Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer

Kristiina Rajamäki, Aurora Taira, Riku Katainen, Niko Välimäki, Anna Kuosmanen, Roosa Maria Plaketti, Toni T. Seppälä, Maarit Ahtiainen, Erkki Ville Wirta, Emilia Vartiainen, Päivi Sulo, Janne Ravantti, Suvi Lehtipuro, Kirsi J. Granberg, Matti Nykter, Tomas Tanskanen, Ari Ristimäki, Selja Koskensalo, Laura Renkonen-Sinisalo, Anna LepistöJan Böhm, Jussi Taipale, Jukka Pekka Mecklin, Mervi Aavikko, Kimmo Palin, Lauri A. Aaltonen

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Background & 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 patients with IBD-CRC. 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 down-regulated 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′untranslated region of TP53 in IBD-CRCs. As reported previously, 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 toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.

Original languageEnglish
Pages (from-to)592-607
Issue number2
Publication statusPublished - 2021
Publication typeA1 Journal article-refereed


  • Colorectal Cancer
  • Consensus Molecular Subtype
  • DNA Methylation
  • Epithelial–Mesenchymal Transition
  • Inflammatory Bowel Disease

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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