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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

This MMPU team, comprising of a computational biology and a clinical group, aims at utilizing novel, large-scale data by innovative computational approaches in tight conjunction with preclinical and clinical research to translate basic scientific concepts into clinically relevant modalities for cancer diagnostics, prevention, or treatment. The major aim is to achieve true practical relevance by most efficient ways to develop basic research into new globally accepted clinical paradigms.

The research structure of the team is designed to foster innovation in molecular medicine by iterating between ‘dry’ and ‘wet’ experiments in longer lasting research themes. This synergy is used to identify key events responsible for the very first steps of cancer transformation, to identify model cancer types for clinical proof of principle, and to channel newly established modalities into the health care system, all in the context of this MMPU team.

 

Background

Cancer is a disease, which is caused by genomic instability and accumulation of mutations. One specific subtype of cancers is caused by DNA mismatch repair deficiency. These tumors are characterized by an excessive mutational load, particularly at regions harboring repetitive DNA sequences (microsatellite instability, MSI). Mutations of coding microsatellites results in the translation of proteins with mutation-induced frameshift peptides (neoantigens) rendering MSI cancers highly immunogenic. MSI cancers express a defined set of shared neoantigens resulting from functionally relevant driver mutations. Patients with MSI cancers and individuals affected by Lynch syndrome, an inherited predisposition for MSI cancers, develop specific immune responses against these neoantigens.

 

Goals

The main goal of the project is the development of novel approaches for early detection, diagnosis and prevention using state-of-the-art bioinformatics tools for the prediction of novel target structures.

 

Research Focus 1

Identification and utilization of novel target genes

Utilization of neo-antigens in cancers caused by deficient DNA mismatch repair mechanisms resulting from the accumulation of mutations particularly in repetitive sequence elements (microsatellite-unstable or MSI-H cancers). These tumors constitute a substantial part of colorectal cancers, but also a wide variety of cancers outside the colorectum. Due to the excessive number of genetic alterations and the predictability of resulting neo-antigens, MSI-H cancers are an ideal cancer type for developing immune intervention and prevention strategies against cancer and for evaluating them in the clinical setting.

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Research Focus 2

The microbiome for cancer diagnosis and treatment

Utilization of changed microbial communities as biomarkers for early stages of cancer and possibly as targets for potential treatment. The group has been involved in major breakthroughs in microbiomics and is actively pursuing gut microbiome biomarker validation for colorectal cancer. The concept is being broadened to include oral samples and to also involve other cancers.

 

Important Publications

High numbers of PDCD1 (PD-1)-positive T cells and B2M mutations in microsatellite-unstable colorectal cancer.
Janikovits J, Müller M, Krzykalla J, Körner S, Echterdiek F, Lahrmann B, Grabe N, Schneider M, Benner A, Doeberitz MVK, Kloor M.
Oncoimmunology. 2017 Nov 6;7(2):e1390640. doi: 10.1080/2162402X.2017.1390640. eCollection 2018. PMID:29308317

 

CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome.
Ahadova A, von Knebel Doeberitz M, Bläker H, Kloor M.
Fam Cancer. 2016 Oct;15(4):579-86. doi: 10.1007/s10689-016-9899-z.

 

Transcriptional interactions suggest niche segregation among microorganisms in the human gut.
Plichta DR, Juncker AS, Bertalan M, Rettedal E, Gautier L, Varela E, Manichanh C, Fouqueray C, Levenez F, Nielsen T, Doré J, Machado AM, de Evgrafov MC, Hansen T, Jørgensen T,
Bork P, Guarner F, Pedersen O; Metagenomics of the Human Intestinal Tract (MetaHIT) Consortium, Sommer MO, Ehrlich SD, Sicheritz-Pontén T, Brunak S, Nielsen HB.
Nat Microbiol.
2016 Aug 26;1:16152. doi: 10.1038/nmicrobiol.2016.152.

 

MOCAT2: a metagenomic assembly, annotation and profiling framework.
Kultima JR, Coelho LP, Forslund K, Huerta-Cepas J, Li SS, Driessen M, Voigt AY, Zeller G, Sunagawa S,
Bork P.
Bioinformatics. 2016 Aug 15;32(16):2520-3. doi: 10.1093/bioinformatics/btw183. Epub 2016 Apr 8.

 

Human gut microbes impact host serum metabolome and insulin sensitivity.
Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G, Le Chatelier E, Levenez F, Doré J, Mattila I, Plichta DR, Pöhö P, Hellgren LI, Arumugam M, Sunagawa S, Vieira-Silva S, Jørgensen T, Holm JB, Trošt K; MetaHIT Consortium, Kristiansen K, Brix S, Raes J, Wang J, Hansen T,
Bork P, Brunak S, Oresic M, Ehrlich SD, Pedersen O.
Nature. 2016 Jul 21;535(7612):376-81.

 

5-aza-2'-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene expression and blocks neoplastic growth of HPV-associated cancer cells.
Stich M, Ganss L, Puschhof J, Prigge ES, Reuschenbach M, Guiterrez A, Vinokurova S, von Knebel Doeberitz M.
Oncotarget. 2016 Jul 16. doi: 10.18632/oncotarget.10631. [Epub ahead of print]
PMID: 27447977

 

Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing.
Vogtmann E, Hua X, Zeller G, Sunagawa S, Voigt AY, Hercog R, Goedert JJ, Shi J, Bork P, Sinha R.
PLoS One. 2016 May 12;11(5):e0155362. doi: 10.1371/journal.pone.0155362. eCollection 2016.

 

Durable coexistence of donor and recipient strains after fecal microbiota transplantation.
Li SS, Zhu A, Benes V, Costea PI, Hercog R, Hildebrand F, Huerta-Cepas J, Nieuwdorp M, Salojärvi J, Voigt AY, Zeller G, Sunagawa S, de Vos WM, Bork P.
Science.
2016 Apr 29;352(6285):586-9. doi: 10.1126/science.aad8852.

 

Gut Microbiota Linked to Sexual Preference and HIV Infection.
Noguera-Julian M, Rocafort M, Guillén Y, Rivera J, Casadellà M, Nowak P, Hildebrand F, Zeller G, Parera M, Bellido R, Rodríguez C, Carrillo J, Mothe B, Coll J, Bravo I, Estany C, Herrero C, Saz J, Sirera G, Torrela A, Navarro J, Crespo M, Brander C, Negredo E, Blanco J, Guarner F, Calle ML,
Bork P, Sönnerborg A, Clotet B, Paredes R.
EBioMedicine. 2016 Jan 28;5:135-46. doi: 10.1016/j.ebiom.2016.01.032. eCollection 2016 Mar.

 

eggNOG 4.5: a hierarchical orthology framework with improved functional annotations for eukaryotic, prokaryotic and viral sequences.
Huerta-Cepas J, Szklarczyk D, Forslund K, Cook H, Heller D, Walter MC, Rattei T, Mende DR, Sunagawa S, Kuhn M, Jensen LJ, von Mering C, Bork P.
Nucleic Acids Res. 2016 Jan 4;44(D1):D286-93. doi: 10.1093/nar/gkv1248. Epub 2015 Nov 17. PMID: 26582926

 

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.
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.
Oncoimmunology. 2015 Nov 11;5(2):e1075692. eCollection 2016 Feb.

 

A new method for detection of tumor driver-dependent changes of protein sialylation in a colon cancer cell line reveals nectin-3 as TGFBR2 target.
Lee J, Warnken U, Schnölzer M, Gebert J, Kopitz J.
Protein Sci. 2015 Oct;24(10):1686-94. doi: 10.1002/pro.2741. Epub 2015 Jul 30. PMID: 26177744

 

Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.
Zhang C, Yin A, Li H, Wang R, Wu G, Shen J, Zhang M, Wang L, Hou Y, Ouyang H, Zhang Y, Zheng Y, Wang J, Lv X, Wang Y, Zhang F, Zeng B, Li W, Yan F, Zhao Y, Pang X, Zhang X, Fu H, Chen F, Zhao N, Hamaker BR, Bridgewater LC, Weinkove D, Clement K, Dore J, Holmes E, Xiao H, Zhao G, Yang S, Bork P, Nicholson JK, Wei H, Tang H, Zhang X, Zhao L.
EBioMedicine. 2015 Jul 10;2(8):966-82. doi: 10.1016/j.ebiom.2015.07.007. eCollection 2015 Aug. PMID:26425705

 

Reconstitution of TGFBR2-Mediated Signaling Causes Upregulation of GDF-15 in HCT116 Colorectal Cancer Cells.
Lee J, Fricke F, Warnken U, Schnölzer M, Kopitz J, Gebert J.
PLoS One. 2015 Jun 26;10(6):e0131506. doi: 10.1371/journal.pone.0131506. eCollection 2015. PMID: 26114631

 

Opens external link in new windowMetabolic dependencies drive species co-occurrence in diverse microbial communities.
Zelezniak A, Andrejev S, Ponomarova O, Mende DR, Bork P, Patil KR.
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6449-54. doi: 10.1073/pnas.1421834112. Epub 2015 May 4. PMID: 25941371

 

Inter-individual differences in the gene content of human gut bacterial species.
Zhu A
, Sunagawa S, Mende DR, Bork P.
Genome Biol. 2015 Apr 21;16:82. doi: 10.1186/s13059-015-0646-9. PMID: 25896518

 

Temporal and technical variability of human gut metagenomes.
Voigt AY, Costea PI, Kultima JR, Li SS, Zeller G, Sunagawa S, Bork P.
Genome Biol. 2015 Apr 8;16:73. doi: 10.1186/s13059-015-0639-8. PMID: 25888008

 

Dose-dependent effect of 2-deoxy-D-glucose on glycoprotein mannosylation in cancer cells.
Ahadova A, Gebert J, von Knebel Doeberitz M, Kopitz J,
Kloor M.
IUBMB Life. 2015 Mar;67(3):218-26. doi: 10.1002/iub.1364. Epub 2015 Apr 9. PMID:25854316

 

Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer.  
Surmann EM, Voigt AY, Michel S, Bauer K, Reuschenbach M, Ferrone S, von Knebel Doeberitz M, Kloor M.
Cancer Immunol Immunother. 2015 Mar;64(3):357-66. doi: 10.1007/s00262-014-1638-4. Epub 2014 Dec 2. PMID:25445815

 

Opens external link in new windowMismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters.
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.
PLoS One. 2015 Mar 27;10(3):e0121980. doi: 10.1371/journal.pone.0121980. eCollection 2015.PMID:25816162 

 

Opens external link in new windowPotential of fecal microbiota for early-stage detection of colorectal cancer.
Zeller G, Tap J, Voigt AY, Sunagawa S, Kultima JR, Costea PI, Amiot A, Böhm J, Brunetti F, Habermann N, Hercog R, Koch M, Luciani A, Mende DR, Schneider MA, Schrotz-King P, Tournigand C, Tran Van Nhieu J, Yamada T, Zimmermann J, Benes V, Kloor M, Ulrich CM, von Knebel Doeberitz M, Sobhani I, Bork P.
Mol Syst Biol. 2014 Nov 28;10:766.doi:10.15252/msb.20145645.PMID:25432777

 

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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