Division of Epigenomics and Cancer Risk Factors
Prof. Dr. Christoph Plass
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. Deregulation of mechanisms that control the establishment of normal DNA methylation patterns leads to both extensive aberrant hypo- and hypermethylation and has been described for several human malignancies. Global DNA hypomethylation in human cancers was one of the earliest changes associated with tumor progression. Our group has shown that human malignancies are characterized by extensive promoter CpG island methylation with non-random and tumor-type specific patterns. It is currently unknown how tumors acquire aberrant DNA methylation patterns.
Our Division is interested in the molecular mechanisms underlying the initiation and progression of malignant cell growth. In particular we are focusing our attention on the contribution of epigenetic alterations in this process and determine how epigenetic and genetic alterations cooperate during tumorigenesis. In our studies we are utilizing current state-of-the-art high throughput epigenomic assays (e.g. Methylation arrays, Next generation sequencing and MassARRAY) on either clinical samples, cell culture models or in mouse tumor models.
Epigenetics is a fast evolving field with links to many research directions in cancer research. A challenge here will be to integrate epigenetic questions with other data sets. For example the profiling of cancer genomes relied heavily in the past on the description of genetic alterations. Now epigenetic datasets will need to be integrated in order to completely understand the molecular defects in cancer. Our division will focus on four major research directions:
- Evaluation of genome-wide epigenetic patterns in tumor genomes
- Identification of novel cancer genes and pathways targeted by epigenetic alterations
- Determining the role of epigenetics in cancer risk and progression
- Evaluate the role of epigenetics in the regulation of DNA repair
Raval, A. et al. (2007). Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell, 129, 879-890
Goeppert, B. et al. (2010). Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology 52, 2023-2033
Claus R, Lucas DM, Stilgenbauer S, Ruppert AS, Yu L, Zucknick M, Mertens D, Bühler A, Oakes CC, Larson RA, Kay NE, Jelinek DF, Kipps TJ, Rassenti LZ, Gribben JG, Döhner H, Heerema NA, Marcucci G, Plass C, Byrd JC. Quantitative DNA methylation analysis identifies a single CpG dinucleotide important for ZAP-70 expression and predictive of prognosis in chronic lymphocytic leukemia. J Clin Oncol. 2012; 30(20): 2483-91.
Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, Wuttig D, Warnatz HJ, Stehr H, Rausch T, Jäger N, Gu L, Bogatyrova O, Stütz AM, Claus R, Eils J, Eils R, Gerhäuser C, Huang PH, Hutter B, Kabbe R, Lawerenz C, Radomski S, Bartholomae CC, Fälth M, Gade S, Schmidt M, Amschler N, Haß T, Galal R, Gjoni J, Kuner R, Baer C, Masser S, von Kalle C, Zichner T, Benes V, Raeder B, Mader M, Amstislavskiy V, Avci M, Lehrach H, Parkhomchuk D, Sultan M, Burkhardt L, Graefen M, Huland H, Kluth M, Krohn A, Sirma H, Stumm L, Steurer S, Grupp K, Sültmann H, Sauter G, Plass C, Brors B, Yaspo ML, Korbel JO, Schlomm T. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 2013 Feb 11;23(2):159-70.