Binder, Hans, Hopp, Lydia, Schweiger, Michal R., Hoffmann, Steve, Juehling, Frank, Kerick, Martin ORCID: 0000-0002-6298-4514, Timmermann, Bernd, Siebert, Susann, Grimm, Christina ORCID: 0000-0002-4676-8870, Nersisyan, Lilit ORCID: 0000-0001-8525-420X, Arakelyan, Arsen ORCID: 0000-0002-6851-1056, Herberg, Maria, Buske, Peter, Loeffler-Wirth, Henry, Rosolowski, Maciej, Engel, Christoph ORCID: 0000-0002-7247-282X, Przybilla, Jens, Peifer, Martin ORCID: 0000-0002-5243-5503, Friedrichs, Nicolaus, Moeslein, Gabriela, Odenthal, Margarete, Hussong, Michelle, Peters, Sophia, Holzapfel, Stefanie, Nattermann, Jacob, Hueneburg, Robert, Schmiegel, Wolff, Royer-Pokora, Brigitte, Aretz, Stefan ORCID: 0000-0002-5228-1890, Kloth, Michael, Kloor, Matthias, Buettner, Reinhard, Galle, Joerg and Loeffler, Markus (2017). Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome. J. Pathol., 243 (2). S. 242 - 255. HOBOKEN: WILEY. ISSN 1096-9896

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Abstract

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Binder, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopp, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, SteveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juehling, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerick, MartinUNSPECIFIEDorcid.org/0000-0002-6298-4514UNSPECIFIED
Timmermann, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siebert, SusannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, ChristinaUNSPECIFIEDorcid.org/0000-0002-4676-8870UNSPECIFIED
Nersisyan, LilitUNSPECIFIEDorcid.org/0000-0001-8525-420XUNSPECIFIED
Arakelyan, ArsenUNSPECIFIEDorcid.org/0000-0002-6851-1056UNSPECIFIED
Herberg, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buske, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeffler-Wirth, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosolowski, MaciejUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Przybilla, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Friedrichs, NicolausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moeslein, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussong, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzapfel, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nattermann, JacobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hueneburg, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmiegel, WolffUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Royer-Pokora, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aretz, StefanUNSPECIFIEDorcid.org/0000-0002-5228-1890UNSPECIFIED
Kloth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloor, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galle, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeffler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-217019
DOI: 10.1002/path.4948
Journal or Publication Title: J. Pathol.
Volume: 243
Number: 2
Page Range: S. 242 - 255
Date: 2017
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1096-9896
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION PATTERNS; MICROSATELLITE INSTABILITY; ULCERATIVE-COLITIS; METHYLATOR PHENOTYPE; CROHNS-DISEASE; COLON-CANCER; MUTATIONS; ASSOCIATION; SIGNATURES; GERMLINEMultiple languages
Oncology; PathologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21701

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