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

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 Barozzi, Ketevan Chkhaidze, Daniel Nichol, Vinaya Gunasri, Alison Berner, Melissa Schmidt, Eszter Lakatos, Ann-Marie Baker, Helena Costa, Miriam Mitchinson, Rocco Piazza, Marnix Jansen, Giulio Caravagna, Daniele Ramazzotti, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Trevor A. Graham () and Andrea Sottoriva ()
Additional contact information
Timon Heide: The Institute of Cancer Research
Jacob Househam: The Institute of Cancer Research
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
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
Ketevan Chkhaidze: The Institute of Cancer Research
Daniel Nichol: The Institute of Cancer Research
Vinaya Gunasri: The Institute of Cancer Research
Alison Berner: Queen Mary University of London
Melissa Schmidt: Queen Mary University of London
Eszter Lakatos: The Institute of Cancer Research
Ann-Marie Baker: The Institute of Cancer Research
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
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
Andrea Sottoriva: The Institute of Cancer Research

Nature, 2022, vol. 611, issue 7937, 733-743

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05202-1 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:611:y:2022:i:7937:d:10.1038_s41586-022-05202-1

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05202-1

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().