Cancer Epigenomics
Overview
Two general mechanisms have been identified that are involved in the silencing of cancer related genes. Genetic alterations, including mutations and deletions, have been known to be involved in tumor suppression for many years. More recently, DNA methylation has been identified as an additional mechanism to silence genes. Aberrant DNA methylation is an early event in tumorigenesis and a major contributor in the development of solid tumors as well as leukemias. As an epigenetic alteration, DNA methylation does not change the sequence of a gene and thus offers the exciting possibility for therapeutic removal of the methylation group by demethylating drugs.
We are investigating aberrant DNA methylation events in human malignancies with a focus on acute myeloid leukemia, chronic lymphocytic leukemia, lung cancer and prostate cancer.
Recent findings include the identification of non-random and tumor-type specific methylation changes in human malignancies, the identification of novel cancer related genes preferentially silenced in these malignancies by epigenetic mechanisms and the development of strategies for the identification of epigenetic markers for diagnosis and those with prognostic value.
With these approaches it should be possible to understand regulation of normal DNA methylation events and to apply this knowledge to better understand the deregulations seen in human cancer.
Projects
Recurrent deletions in cancer genomes overlap with the chromosomal locations of tumor-suppressor genes. Knudson's two-hit hypothesis has successfully guided cancer biologists for the past fifty years in the identification of such tumor-suppressor genes. However, in many cases monoallelic loss can only explain haploinsufficiency of tumor-suppressor genes. Preliminary work in the division indicates that altered chromosome topology and epigenetic gene regulation can also affected by deletions, resulting in the activation of oncogenes located outside of the deleted segment.
We aim to establish a novel paradigm in interpreting (epi)genomic data in cancer. We hypothesize that oncogene activation, in concert with haploinsufficient tumor-suppressor genes, deregulated because of a single genetic event, could lead to the discovery of novel intertwined oncogenic pathways.
Using acute myeloid leukemia as a model, we aim:
- to reveal oncogene activation through novel molecular pathways in cases carrying deletions of 5q and 7q by molecular sequencing-based profiling and to validate the requirement of the novel oncogene(s) for leukemic growth.
- to determine the molecular mechanisms resulting from oncogene overexpression and to test the accelerated tumorigenesis dependent on haploinsufficient tumor suppressor genes.
- to determine the contribution of oncogene activation through structural variation in combination with haploinsufficiency in a pan-cancer setting.
Non-genetic therapy resistance driven by haploinsufficient epigenome regulators
Members
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Prof. Dr. Christoph Plass
Division Head
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Dr. habil. Dieter Weichenhan
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Dr. Fiona Brown
Postdoctoral Researcher
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Dr. Jonas Becker
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Katherine Kelly
PhD Student
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Elena Everatt
PhD Student
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Thekli Paschali
Master Student
