Molecular Medicine Partnership UnitResearch Groups
Cancer Early Detection, Diagnosis and Prevention (CED-DAP)
Peer Bork and Magnus von Knebel Doeberitz
Project Summary
Molecular Pathogenesis of Colorectal Cancer and Development of Novel Approaches for Early Detection, Diagnosis and Prevention
Aim of the project is to delineate potential novel diagnostic markers and therapeutic targets on the basis of comprehensive data sets obtained in the frame of the human genome project using state of the art bioinformatics technology. Candidate markers are being validated by the Department of Applied Tumor Biology, and novel diagnostic as well as preventive and/or therapeutic strategies are designed and validated in clinical trials. We outline here our research program on microsatellite unstable tumors with focus on colorectal cancer.
Background
Genetic instability and accumulation of mutations are characteristics of malignant tumors. In consequence of a defective mismatch repair system, microsatellite unstable (MSI) tumors accumulate mutations in multiple genes, particularly in regions harboring repetitive DNA sequences. If such mutations affect the coding region of microsatellites the frameshifts lead to truncated proteins or proteins with altered functions. In addition, the frameshifts result in expression of c-terminal neo-peptides that might induce an immune response.
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Goals
The main goal of the project is the development of novel approaches for early detection, diagnosis and prevention using state-of-the-art bioinformatic tools for the prediction of novel target structures. In detail, systematic analysis of MSI-specific changes in cell surface glycosylation pattern and the final identification and characterization of such glycostructures.
Research Focus 1: Identification of novel target genes
In this initial collaboration, we have established a comprehensive database comprising all coding, untranslated and intronic mononucleotide repeats (MNRs) of the human genome. This project has led to the identification of novel target genes that contribute to MSI tumor development. A particular feature of this project is a phase of in-depth validation of candidate targets in the Department of Applied Tumor Biology following a genome-wide bionformatics screen performed in the group of P. Bork.
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Research Focus 2: Pathogenetic mechanisms of MSI tumors
Microsatellite unstable (MSI) tumors exhibit a variety of histoclinicopathological features including mucinous histology and improved prognosis when compared to their microsatellite stable (MSS) counterparts. Biallelic mutational inactivation of some MSI target genes is frequently observed and is generally believed to drive MSI tumorigenesis. Focussing on the pathogenetic mechanisms of these MSI tumors we recently uncovered a potential correlation between functional inactivation of specific MSI target genes and cell surface glycosylation pattern.
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Research Focus 3: Dose and toxicity of a frameshift peptide vaccine in MSI tumor patients
Expression of highly mutated genes leads to the synthesis of truncated proteins with c-terminal frameshift neopeptides which can be presented in the MHC context on MSI tumor cells. Therefore, genes with coding MNRs with high mutation frequency represent ideal targets for immunological response. In immunological studies we identified several frameshift derived immunogenic peptides and subsequently showed that MSI tumor cells can be lysed in vitro by cytotoxic T-cells in a peptide specific manner 2-4. A Phase I/II study has been initiated to evaluate vaccination with MSI-specific frameshift peptides in patients with MSI-H colorectal cancer of stage III and IV.
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Important Publications
BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer
Capper D, Voigt A, Bozukova G, Ahadova A, Kickingereder P, von Deimling A, von Knebel Doeberitz M, Kloor M.
Int J Cancer. 2013 Mar 30. doi: 10.1002/ijc.28183
Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions.
Chaiwongkot A, Vinokurova S, Pientong C, Ekalaksananan T, Kongyingyoes B, Kleebkaow P, Chumworathayi B, Patarapadungkit N, Reuschenbach M, von Knebel Doeberitz M.
Int J Cancer. 2013 May 1;132(9):2087-94. doi: 10.1002/ijc.27906. Epub 2012 Nov 26
T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer.
Bauer K, Nelius N, Reuschenbach M, Koch M, Weitz J, Steinert G, Kopitz J, Beckhove P, Tariverdian M, von Knebel Doeberitz M, Kloor M.
Cancer Immunol Immunother. 2013 Jan;62(1):27-37. doi: 10.1007/s00262-012-1303-8. Epub 2012 Jun 23.
Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study.
Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel Doeberitz M, Bläker H.
Lancet Oncol. 2012 Jun;13(6):598-606. Epub 2012 May 1
The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors.
Huth C, Kloor M, Voigt AY, Bozukova G, Evers C, Gaspar H, Tariverdian M, Schirmacher P, von Knebel Doeberitz M, Bläker H.
Mod Pathol. 2012 Jun;25(6):911-6. doi: 10.1038/modpathol.2012.30. Epub 2012 Mar 2
Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial.
Tikidzhieva A, Benner A, Michel S, Formentini A, Link KH, Dippold W, von Knebel Doeberitz M, Kornmann M, Kloor M.
Br J Cancer. 2012 Mar 13;106(6):1239-45. doi: 10.1038/bjc.2012.53. Epub 2012 Feb 21
Analysis of EPCAM protein expression in diagnostics of Lynch syndrome
Kloor M, Voigt AY, Schackert HK, Schirmacher P, von Knebel Doeberitz M, Bläker H
J Clin Oncol. 2011 Jan 10;29(2):223-7. Epub 2010 Nov 29
A network of conserved co-occurring motifs for the regulation of alternative splicing
Suyama M, Harrington ED, Vinokourova S, von Knebel Doeberitz M, Ohara O, Bork P
Nucleic Acids Res. 2010 Aug 11
SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology
Woerner SM, Yuan YP, Benner A, Korff S, von Knebel Doeberitz M, Bork P
Nucleic Acids Res. 2010 Jan; 38 (Database issue)
High frequency of LMAN1 abnormalities in colorectal tumors with microsatellite instability.
Roeckel N, Woerner SM, Kloor M, Yuan YP, Patsos G, Gromes R, Kopitz J, Gebert, J.
Cancer Res 2009; 69(1):292-9
ASTD: The Alternative Splicing and Transcript Diversity database.
Koscielny G, Le Texier V, Gopalakrishnan C, Kumanduri V, Riethoven JJ, Nardone F, Stanley E, Fallsehr C, Hofmann O, Kull M, Harrington E, Boué S, Eyras E, Plass M, Lopez F, Ritchie W, Moucadel V, Ara T, Pospisil H, Herrmann A, G Reich J, Guigó R, Bork P, Doeberitz MK, Vilo J, Hide W,Apweiler R, Thanaraj TA, Gautheret D.
Genomics. 2009 Mar;93(3):213-20. Epub 2008 Dec 24
Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability.
Korff S, Woerner SM, Yuan YP, Bork P, von Knebel Doeberitz M, Gebert J.
BMC Cancer. 2008 Nov 10;8:329
Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers.
Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M.
Gastroenterology 2008; 134(4):988-97
Previous publications of the Applied Tumor Biology Department
Previous publications of the Bork Group