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The co-evolution of the genome and epigenome in colorectal cancer

Author

Listed:
  • Timon Heide

    (The Institute of Cancer Research
    Human Technopole)

  • Jacob Househam

    (The Institute of Cancer Research
    Queen Mary University of London)

  • George D. Cresswell

    (The Institute of Cancer Research)

  • Inmaculada Spiteri

    (The Institute of Cancer Research)

  • Claire Lynn

    (The Institute of Cancer Research)

  • Maximilian Mossner

    (The Institute of Cancer Research
    Queen Mary University of London)

  • Chris Kimberley

    (Queen Mary University of London)

  • Javier Fernandez-Mateos

    (The Institute of Cancer Research)

  • Bingjie Chen

    (The Institute of Cancer Research)

  • Luis Zapata

    (The Institute of Cancer Research)

  • Chela James

    (The Institute of Cancer Research)

  • Iros Barozzi

    (Imperial College London
    Medical University of Vienna)

  • Ketevan Chkhaidze

    (The Institute of Cancer Research)

  • Daniel Nichol

    (The Institute of Cancer Research)

  • Vinaya Gunasri

    (The Institute of Cancer Research
    Queen Mary University of London)

  • Alison Berner

    (Queen Mary University of London)

  • Melissa Schmidt

    (Queen Mary University of London)

  • Eszter Lakatos

    (The Institute of Cancer Research
    Queen Mary University of London)

  • Ann-Marie Baker

    (The Institute of Cancer Research
    Queen Mary University of London)

  • Helena Costa

    (University College London)

  • Miriam Mitchinson

    (University College London)

  • Rocco Piazza

    (University of Milano-Bicocca)

  • Marnix Jansen

    (University College London)

  • Giulio Caravagna

    (The Institute of Cancer Research
    University of Triest)

  • Daniele Ramazzotti

    (University of Milano-Bicocca)

  • Darryl Shibata

    (University of Southern California Keck School of Medicine)

  • John Bridgewater

    (University College London)

  • Manuel Rodriguez-Justo

    (University College London)

  • Luca Magnani

    (Imperial College London)

  • Trevor A. Graham

    (The Institute of Cancer Research
    Queen Mary University of London)

  • Andrea Sottoriva

    (The Institute of Cancer Research
    Human Technopole)

Abstract

Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Suggested Citation

  • Timon Heide & Jacob Househam & George D. Cresswell & Inmaculada Spiteri & Claire Lynn & Maximilian Mossner & Chris Kimberley & Javier Fernandez-Mateos & Bingjie Chen & Luis Zapata & Chela James & Iros, 2022. "The co-evolution of the genome and epigenome in colorectal cancer," Nature, Nature, vol. 611(7937), pages 733-743, November.
    • Handle: RePEc:nat:nature:v:611:y:2022:i:7937:d:10.1038_s41586-022-05202-1
    DOI: 10.1038/s41586-022-05202-1
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    Cited by:

    1. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Bingjie Chen & Daniele Ramazzotti & Timon Heide & Inmaculada Spiteri & Javier Fernandez-Mateos & Chela James & Luca Magnani & Trevor A. Graham & Andrea Sottoriva, 2023. "Contribution of pks+ E. coli mutations to colorectal carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

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