MSI cancer

Microsatellite Instability (MSI) is one of the major phenotypes of genomic instability in human cancers. MSI is characterized by the accumulation of insertion/deletion mutations, which develop as a consequence of MMR deficiency. MSI cancers have a significantly elevated mutational load. Indels at defined coding microsatellites lead to the generation of frameshift peptide neoantigens. These neoantigens can be recognized by the host’s immune system and elicit a strong anti-tumor immune response.

Our group has pioneered research on the immune biology of MSI cancers and prepared the first-in-human vaccine against these cancers. This is particularly important, as it opens the possibility of tumor-preventive vaccines for Lynch syndrome patients who have an inherited predisposition to develop MSI cancer (for more information on MSI cancer pathogenesis click here).

Our main research directions

Our team

Recent publications

Busch E, Ahadova A, Kosmalla K, Bohaumilitzky L, Pfuderer PL, Ballhausen A, Witt J, Wittemann JN, Bläker H, Holinski-Feder E, Jäger D, von Knebel Doeberitz M, Haag GM, Kloor M. Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers. Front Oncol. 2021 Jun 8;11:669774. eCollection 2021. PMID: 34168989

International Mismatch Repair Consortium. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study. Lancet Oncol. 2021 Jun 7:S1470-2045(21)00189-3. Online ahead of print. PMID: 34111421

Seppälä TT, Latchford A, Negoi I, Sampaio Soares A, Jimenez-Rodriguez R, Sánchez-Guillén L, Evans DG, Ryan N, Crosbie EJ, Dominguez-Valentin M, Burn J, Kloor M, Knebel Doeberitz MV, Duijnhoven FJBV, Quirke P, Sampson JR, Møller P, Möslein G; European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP). European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021 May 27;108(5):484-498. PMID: 34043773

Haupt S, Zeilmann A, Ahadova A, Bläker H, von Knebel Doeberitz M, Kloor M, Heuveline V. Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure. PLoS Comput Biol. 2021 May 18;17(5):e1008970. eCollection 2021 May. PMID: 34003820

Krause J, Grabsch HI, Kloor M, Jendrusch M, Echle A, Buelow RD, Boor P, Luedde T, Brinker TJ, Trautwein C, Pearson AT, Quirke P, Jenniskens J, Offermans K, van den Brandt PA, Kather JN. Deep learning detects genetic alterations in cancer histology generated by adversarial networks. J Pathol. 2021 May;254(1):70-79. Epub 2021 Mar 16. PMID: 33565124

Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, Steinke-Lange V, Möslein G, Nielsen M, Ten Broeke SW, Laghi L, Dominguez-Valentin M, Capella G, Macrae F, Scott R, Hüneburg R, Nattermann J, Hoffmeister M, Brenner H, Bläker H, von Knebel Doeberitz M, Sampson JR, Vasen H, Mecklin JP, Møller P, Kloor M. The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer. 2021 Feb 15;148(4):800-811. doi: 10.1002/ijc.33224. Epub 2020 Aug 3. PMID: 32683684

Bläker H, Haupt S, Morak M, Holinski-Feder E, Arnold A, Horst D, Sieber-Frank J, Seidler F, von Winterfeld M, Alwers E, Chang-Claude J, Brenner H, Roth W, Engel C, Löffler M, Möslein G, Schackert HK, Weitz J, Perne C, Aretz S, Hüneburg R, Schmiegel W, Vangala D, Rahner N, Steinke-Lange V, Heuveline V, von Knebel Doeberitz M, Ahadova A, Hoffmeister M, Kloor M; German Consortium for Familial Intestinal Cancer. Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics. Int J Cancer. 2020 Nov 15;147(10):2801-2810. Epub 2020 Sep 14. PMID: 32875553

Arnold A, Tronser M, Sers C, Ahadova A, Endris V, Mamlouk S, Horst D, Möbs M, Bischoff P, Kloor M, Bläker H. The majority of β-catenin mutations in colorectal cancer is homozygous. BMC Cancer. 2020 Oct 28;20(1):1038. PMID: 33115416

Ballhausen A, Przybilla MJ, Jendrusch M, Haupt S, Pfaffendorf E, Seidler F, Witt J, Hernandez Sanchez A, Urban K, Draxlbauer M, Krausert S, Ahadova A, Kalteis MS, Pfuderer PL, Heid D, Stichel D, Gebert J, Bonsack M, Schott S, Bläker H, Seppälä T, Mecklin JP, Ten Broeke S, Nielsen M, Heuveline V, Krzykalla J, Benner A, Riemer AB, von Knebel Doeberitz M, Kloor M. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat Commun. 2020 Sep 21;11(1):4740. PMID: 32958755

Kloor M, Reuschenbach M, Pauligk C, Karbach J, Rafiyan MR, Al-Batran SE, Tariverdian M, Jäger E, von Knebel Doeberitz M. A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial. Clin Cancer Res. 2020 Sep 1;26(17):4503-4510. PMID: 32540851

Bläker H, Haupt S, Morak M, Holinski-Feder E, Arnold A, Horst D, Sieber-Frank J, Seidler F, von Winterfeld M, Alwers E, Chang-Claude J, Brenner H, Roth W, Engel C, Löffler M, Möslein G, Schackert HK, Weitz J, Perne C, Aretz S, Hüneburg R, Schmiegel W, Vangala D, Rahner N, Steinke-Lange V, Heuveline V, von Knebel Doeberitz M, Ahadova A, Hoffmeister M, Kloor M; German Consortium for Familial Intestinal Cancer. Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics. Int J Cancer. 2020 Nov 15;147(10):2801-2810. PMID: 32875553

Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, Steinke-Lange V, Möslein G, Nielsen M, Ten Broeke SW, Laghi L, Dominguez-Valentin M, Capella G, Macrae F, Scott R, Hüneburg R, Nattermann J, Hoffmeister M, Brenner H, Bläker H, von Knebel Doeberitz M, Sampson JR, Vasen H, Mecklin JP, Møller P, Kloor M. The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer. 2020 Jul 19. PMID: 32683684

Bohaumilitzky L, von Knebel Doeberitz M, Kloor M, Ahadova A. Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review. J Clin Med. 2020 Jun 4;9(6):1741. PMID: 32512823

Engel C, Ahadova A, Seppälä T, Aretz S, Bigirwamungu-Bargeman M, Bläker H, Bucksch K, Büttner R, de Vos Tot Nederveen Cappel W, Endris V, Holinski-Feder E, Holzapfel S, Hüneburg R, Jacobs MAJM, Koornstra JJ, Langers AM, Lepistö A, Morak M, Möslein G, Peltomäki P, Pylvänäinen K, Rahner N, Renkonen-Sinisalo L, Schulmann K, Steinke-Lange V, Stenzinger A, Strassburg CP, van de Meeberg PC, van Kouwen M, van Leerdam M, Vangala DB, Vecht J, Verhulst ML, von Knebel Doeberitz M, Weitz J, Zachariae S, Loeffler M, Mecklin JP, Kloor M, Vasen HF; German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology. 2020 Apr;158(5):1326-1333. PMID: 31926173

Kloor M. Resistance of the stable-towards more precise prediction of response to immune checkpoint blockade in microsatellite-unstable cancer patients. Ann Transl Med. 2019 Nov;7(21):603. PMID: 32047764

Pfuderer PL, Ballhausen A, Seidler F, Stark HJ, Grabe N, Frayling IM, Ager A, von Knebel Doeberitz M, Kloor M, Ahadova A. High endothelial venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer. Br J Cancer. 2019 Jul 30  doi: 10.1038/s41416-019-0514-6. PMID: 31358939

Haag GM, Czink E, Ahadova A, Schmidt T, Sisic L, Blank S, Heger U, Apostolidis L, Berger AK, Springfeld C, Lasitschka F, Jäger D, von Knebel Doeberitz M, Kloor M. Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer. 2019 Apr 1;144(7):1697-1703. doi: 10.1002/ijc.32030. Epub 2019 Jan 4. PMID: 30499151

Ozcan M, Janikovits J, von Knebel Doeberitz M, Kloor M. Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology. 2018 Mar 26;7(7):e1445453. PMID: 29900056

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

Janikovits J, Müller M, Krzykalla J, Körner S, Echterdiek F, Lahrmann B, Grabe N, Schneider M, Benner A, Doeberitz MVK, Kloor M. High numbers of PDCD1 (PD-1)-positive T cells and B2Mmutations in microsatellite-unstable colorectal cancer. Oncoimmunology. 2017 Nov 6;7(2):e1390640. PMID: 29308317

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

Kloor M, von Knebel Doeberitz M. The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer. 2016 Mar;2(3):121-133. Review. PMID: 28741532

Echterdiek F, Janikovits J, Staffa L, Müller M, Lahrmann B, Frühschütz M, Hartog B, Nelius N, Benner A, Tariverdian M, von Knebel Doeberitz M, Grabe N, Kloor M. Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer. Oncoimmunology. 2015 Nov 11;5(2):e1075692. PMID: 27057447.

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

von Knebel Doeberitz M, Kloor M. Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer. 2013 Jun;12(2):307-12. doi: 10.1007/s10689-013-9662-7. Review. PMID: 23760517

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

Tikidzhieva A, Benner A, Michel S, Formentini A, Link KH, Dippold W, von Knebel Doeberitz M, Kornmann M, Kloor M. Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial. Br J Cancer. 2012 Mar 13;106(6):1239-45. PMID: 22353804

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

Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010 Sep 1;127(5):1001-10. Review. PMID: 20198617

Michel S, Linnebacher M, Alcaniz J, Voss M, Wagner R, Dippold W, Becker C, von Knebel Doeberitz M, Ferrone S, Kloor M. Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int J Cancer. 2010 Aug 15;127(4):889-98. PMID: 20013806

Reuschenbach M, Kloor M, Morak M, Wentzensen N, Germann A, Garbe Y, Tariverdian M, Findeisen P, Neumaier M, Holinski-Feder E, von Knebel Doeberitz M. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam Cancer. 2010 Jun;9(2):173-9. PMID: 19957108

Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol. 2009 Sep;10(9):840-1. PMID: 19717085

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

Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, von Knebel Doeberitz M, Kloor M. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008 Dec 2;99(11):1867-73. PMID: 18985040

Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008 Apr;134(4):988-97. PMID: 18395080

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

Kloor M, Michel S, Buckowitz B, Rüschoff J, Büttner R, Holinski-Feder E, Dippold W, Wagner R, Tariverdian M, Benner A, Schwitalle Y, Kuchenbuch B, von Knebel Doeberitz M. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer. 2007 Jul 15;121(2):454-8. PMID: 17373663

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

Kloor M, Becker C, Benner A, Woerner SM, Gebert J, Ferrone S, von Knebel Doeberitz M. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res. 2005 Jul 15;65(14):6418-24. PMID: 16024646

Wüllenweber HP, Sutter C, Autschbach F, Willeke F, Kienle P, Benner A, Bähring J, Kadmon M, Herfarth C, von Knebel Doeberitz M, Gebert J. Evaluation of Bethesda guidelines in relation to microsatellite instability. Dis Colon Rectum. 2001 Sep;44(9):1281-9. PMID: 11584201

Haack K, Linnebacher M, Eisold S, Zöller M, von Knebel Doeberitz M, Gebert J. Induction of protective immunity against syngeneic rat cancer cells by expression of the cytosine deaminase suicide gene. Cancer Gene Ther. 2000 Oct;7(10):1357-64. PMID: 11059694

Gebert J, Sun M, Ridder R, Hinz U, Lehnert T, Möller P, Schackert HK, Herfarth C, von Knebel Doeberitz M. Molecular profiling of sporadic colorectal tumors by microsatellite analysis. Int J Oncol. 2000 Jan;16(1):169-79. PMID: 10601563

Recent grants

We are dedicated to connecting basic research and clinic. Therefore we are highly interested in unraveling biological mechanisms that may be used for development of therapeutic and preventive approaches. Our research on development of the first vaccine for MSI cancers was awarded with Felix Burda Award 2015 in the category “Medicine and Science”.

Our collaborators

Prof. John Burn, Institute of Genetic Medicine, Newcastle University, UK

Prof. Jukka-Pekka Mecklin, Jyväskylä University, Finland

Prof. Elke Jäger, Krankehaus Nordwest, Frankfurt, Germany

Prof. Salah-Eddin Albatran, Krankehaus Nordwest, Frankfurt, Germany

Prof. Hendrik Bläker, Charite Berlin, Germany

Prof. Annete Paschen, University Hospital Essen, Germany

Prof. Gabriela Möslein, Helios Klinik, Wuppertal, Germany

Prof. Alex Duval, Sorbonne University, Paris, France

Dr. Steven Lipkin, Weill Cornell University, New York, US

Dr. Robert Shoemaker, NCI, Washington, US

Dr. Asad Umar, NCI, Washington, US

Dr. Pål Møller, Oslo University, Norway

Dr. Toni Seppälä, Helsinki University, Finland

Dr. Ian Frayling, University of Cardiff, UK

Dr. Mirjam Tariverdian, University Hospital Heidelberg, Germany

Dr. Peer Bork, EMBL, Heidelberg. Germany

Activities in clinical and scientific organizations