Kristiina Rajamäki1, Aurora Taira2, Riku Katainen2, Niko Välimäki2, Anna Kuosmanen2, Roosa-Maria Plaketti2, Toni T Seppälä3, Maarit Ahtiainen4, Erkki-Ville Wirta5, Emilia Vartiainen2, Päivi Sulo2, Janne Ravantti2, Suvi Lehtipuro6, Kirsi J Granberg6, Matti Nykter6, Tomas Tanskanen7, Ari Ristimäki8, Selja Koskensalo9, Laura Renkonen-Sinisalo9, Anna Lepistö9, Jan Böhm4, Jussi Taipale10, Jukka-Pekka Mecklin11, Mervi Aavikko12, Kimmo Palin2, Lauri A Aaltonen13. 1. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. Electronic address: ekristiina.rajamaki@helsinki.fi. 2. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. 3. Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Surgery, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; Department of Surgical Oncology, Johns Hopkins University, Baltimore, Maryland. 4. Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland. 5. Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland. 6. Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Tays Cancer Center, Tampere University Hospital, Tampere, Finland. 7. Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland. 8. Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 9. Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. 10. Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Biochemistry, University of Cambridge, Cambridge, UK. 11. Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Department of Education and Research, Central Finland Central Hospital, Jyväskylä, Finland. 12. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland. 13. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. Electronic address: lauri.aaltonen@helsinki.fi.
Abstract
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.
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.
Authors: Rachel E Brown; Justin Jacobse; Shruti A Anant; Koral M Blunt; Bob Chen; Paige N Vega; Chase T Jones; Jennifer M Pilat; Frank Revetta; Aidan H Gorby; Kristy R Stengel; Yash A Choksi; Kimmo Palin; M Blanca Piazuelo; Mary Kay Washington; Ken S Lau; Jeremy A Goettel; Scott W Hiebert; Sarah P Short; Christopher S Williams Journal: JCI Insight Date: 2022-05-23
Authors: Satu Mäki-Nevala; Sanjeevi Ukwattage; Erkki-Ville Wirta; Maarit Ahtiainen; Ari Ristimäki; Toni T Seppälä; Anna Lepistö; Jukka-Pekka Mecklin; Päivi Peltomäki Journal: Biomolecules Date: 2021-09-30