Journal Article

Phenotypic plasticity and genetic control in colorectal cancer evolution

Zapata, Luis, Bridgewater, John, Gunasri, Vinaya, Rodriguez-Justo, Manuel, Mossner, Maximilian, Lakatos, Eszter, Cresswell, George D., Costa, Helena, Shibata, Darryl, Werner, Benjamin, Kimberley, Chris, Baker, Ann-Marie, Nichol, Daniel, Sottoriva, Andrea, James, Chela, Mitchinson, Miriam, Berner, Alison, Chen, Bingjie, Spiteri, Inmaculada, Gabbutt, Calum, Househam, Jacob, Fernandez-Mateos, Javier, Iorio, Francesco, Barnes, Chris P., Ramazzotti, Daniele, Schmidt, Melissa, Vinceti, Alessandro, Heide, Timon, Jansen, Marnix, Magnani, Luca, Graham, Trevor A., Caravagna, Giulio, Lynn, Claire

2022

Overview

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. Intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer, with most genetic intratumour variation having no detected phenotypic consequence and transcriptional plasticity being widespread within a tumour.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/47 / 631/114/2397 / 631/181/2474 / 631/67/2329 / 631/67/69 / 692/699/67/1504/1885/1393 / Adaptation, Physiological - genetics / Biological activity / Cancer / Clone Cells - metabolism / Clone Cells - pathology / Cloning / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Computer applications / Epigenetics / Evolution / Evolution & development / Exome Sequencing / Gene expression / Gene Expression Regulation, Neoplastic / Gene mapping / Gene sequencing / Genetic control / Genetic diversity / Genomes / Genomics / Genotype & phenotype / Humanities and Social Sciences / Humans / multidisciplinary / Mutation / Phenotype / Phenotypic plasticity / Phylogenetics / Plastic properties / Plasticity / Quantitative trait loci / Science / Science (multidisciplinary) / Statistical analysis / Transcription, Genetic / Transcriptomes / Tumors