Abstract IA024: The role of the epigenome and phenotypic plasticity in colorectal cancer evolution

Abstract

Abstract The evolutionary dynamics of colorectal metastasis and the role of the epigenome in disease progression remain to be fully determined. We have used multi-region, multi-omic profiling (DNA, RNA and chromatin), together with computational modelling, of a prospectively collected cohort of primary CRCs (pCRCs) and DNA and RNA analysis of a retrospective series of metastatic CRCs (mCRCs) to define pCRC biology and track clonal evolution from primary tumour to metastasis. Computational analysis of multi-region sequencing data provided a sensitive test confirming subclonal selection is rare in pCRCs. We detected substantial epigenetic rewiring at the outset of pCRC formation, implicating changes in chromatin accessibility in the initial genesis of CRCs. Using DNA to trace clonal ancestry and overlaying RNA to measure gene expression phenotypes, we observe widespread gene expression changes without underlying clonal selection, indicative that pCRC cells are phenotypically plastic. In mCRCs, we observe that the karyotype of the primary tumour is often not substantially modified in metastasis, across multiple organs, through treatment and over substantial periods of time. This is suggestive that stabilising selection, acting on copy number alterations, constrains karyotype evolution. Paired analysis of DNA and RNA in metastasis indicate that the phenotypic plasticity persists during metastatic spread. Epigenetic rewiring and phenotypic plasticity play potentially causative roles in the genesis and progression of colorectal cancer. Citation Format: Trevor A. Graham. The role of the epigenome and phenotypic plasticity in colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA024.