Phenotypic plasticity and genetic control in colorectal cancer evolution

• DOI: 10.1038/s41586-022-05311-x
• Publication Date: 2022-10-26T16:04:06Z
• Authors: Jacob Househam; Timon Heide; George D. Cresswell; Inmaculada Spiteri; Chris Kimberley; Luis Zapata; Claire Lynn; Chela James; Maximilian Mossner; Javier Fernandez-...; 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-...; Luca Magnani; Andrea Sottoriva; Trevor A. Graham
• Keywords: 570; 0303 health sciences; Transcription, Genetic; colorectal cancer genomics; Cancer genomics; Colon cancer; Computational models; Evolutionary genetics; Tumour heterogeneity; Adaptation, Physiological; Article; Clone Cells; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Phenotype; 616; Mutation; Exome Sequencing; Humans; Colorectal Neoplasms

Abstract Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity 1 . The interplay of these biological processes their respective contributions tumour evolution remain unknown. Here we show that genetic ancestry only infrequently affects gene expression traits subclonal in colorectal cancer (CRC). Using spatially resolved paired whole-genome transcriptome sequencing, find the majority variation is not strongly heritable but rather ‘plastic’. Somatic quantitative trait loci analysis identified a number putative controls by cis -acting coding non-coding mutations, which were clonal within tumour, alongside frequent structural alterations. Consistently, computational inference on spatial patterning phylogenies finds considerable proportion CRCs did evidence selection, subset drivers associated subclone expansions. Spatial intermixing clones common, some tumours growing exponentially others at periphery. Together, our data suggest most CRC has no major phenotypic consequence plasticity is, instead, widespread tumour.