Applied Tumor Biology … Research Mismatch… Pathogenesis

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.



Key publications

  • Fricke F, Lee J, Michalak M, Warnken U, Hausser I, Suarez-Carmona M, Halama N, Schnölzer M, Kopitz J, Gebert J. TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells. Cell Commun Signal. 2017 Apr 4;15(1):14.
  • Ahadova A, von Knebel Doeberitz M, Bläker H, Kloor M. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer. 2016 Oct;15(4):579-86.
  • Lee J, Katzenmaier EM, Kopitz J, Gebert J. Reconstitution of TGFBR2 in HCT116 colorectal cancer cells causes increased LFNG expression and enhanced N-acetyl-d-glucosamine incorporation into Notch1. Cell Signal. 2016;28(8):1105-13.
  • Staffa L, Echterdiek F, Nelius N, Benner A, Werft W, Lahrmann B, Grabe N, Schneider M, Tariverdian M, von Knebel Doeberitz M, Bläker H, Kloor M. Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters. PLoS One. 2015 Mar 27;10(3).e0121980.
  • Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel Doeberitz M, Bläker H. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol. 2012 Jun;13(6):598-606.
  • Woerner SM, Yuan YP, Benner A, Korff S, von Knebel Doeberitz M, Bork P. SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology. Nucleic Acids Res. 2010 Jan;38(Database issue):D682-9.