RT Journal Article
SR Electronic
T1 Phenotypic plasticity and genetic control in colorectal cancer evolution
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.18.451272
DO 10.1101/2021.07.18.451272
A1 Jacob Househam
A1 Timon Heide
A1 George D Cresswell
A1 Claire Lynn
A1 Inmaculada Spiteri
A1 Max Mossner
A1 Chris Kimberley
A1 Calum Gabbutt
A1 Eszter Lakatos
A1 Javier Fernandez-Mateos
A1 Bingjie Chen
A1 Luis Zapata
A1 Chela James
A1 Alison Berner
A1 Melissa Schmidt
A1 Ann-Marie Baker
A1 Daniel Nichol
A1 Helena Costa
A1 Miriam Mitchinson
A1 Marnix Jansen
A1 Giulio Caravagna
A1 Darryl Shibata
A1 John Bridgewater
A1 Manuel Rodriguez-Justo
A1 Luca Magnani
A1 Andrea Sottoriva
A1 Trevor A Graham
YR 2021
UL http://biorxiv.org/content/early/2021/07/19/2021.07.18.451272.abstract
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.