi:10.1016/j.celrep.2015.11.024.

Contact

Johanna Klughammer, PhD
Broad Institute of MIT and Harvard
Regev Lab
415 Main Street
Cambridge, MA 02142
jklugham@broadinstitute.org

 

Dr. Barbara Kiesel
Medizinische Universität Wien
Universitätsklinik für Neurochirurgie
Währinger Gürtel 18-20
1090 Wien
T: +43 (0)1 40400-25650 
barbara.kiesel@meduniwien.ac.at