SP 4
The clinical impact of microsatellite instability in colorectal cancer
The subproject provides microsatellite instability (MSI) testing for all cancers analyzed in the Clinical Research Unit. High level MSI (MSI-H) is observed in about 15% of all CRC and represents a subgroup of CRC with fundamental differences regarding molecular pathogenesis, tumor cell dissemination and metastasis formation, tumor immunology and patients' prognosis. Therefore knowledge on the MSI status of the tumors analyzed in frame of the Clinical Research Unit is essential to enhance the scientific output of the proposed project.
Further goals of the subproject are analyses on the mechanisms that play a role during metastasis formation of MSI-H CRC. In our previous studies we could demonstrate that loss of the pivotal surface protein HLA class I, caused by mutations of the Beta2-microglobulin gene, that presents the cellular identity towards the immune system, leads to a lack of metastasis formation. These unexpected results could be confirmed by a spectrum of functional studies and analyses of tumor tissue. Our results identified Beta2-microglobulin mutations as a novel prognostic marker in colorectal cancer. Our current research is directed towards a better understanding of the mechanisms underlying these observations. To that end, genome-wide expression profiling and novel techniques for deep sequencing of tumor genomes will be used.
Team SP4:
Dr. med. M. Kloor, Prof. Dr. med. M. von Knebel Doeberitz, A. Ahadova, G. Bozukova, F. Echterdiek, P. Höfler, B. Kuchenbuch, N. Nelius, A. Tikidziehva, A. Voigt
Dr. med. M. Kloor, Prof. med. Dr. M. von Knebel Doeberitz
Project-related key publications
Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel Doeberitz M, Kloor M. Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Fam Cancer 2011 Sep;10(3):557-65.
Kloor M, Voigt AY, Schackert HK, Schirmacher P, von Knebel Doeberitz M, Bläker H. Analysis of EPCAM proteine xpression in diagnosticsof Lynch syndrome. J Clin Oncol 2011 Jan 10;29(2):223-7. Epub 2010 Nov 29.
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.
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 FOGT4 trial. Br J Cancer 2012 Mar 13;106(6):1239-45. doi: 10.1038/bjc.2012.53. Epub 2012 Feb 21.
Bauer K, Nelius N, Reuschenbach M, Koch M, Weitz J, Steinert G, Kopitz J, Beckhove P, Tariverdian M, von Knebel Doeberitz M, Kloor M. T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer. Cancer Immunol Immunother 2012 Jun 23. [Epub ahead of print]
Huth M, Kloor M, Voigt A, Bozukova G, Evers C, Gaspar H, Tariverdian M, Schirmacher P, von Knebel Doeberitz M, Blaeker H. The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors. Modern Pathology 2012 Jun;25(6):911-6. doi: 10.1038/modpathol.2012.30. Epub 2012 Mar 2.
Kloor M, Huth C, Voigt A, Benner A, Schirmacher P, von Knebel Doeberitz M, Blaeker H. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncology 2012 Jun;13(6):598-606. Epub 2012 May 1.
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.
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.
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.
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. Epub 2008 Jan 11.
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 December 2; 99(11): 1867–1873. Published online 2008 November 4.
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.
Woerner SM, Kloor M, Schwitalle Y, Youmans H, Doeberitz MK, Gebert J, Dihlmann S. The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosomes Cancer 2007 Dec;46(12):1080-9.
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.
Findeisen P, Kloor M, Merx S, Sutter C, Woerner SM, Dostmann N, Benner A, Dondog B, Pawlita M, Dippold W, Wagner R, Gebert J, von Knebel Doeberitz M. T25 repeat in the 3' untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer. Cancer Res 2005 Sep 15;65(18):8072-8.
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.
Kloor M, von Knebel Doeberitz M, Gebert JF. Molecular testing for microsatellite instability and its value in tumor characterization. Expert Rev Mol Diagn 2005 Jul;5(4):599-611.
Woerner SM, Kloor M, Mueller A, Rueschoff J, Friedrichs N, Buettner R, Buzello M, Kienle P, Knaebel HP, Kunstmann E, Pagenstecher C, Schackert HK, Moslein G, Vogelsang H, von Knebel Doeberitz M, Gebert JF. Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. Oncogene 2005 Apr 7;24(15):2525-35.
Schwitalle Y, Linnebacher M, Ripberger E, Gebert J, von Knebel Doeberitz M. Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun 2004 Nov 25;4:14.
Woerner SM, Benner A, Sutter C, Schiller M, Yuan YP, Keller G, Bork P, von Knebel Doeberitz M, Gebert JF. Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene 2003 Apr 17;22(15):2226-35.
Ripberger E, Linnebacher M, Schwitalle Y, Gebert J, von Knebel Doeberitz M. Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol 2003 Sep;23(5):415-23.
Woerner SM, Gebert J, Yuan YP, Sutter C, Ridder R, Bork P, von Knebel Doeberitz M. Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. Int J Cancer 2001 Jul 1;93(1):12-9.
Linnebacher M, Gebert J, Rudy W, Woerner S, Yuan YP, Bork P, von Knebel Doeberitz M. Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 2001 Jul 1;93(1):6-11.
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