Molecular Medicine Partnership Unit

 

Cancer Early Detection, Diagnosis and Prevention (CED-DAP)

Peer Bork and Magnus von Knebel Doeberitz
Peer Bork and Magnus von Knebel Doeberitz


Magnus von Knebel Doeberitz and Peer Bork

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 Opens external link in new windowPhase 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

Opens external link in new windowDetection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors.
Woerner SM, Tosti E, Yuan YP, Kloor M, Bork P, Edelmann W, Gebert J.
Mol Carcinog. 2014 Sep 11. doi: 10.1002/mc.22213.

 

Opens external link in new windowIdentification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes.
Nielsen HB, Almeida M, Juncker AS, Rasmussen S, Li J, Sunagawa S, Plichta DR, Gautier L, Pedersen AG, Le Chatelier E, Pelletier E, Bonde I, Nielsen T, Manichanh C, Arumugam M, Batto JM, Quintanilha Dos Santos MB, Blom N, Borruel N, Burgdorf KS, Boumezbeur F, Casellas F, Doré J, Dworzynski P, Guarner F, Hansen T, Hildebrand F, Kaas RS, Kennedy S, Kristiansen K, Kultima JR, Léonard P, Levenez F, Lund O, Moumen B, Le Paslier D, Pons N, Pedersen O, Prifti E, Qin J, Raes J, Sørensen S, Tap J, Tims S, Ussery DW, Yamada T; MetaHIT Consortium, Renault P, Sicheritz-Ponten T, Bork P, Wang J, Brunak S, Ehrlich SD; MetaHIT Consortium.
Nat Biotechnol. 2014 Aug;32(8):822-8. doi: 10.1038/nbt.2939. Epub 2014 Jul 6.

 

Opens external link in new windowAn integrated catalog of reference genes in the human gut microbiome.
Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, Arumugam M, Kultima JR, Prifti E, Nielsen T, Juncker AS, Manichanh C, Chen B, Zhang W, Levenez F, Wang J, Xu X, Xiao L, Liang S, Zhang D, Zhang Z, Chen W, Zhao H, Al-Aama JY, Edris S, Yang H, Wang J, Hansen T, Nielsen HB, Brunak S, Kristiansen K, Guarner F, Pedersen O, Doré J, Ehrlich SD; MetaHIT Consortium, Bork P, Wang J; MetaHIT Consortium.
Nat Biotechnol. 2014 Aug;32(8):834-41. doi: 10.1038/nbt.2942. Epub 2014 Jul 6.

 

Opens external link in new windowClinical significance of microsatellite instability in colorectal cancer.
Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M.
Langenbecks Arch Surg. 2014 Jan;399(1):23-31. doi: 10.1007/s00423-013-1112-3. Epub 2013 Sep 19.

Opens external link in new windowChromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract - a systematic review and meta-analysis.
Thomas LK, Bermejo JL, Vinokurova S, Jensen K, Bierkens M, Steenbergen R, Bergmann M, von Knebel Doeberitz M, Reuschenbach M.
Eur J Cancer. 2014 Jan;50(1):85-98. doi: 10.1016/j.ejca.2013.08.022. Epub 2013 Sep 17.

 

Opens external link in new windowMetagenomic species profiling using universal phylogenetic marker genes.
Sunagawa S, Mende DR, Zeller G, Izquierdo-Carrasco F, Berger SA, Kultima JR, Coelho LP, Arumugam M, Tap J, Nielsen HB, Rasmussen S, Brunak S, Pedersen O, Guarner F, de Vos WM, Wang J, Li J, Doré J, Ehrlich SD, Stamatakis A, Bork P.
Nat Methods. 2013 Dec;10(12):1196-9. doi: 10.1038/nmeth.2693. Epub 2013 Oct 20.

 

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

 

Opens external link in new windowAccurate and universal delineation of prokaryotic species
Mende, D.R., Sunagawa, S., Zeller, G. & Bork, P.
Nat Methods. 2013 Jul 28. doi: 10.1038/nmeth.2575.

 

Opens external link in new windowBRAF 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

 

Opens external link in new windowDifferential 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

 

Opens external link in new windowT 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.

 

Opens external link in new windowGenomic variation landscape of the human gut microbiome.
Schloissnig, S., Arumugam, M., Sunagawa, S., Mitreva, M., Tap, J., Zhu, A., Waller, A., Mende, D.R., Kultima, J.R., Martin, J., Kota, K., Sunyaev, S.R., Weinstock, G.M. & Bork, P.
Nature. 2013 Jan 3;493(7430):45-50. doi: 10.1038/nature11711. Epub 2012 Dec 5

Opens external link in new windowMOCAT: a metagenomics assembly and gene prediction toolkit.
Kultima, J.R., Sunagawa, S., Li, J., Chen, W., Chen, H., Mende, D.R., Arumugam, M., Pan, Q., Liu, B., Qin, J., Wang, J. & Bork, P.
PLoS One. 2012;7(10):e47656. doi: 10.1371/journal.pone.0047656. Epub 2012 Oct 17.

 

Opens external link in new windowPrevalence 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

 

Opens external link in new windowThe 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

 

Opens external link in new windowMicrosatellite 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

 

Opens external link in new windowAnalysis 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

 

Opens external link in new windowA 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

 

Opens external link in new windowSelTarbase, 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)

 

Opens external link in new windowHigh 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

 

Opens external link in new windowASTD: 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

 

Opens external link in new windowFrameshift 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

 

Opens external link in new windowImmune 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 

 

 

Opens external link in new windowPrevious publications of the Applied Tumor Biology Department

Opens external link in new windowPrevious publications of the Bork Group 

Opens external link in new windowResearch group's MMPU link to EMBL web page

 

 

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