PT  - JOURNAL ARTICLE
AU  - Jacob Househam
AU  - Timon Heide
AU  - George D Cresswell
AU  - Claire Lynn
AU  - Inmaculada Spiteri
AU  - Max Mossner
AU  - Chris Kimberley
AU  - Calum Gabbutt
AU  - Eszter Lakatos
AU  - Javier Fernandez-Mateos
AU  - Bingjie Chen
AU  - Luis Zapata
AU  - Chela James
AU  - Alison Berner
AU  - Melissa Schmidt
AU  - Ann-Marie Baker
AU  - Daniel Nichol
AU  - Helena Costa
AU  - Miriam Mitchinson
AU  - Marnix Jansen
AU  - Giulio Caravagna
AU  - Darryl Shibata
AU  - John Bridgewater
AU  - Manuel Rodriguez-Justo
AU  - Luca Magnani
AU  - Andrea Sottoriva
AU  - Trevor A Graham
TI  - Phenotypic plasticity and genetic control in colorectal cancer evolution
AID  - 10.1101/2021.07.18.451272
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.18.451272
4099  - http://biorxiv.org/content/early/2021/07/19/2021.07.18.451272.short
4100  - http://biorxiv.org/content/early/2021/07/19/2021.07.18.451272.full
AB  - Cancer evolution is driven by natural selection acting upon phenotypic trait variation. However, the extent to which phenotypic variation within a tumour is a consequence of intra-tumour genetic heterogeneity remains undetermined. Here we show that colorectal cancer cells frequently have highly plastic phenotypic traits in vivo in patient tumours. We measured the degree to which trait variation reflects genetic ancestry by quantifying the phylogenetic signal of gene expression across 297 samples with multi-region paired whole genome and transcriptome sequencing collected from 27 primary colorectal cancers. Within-tumour phylogenetic signal for genes and pathways was detected only infrequently, suggesting that the majority of intra-tumour variation in gene expression programmes was not strongly heritable. Expression quantitative trait loci analyses (eQTL) identified a small number of putative mechanisms of genetic control of gene expression due to the cis-acting coding, non-coding and structural genetic alteration, but most gene expression variation was not explained by our genetic analysis. Leveraging matched chromatin-accessibility sequencing data, enhancer mutations with cis regulatory effects on gene expression were associated with a change in chromatin accessibility, indicating that non-coding variation can have phenotypic consequence through modulation of the 3D architecture of the genome. This study maps the evolution of transcriptional variation during cancer evolution, highlighting that intra-tumour phenotypic plasticity is pervasive in colorectal malignancies, and may play key roles in further tumour evolution, from metastasis to therapy resistance.Competing Interest StatementThe authors have declared no competing interest.