Phenotypic plasticity and genetic control in colorectal cancer evolution.

Autor: Househam J; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Heide T; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Computational Biology Research Centre, Human Technopole, Milan, Italy., Cresswell GD; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Spiteri I; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Kimberley C; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Zapata L; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Lynn C; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., James C; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Mossner M; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Fernandez-Mateos J; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Vinceti A; Computational Biology Research Centre, Human Technopole, Milan, Italy., Baker AM; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Gabbutt C; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Berner A; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Schmidt M; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Chen B; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Lakatos E; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Gunasri V; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Nichol D; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK., Costa H; UCL Cancer Institute, University College London, London, UK., Mitchinson M; Histopathology Department, University College London Hospitals NHS Foundation Trust, London, UK., Ramazzotti D; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Werner B; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Iorio F; Computational Biology Research Centre, Human Technopole, Milan, Italy., Jansen M; UCL Cancer Institute, University College London, London, UK., Caravagna G; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.; Department of Mathematics and Geosciences, University of Trieste, Trieste, Italy., Barnes CP; Department of Cell and Developmental Biology, University College London, London, UK., Shibata D; Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Bridgewater J; UCL Cancer Institute, University College London, London, UK., Rodriguez-Justo M; UCL Cancer Institute, University College London, London, UK., Magnani L; Department of Surgery and Cancer, Imperial College London, London, UK., Sottoriva A; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. andrea.sottoriva@fht.org.; Computational Biology Research Centre, Human Technopole, Milan, Italy. andrea.sottoriva@fht.org., Graham TA; Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. trevor.graham@icr.ac.uk.; Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK. trevor.graham@icr.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Nov; Vol. 611 (7937), pp. 744-753. Date of Electronic Publication: 2022 Oct 26.
DOI: 10.1038/s41586-022-05311-x
Abstrakt: Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity 1 . The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.
(© 2022. The Author(s).)
Databáze: MEDLINE
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