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

Colorectal malignancies are a leading cause of cancer-related death 1 and have undergone extensive genomic study 2 , 3 . However, DNA mutations alone do not fully explain malignant transformation 4 – 7 . Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single...

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Veröffentlicht in:Nature (London) Jg. 611; H. 7937; S. 733 - 743
Hauptverfasser: Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., Sottoriva, Andrea
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 24.11.2022
Nature Publishing Group
Schlagworte:
45
45/23
631/114
631/208/177
631/67/2329
631/67/69
692/699/67/1504/1885
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Adenoma - genetics
Adenoma - pathology
Biological evolution
Cancer
Cell growth
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Chromatin
Chromatin - genetics
Chromatin - metabolism
Cloning
Coevolution
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Datasets
Deoxyribonucleic acid
DNA
DNA methylation
Epigenetics
Epigenome - genetics
Evolution
Evolution & development
Genes
Genome, Human - genetics
Genomes
Heterogeneity
Humanities and Social Sciences
Humans
Interferon
Interferons
Malignancy
multidisciplinary
Mutation
Oncogenes - genetics
Patients
Positive selection
Regulatory sequences
Science
Science (multidisciplinary)
Signature analysis
Transcription factors
Transcription Factors - metabolism
Transcriptomes
Tumorigenesis
Tumors
ISSN:0028-0836, 1476-4687, 1476-4687
Online-Zugang:Volltext
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Zusammenfassung:Colorectal malignancies are a leading cause of cancer-related death 1 and have undergone extensive genomic study 2 , 3 . However, DNA mutations alone do not fully explain malignant transformation 4 – 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. A study maps genetic and epigenetic heterogeneity of primary colorectal adenomas and cancers at single-clone resolution through spatial multi-omic profiling of individual glands and adjacent normal tissue.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-022-05202-1