Identification of genetic and epigenetic alterations underlying colon cancer progression
Colon cancer (CRC) is the third most common cancer type worldwide and in 2004 over 1 million new cancer cases have been diagnosed. Thus, one focus of the group is to identify colon cancer progression markers e.g. methylation markers and to set them in relation to the pathomechanism of tumour formation and progression. We have already identified a set of biomarkers – miRNAs as well as differentially methylated regions (cDMRs) which we are validating. We have picked the candidate biomarkers out of genome-wide screens which we had performed on a large cohort of CRC cases. Now, having these data sets completed, we are in the privileged position to investigate them more intensively and to develop a picture of CRC alterations. Based on our extensive data sets on gene and miRNA expression, mutations and methylation alterations, we are now working on an integrative view of colorectal cancer. Using diverse bioinformatics visualization tools we try to get hold on genome-wide pathogenic alterations and to identify a temporal order of modifications.
Functional analyses of cervical cancer pathogenesis and development of antiviral substances
Cervical cancer is the second most common cancer among women with a world- wide prevalence of 2,27 millions and with an estimated 490,000 new cases and
270,000 deaths per year. “High risk” human papillomaviruses are detected in over 98% of cervical carcinoma cases. Together with Prof. Dr. Peter Howley (Harvard Medical School, Boston) we have found that the interaction between the viral E2 protein and the cellular bromodomain containing protein Brd4 is required for the genome maintenance and the viral transcriptional regulation functions and thereby regulate cervical cancer pathogenesis. We are now working on specific inhibitors of this interaction and we are using NGS technologies for an investigation of functional consequences for cervical cancer pathogenesis. Our experiments show that a disruption of the interaction between E2 and Brd4 leads to a curing of cells from papillomavirus infections and thereby might prevent cervical cancer.
Brd4 with its two bromodomains binds to acetylated histones, pTEFb (positive transcription elongation factor) and is dealt as master regulator of the epigen- etic memory. We have found that Brd4 plays a significant role in transcriptional regulation, but that it is also a central partner in the oxidative stress response. Preliminary experiments indicate that an epigenetic regulation of the defense mechanisms against reactive oxygen species functions over histone methylations.
Taken together, the goals of the Cancer Genomics Group are to integrate different fields of medicine, biology and natural science in order to better understand how tumor cells work and how carcinogenic processes are regulated. Knowledge of disease- relevant alterations in gene sequences and molecules of the metabolic network will reveal targets for effective diagnostic and therapeutic applications. With the availability of these techniques we are on a turning point of cancer di- agnosis and treatment.