Phenotypic plasticity and genetic control in colorectal cancer evolution

Jacob Househam, Timon Heide, George D. Cresswell, Inmaculada Spiteri, Chris Kimberley, Luis Zapata, Claire Lynn, Chela James, Maximilian Mossner, Javier Fernandez-Mateos, Alessandro Vinceti, Ann-Marie Baker, Calum Gabbutt, Alison Berner, Melissa Schmidt, Bingjie Chen, Eszter Lakatos, Vinaya Gunasri, Daniel Nichol, Helena Costa, Miriam Mitchinson, Daniele Ramazzotti, Benjamin Werner, Francesco Iorio, Marnix Jansen, Giulio Caravagna, Chris P. Barnes, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Andrea Sottoriva () and Trevor A. Graham ()
Additional contact information
Jacob Househam: The Institute of Cancer Research
Timon Heide: The Institute of Cancer Research
George D. Cresswell: The Institute of Cancer Research
Inmaculada Spiteri: The Institute of Cancer Research
Chris Kimberley: Queen Mary University of London
Luis Zapata: The Institute of Cancer Research
Claire Lynn: The Institute of Cancer Research
Chela James: The Institute of Cancer Research
Maximilian Mossner: The Institute of Cancer Research
Javier Fernandez-Mateos: The Institute of Cancer Research
Alessandro Vinceti: Human Technopole
Ann-Marie Baker: The Institute of Cancer Research
Calum Gabbutt: The Institute of Cancer Research
Alison Berner: Queen Mary University of London
Melissa Schmidt: Queen Mary University of London
Bingjie Chen: The Institute of Cancer Research
Eszter Lakatos: The Institute of Cancer Research
Vinaya Gunasri: The Institute of Cancer Research
Daniel Nichol: The Institute of Cancer Research
Helena Costa: University College London
Miriam Mitchinson: University College London Hospitals NHS Foundation Trust
Daniele Ramazzotti: University of Milano-Bicocca
Benjamin Werner: Queen Mary University of London
Francesco Iorio: Human Technopole
Marnix Jansen: University College London
Giulio Caravagna: The Institute of Cancer Research
Chris P. Barnes: University College London
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
Andrea Sottoriva: The Institute of Cancer Research
Trevor A. Graham: The Institute of Cancer Research

Nature, 2022, vol. 611, issue 7937, 744-753

Abstract: Abstract Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05311-x

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