Predictive Genetics and Preventive Oncology

Current WHO estimates suggest that 50-75% of all cancers could be avoided by primary and secondary prevention. Hence, prevention has the greatest potential to reduce cancer mortality. Within the last decade cancer susceptibility genes have been identified for colon, breast and ovarian cancer. They account for 3-5% of the cases and are transmitted as an autosomal dominant genetic trait. Epidemiological studies, however, suggest that genetic factors may play a crucial role in up to 20%, presumably being transmitted as a complex genetic trait, i.e. by multiple low penetrance genes. Moreover, accumulating evidence suggests the existence of genetic and environmental modifiers that influence both penetrance and expression of the disease. We therefore aim to:

1. discover new susceptibility genes and biomarkers
2. develop complex genetic models of cancer predisposition
3. develop new preventive strategies
4. deliver evidence-based concepts for risk-adapted prevention

Contributing Projects

The Universities of Köln and Bonn have established the following projects in the field of predictive genetics and preventive oncology:

• F. Lammert has initiated a new project towards the identification of modifier genes influencing the progression and therapeutic response in cholangio- and hepatocellular cancer.
• The closely cooperating and multi-disciplinary Center for Familial Colorectal Cancer (Hereditary Non-Polyposis Colorectal Cancer, HNPCC and Polyposis syndromes) and Centre for Hereditary Breast and Ovarian Cancer (HBOC) are supported by the Deutsche Krebshilfe. The centers have long standing experience in genetic predictive diagnosis as well as in clinical prevention for individuals at risk. The center heads P. Propping and R. Schmutzler are co-coordinating the national consortia for HNPCC and HBOC. M. Nöthen is an expert in the field of complex genetic traits and will extend the HNPCC program to the search for new susceptibility genes by SNP-based genome-wide association and linkage studies.

Clinical Research

The centers for HNPCC and HBOC focus on the evaluation of different and preventive measures and trials on new therapeutic substances. Both centers have been in the forefront of establishing structured prevention concepts that are now financed by the statutory German public health insurance funds. For the evaluation of multimodal imaging procedures a close co-operation exists with the department of diagnostic radiology.

Basic and Translational Research

The HNPCC and HBOC consortia have established a Reference Pathology (R. Büttner). A unique and comprehensive tissue bank of hereditary tumors has been set up for gene expression profiling. The center for HBOC has collected over 900 DNA samples in a national DNA bank from BRCA mutation carriers to search for modifier genes. In co-operation with other centers the HBOC has started a genome-wide search for susceptibility genes in BRCA1/2 negative families by SNP chip technology. In 2005, the CoSmoS team in collaboration with the Lung Cancer Research program (J. Wolf; 8.2) started to systematically collect blood, DNA and RNA from lung cancer patients; tumor tissue will be stored starting in 2007[Thilo: aktualisieren!]. Based on a large cohort of families with atypical polyposis syndromes, a genome-wide mapping approach will be initiated by M. Nöthen. 

For these activities, the genomics unit provides platforms for high
throughput, genome-wide searches to identify new susceptibility genes by hypothesis-free genome-wide screens (Affymetrix and Illumina Chip-Technology). These efforts strongly benefit from the outstanding expertise in complex genetic diseases and genetic epidemiology.

Outlook

The genetic breakthroughs of the last decade have revolutionized our understanding of cancer and led to preventive concepts ready for clinical use. Clinical application in this field needs to be embedded in interdisciplinary and highly specialized centers. The existence of a Centre for Hereditary Cancer Syndromes within the Center for Integrated Oncology (CIO) Köln-Bonn described previously is unparalleled and unique in Germany and is considered to be in a premier position among national cancer centers, both in clinical and basic research. A major result of the research on hereditary carcinomas is the finding that most sporadic carcinomas arise from somatic mutations of the same genes as in hereditary carcinoma. Hence, hereditary carcinomas are an excellent tool for identifying the cause of malignant disease.