Pathogenesis of MSI-H cancers
MSI-H cancers arise as a consequence of mismatch repair deficiency. The MSI-H phenotype occurs in 15% of colorectal cancers and a significant number of other common tumors, such as endometrial cancer, gastric cancer, small bowel cancer and many others. Deficiency of the DNA mismatch repair system leads to the generation of multiple frameshift mutations in tumor cells. These frameshift mutations cause loss of functionally relevant tumor suppressor genes. The precise definition of tumor suppressor genes, which are affected and inactivated by this mechanism can help to develop new diagnostic and therapeutic tools for treatment and prevention of MSI-H cancer and, further down the road, cancer in general.
What we do
Our group has been working on MSI-H cancer for more than 15 years. Our research on the pathogenesis of MSI-H cancers, which combines computational, laboratory and clinical resources, is the backbone for all other more clinically oriented research projects dedicated to MSI-H cancer development.
Focusing on the very first steps responsible for MSI-H colon cancer formation, we have been able to establish a new model of tumorigenesis. This model encompasses newly identified precursor lesions, which seem to be responsible for a substantial proportion of hereditary colon cancers, and newly identified molecular alterations that result from MMR deficiency and drive tumorigenesis. The results of our pathogenesis research program have enabled us to develop clinical applications such as a vaccine directed against immunogenic target antigens that are shared by the vast majority of MSI-H cancers.
Collaboration within the Molecular Medicine Partnership Unit (MMPU), where our department has a research group together with Prof. P. Bork at the EMBL in Heidelberg, has been an essential basis for the success of this research.
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