Download Cancer: Cell of Origin and Epigenetics

Cancer: Cell of Origin and Epigenetics
Prof Dr Christoph Plass
Division Head, Epigenomics and Cancer Risk Factors
German Cancer Research Center
DKFZ Main building
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg, Germany
[email protected]
+49 6221 423300
Epigenomes are cell-type, developmental-stage- and age- specific. The specific epigenome of a
cell is not only determined by cell intrinsic mechanisms, but also by cell extrinsic factors such as
environmental stimuli as well as the microenvironment in which a cell resides. While this concept
has been discussed for many years, its implications on the cancer epigenome are not well
understood. Only recently, it was shown that the methylome of chronic lymphocytic leukemias
(CLL) represents the methylome of the cell-of-origin, in this case B-cells undergoing massive
reprogramming from naive B cells to mature B cells.
Charting differences between tumor and normal tissues is a mainstay of cancer research. Yet, as
malignant cells typically expand clonally and normal tissues retain complex mixtures of various
cell types, reported cancer-specific events are potentially inaccurate. Using whole genome
bisulfite sequencing and other methods, we assess the dynamic DNA methylation events that
occur as part of a broad epigenetic program established during the maturation of B cells.
In comparison to malignant B cells from 268 chronic lymphocytic leukemia (CLL) patients, we
reveal that tumors have the potential to derive from a continuum of possible maturation states
that are reflected in the maturation stages of normal cells. The degree of maturation achieved in
tumors closely associates with the acquisition of a more indolent pattern of gene expression and
increasingly favorable clinical outcomes.
We further uncover that nearly all methylation differences previously reported between
tumor/normal or between defined disease subtypes are naturally present in healthy, nonmalignant B cells. Instead, we expose a novel pathogenic role of transcription factor (TF)
dysregulation in CLL, where excess activity of NFAT and EGR and loss of EBF and AP-1 TF
families’ imbalances the normal B cell epigenetic program.
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Epigenetics: Reprogramming cancer – overcoming drug resistance | 11 4SC Scientific Symposium
29 September 2016