Pathogenesis of MSI cancers

Microsatellite instability (MSI) is a major phenotype of genomic instability in cancer. MSI is caused by a deficiency of the DNA mismatch repair system. It occurs in 15% of colorectal cancers and up to 30% of endometrial cancers, and at a lower frequency in all types of human cancer. MSI is observed in virtually all tumors developing in people affected by Lynch syndrome, the most common inherited cancer syndrome, which affects 1 out of 200 individuals in the general population, but is largely underdiagnosed.

Our group has been working on MSI cancer pathogenesis for many years. We identified key molecular events responsible for MSI tumor formation. One particular focus of our work is on the transformation steps from molecular tumor initiation towards manifest cancers. We could identify major driver mutations in MSI tumorigenesis. Our recent research shows that colorectal cancers in Lynch syndrome in contrast to sporadic colorectal cancers frequently follow a non-polypous pathway of progression.

Current projects

Funding

Publications / Output

Ahadova A, Gallon R, Gebert J, Ballhausen A, Endris V, Kirchner M, Stenzinger A, Burn J, von Knebel Doeberitz M, Bläker H, Kloor M. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.Int J Cancer. 2018 Jul 1. PMID: 29424427

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. PMID: 28376875

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. PMID: 26960970.

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. PMID: 25816162

Woerner SM, Tosti E, Yuan YP, Kloor M, Bork P, Edelmann W, Gebert J. Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors.Mol Carcinog. 2015 Nov;54(11):1376-86. PMID: 25213383

Brenner H, Kloor M, Pox CP. Colorectal cancer.Lancet. 2014 Apr 26;383(9927):1490-1502. PMID: 24225001

Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M. Clinical significance of microsatellite instability in colorectal cancer.Langenbecks Arch Surg. 2014 Jan;399(1):23-31. Review. PMID: 24048684

Capper D, Voigt A, Bozukova G, Ahadova A, Kickingereder P, von Deimling A, von Knebel Doeberitz M, Kloor M. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer.Int J Cancer. 2013 Oct 1;133(7):1624-30. PMID: 23553055

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. PMID: 22552011

Kloor M, Voigt AY, Schackert HK, Schirmacher P, von Knebel Doeberitz M, Bläker H. Analysis of EPCAM protein expression in diagnostics of Lynch syndrome.J Clin Oncol. 2011 Jan 10;29(2):223-7. doi: 10.1200/JCO.2010.32.0820. Epub 2010 Nov 29. PMID: 21115857

Michel S, Kloor M, Singh S, Gdynia G, Roth W, von Knebel Doeberitz M, Schirmacher P, Bläker H. Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation.Mol Carcinog. 2010 Feb;49(2):175-82. PMID: 19852062

Roeckel N, Woerner SM, Kloor M, Yuan YP, Patsos G, Gromes R, KopitzJ, Gebert J. High frequency of LMAN1 abnormalities in colorectal tumors with microsatellite instability. Cancer Res. 2009 Jan 1;69(1):292-9. PMID:19118014

Korff S, Woerner SM, Yuan YP, Bork P, von Knebel Doeberitz M, Gebert J. Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability. BMC Cancer. 2008 Nov 10;8:329. PMID: 19000305

Woerner SM, Kloor M, von Knebel Doeberitz M, Gebert JF. Microsatellite instability in the development of DNA mismatch repair deficient tumors.Cancer Biomark. 2006;2(1-2):69-86. Review. PMID: 17192061

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