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dc.contributor.authorRajamäki, Kristiina
dc.contributor.authorTaira, Aurora
dc.contributor.authorKatainen, Riku
dc.contributor.authorVälimäki, Niko
dc.contributor.authorKuosmanen, Anna
dc.contributor.authorPlaketti, Roosa-Maria
dc.contributor.authorSeppälä, Toni T.
dc.contributor.authorAhtiainen, Maarit
dc.contributor.authorWirta, Erkki-Ville
dc.contributor.authorVartiainen, Emilia
dc.contributor.authorSulo, Päivi
dc.contributor.authorRavantti, Janne
dc.contributor.authorLehtipuro, Suvi
dc.contributor.authorGranberg, Kirsi J.
dc.contributor.authorNykter, Matti
dc.contributor.authorTanskanen, Tomas
dc.contributor.authorRistimäki, Ari
dc.contributor.authorKoskensalo, Selja
dc.contributor.authorRenkonen-Sinisalo, Laura
dc.contributor.authorLepistö, Anna
dc.contributor.authorBöhm, Jan
dc.contributor.authorTaipale, Jussi
dc.contributor.authorMecklin, Jukka-Pekka
dc.contributor.authorAavikko, Mervi
dc.contributor.authorPalin, Kimmo
dc.contributor.authorAaltonen, Lauri A.
dc.date.accessioned2021-08-10T08:02:54Z
dc.date.available2021-08-10T08:02:54Z
dc.date.issued2021
dc.identifier.citationRajamäki, K., Taira, A., Katainen, R., Välimäki, N., Kuosmanen, A., Plaketti, R.-M., Seppälä, T. T., Ahtiainen, M., Wirta, E.-V., Vartiainen, E., Sulo, P., Ravantti, J., Lehtipuro, S., Granberg, K. J., Nykter, M., Tanskanen, T., Ristimäki, A., Koskensalo, S., Renkonen-Sinisalo, L., . . . Aaltonen, L. A. (2021). Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer. <i>Gastroenterology</i>, <i>161</i>(2), 592-607. <a href="https://doi.org/10.1053/j.gastro.2021.04.042" target="_blank">https://doi.org/10.1053/j.gastro.2021.04.042</a>
dc.identifier.otherCONVID_68067829
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/77302
dc.description.abstractBackground and aims Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. Methods Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 IBD-CRC patients. Results Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly downregulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5’UTR of TP53 in IBD-CRCs. As previously reported, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. Conclusions Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs towards mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in IBD patients.en
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofseriesGastroenterology
dc.rightsCC BY-NC-ND 4.0
dc.subject.othercolorectal cancer
dc.subject.otherinflammatory bowel disease
dc.subject.otherepithelial-mesenchymal transition
dc.subject.otherDNA methylation
dc.subject.otherconsensus molecular subtype
dc.titleGenetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202108104467
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.description.reviewstatuspeerReviewed
dc.format.pagerange592-607
dc.relation.issn0016-5085
dc.relation.numberinseries2
dc.relation.volume161
dc.type.versionpublishedVersion
dc.rights.copyright© 2021 the AGA Institute
dc.rights.accesslevelopenAccessfi
dc.subject.ysosuolistosyövät
dc.subject.ysoepigenetiikka
dc.subject.ysogeneettiset tekijät
dc.subject.ysotulehdukselliset suolistosairaudet
dc.subject.ysoDNA-metylaatio
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p25845
jyx.subject.urihttp://www.yso.fi/onto/yso/p24631
jyx.subject.urihttp://www.yso.fi/onto/yso/p21661
jyx.subject.urihttp://www.yso.fi/onto/yso/p38636
jyx.subject.urihttp://www.yso.fi/onto/yso/p38350
dc.rights.urlhttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.relation.doi10.1053/j.gastro.2021.04.042
jyx.fundinginformationThis study was supported by grants from The Finnish Center of Excellence in Tumor Genetics (L.A.A.), Academy of Finland's professorship (L.A.A.), Cancer Foundation Finland (L.A.A.; J.-P.M.; T.S.), iCAN Digital Precision Cancer Medicine Flagship (L.A.A.; K.P.), Sigrid Jusélius Foundation (L.A.A.; A.R.; T.S.), Doctoral Programme In Biomedicine, University of Helsinki (A.T.), Jane and Aatos Erkko Foundation (J.-P.M.), UEF state research funding (J.-P.M.), Emil Aaltonen Foundation (T.S.), Finnish Medical Foundation (T.S.), Finnish Cancer Organizations (A.R.), Finska Läkaresällskapet (A.R.), Helsinki University Central Hospital Research Funds (A.R.), and Instrumentarium Science Foundation (T.S.).


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