An in-depth examination of genomic heterogeneity of disseminated colorectal cancer: a post mortem study

Tumour evolution and heterogeneity is a key concept in the understanding and treatment of cancer.In patients who have died of advanced colorectal cancer (CRC), we used microscopy, immunohistochemistry and genomic analyses to study the mismatch repair (MMR), mutational and copy number alteration (CNA) profiles of 354 samples from eight individuals. We show, for the first time, the range of evolutionary complexity in CRC. We demonstrate homogeneity in targetable mutations in over 250 metastases; that MMR deficient tumours do not evolve through CNA; and that chromosomally unstable tumours demonstrate a range of evolutionary patterns, from rapid development of a homogenous, aggressive clone, to gradual evolution of multiple sub-clones, associated with site or mode of spread.This is the most comprehensive and systematic examination of the genomic variation in disseminated CRC, showing the breadth of evolutionary diversity in advanced carcinoma and highlighting the utility of postmortem examination as a research tool.