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 Lepistö; Jan Böhm; Jussi Taipale; Jukka-Pekka Mecklin; Mervi Aavikko; Kimmo Palin; Lauri A Aaltonen

doi:10.1053/j.gastro.2021.04.042

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

Gastroenterology. 2021 Aug;161(2):592-607. doi: 10.1053/j.gastro.2021.04.042. Epub 2021 Apr 27.

Authors

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

Affiliations

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.

PMID: 33930428
DOI: 10.1053/j.gastro.2021.04.042

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.

Keywords: Colorectal Cancer; Consensus Molecular Subtype; DNA Methylation; Epithelial–Mesenchymal Transition; Inflammatory Bowel Disease.

Publication types

Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / genetics*
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / immunology
Cell Transformation, Neoplastic / pathology
Colitis-Associated Neoplasms / genetics*
Colitis-Associated Neoplasms / immunology
Colitis-Associated Neoplasms / pathology
DNA Methylation*
DNA Mutational Analysis
Epigenesis, Genetic*
Epigenomics
Female
Finland
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Inflammatory Bowel Diseases / genetics*
Inflammatory Bowel Diseases / immunology
Inflammatory Bowel Diseases / pathology
Male
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Sequence Analysis, RNA
Transcriptome*
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology
Whole Genome Sequencing

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding