| Autor: |
Timon Heide, Jacob Househam, George D Cresswell, Inmaculada Spiteri, Claire Lynn, Max Mossner, Chris Kimberley, Javier Fernandez-Mateos, Bingjie Chen, Luis Zapata, Chela James, Iros Barozzi, Ketevan Chkhaidze, Daniel Nichol, Alison Berner, Melissa Schmidt, Eszter Lakatos, Ann-Marie Baker, Helena Costa, Miriam Mitchinson, Marnix Jansen, Giulio Caravagna, Daniele Ramazzotti, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Trevor A Graham, Andrea Sottoriva |
| Rok vydání: |
2021 |
| Popis: |
Colorectal malignancies are a leading cause of cancer death. Despite large-scale genomic efforts, DNA mutations do not fully explain malignant evolution. Here we study 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 1,373 samples from 30 primary cancers and 9 concomitant adenomas and generated 1,212 chromatin accessibility profiles, 527 whole-genomes and 297 whole-transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent chromatin changes in regulatory regions of cancer drivers with otherwise no mutation. Genome-wide alterations in transcription factor binding accessibility involved CTCF, downregulation of interferon, and increased accessibility for SOX and HOX, indicating developmental genes reactivation. Epigenetic aberrations were heritable, distinguishing adenomas from cancers. Mutational signature analysis showed the epigenome influencing DNA mutation accumulation. This study provides a map of (epi)genetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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