The co-evolution of the genome and epigenome in colorectal cancer

Abstract

Colorectal malignancies are a leading cause of cancer death. Despite large-scale genomic efforts, DNA mutations do not fully explain malignant evolution. Here we study the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,373 samples from 30 primary cancers and 9 concomitant adenomas and generated 1,212 chromatin accessibility profiles, 527 whole-genomes and 297 whole-transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent chromatin changes in regulatory regions of cancer drivers with otherwise no mutation. Genome-wide alterations in transcription factor binding accessibility involved CTCF, downregulation of interferon, and increased accessibility for SOX and HOX, indicating developmental genes reactivation. Epigenetic aberrations were heritable, distinguishing adenomas from cancers. Mutational signature analysis showed the epigenome influencing DNA mutation accumulation. This study provides a map of (epi)genetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

“…Single-cell RNA-Seq suggested that the ISG signature observed correlated with chromatin status in Mre11 ATLD1/ATLD1 organoids. To visualize chromatin status and ISG signature simultaneously at single-cell level, expression levels of 113 chromatin modifiers and remodelers examined in a previous study 39 were used as a proxy of chromatin status. Potential of Heat-diffusion for Affinity-based Trajectory Embedding (PHATE) analysis was performed, which was then color-coded by ISG signature score.…”