Ordered and deterministic cancer genome evolution after p53 loss

The tumor suppressor TP53 is disabled in more than half of all tumors, but the principles that predicate the evolution of malignant genomes following p53 inactivation remain elusive. Here, single-cell genomics applied to a mouse model of pancreatic ductal adenocarcinoma (PDAC) that reports p53 status in vivo reveals ordered and selective patterns of copy number alterations (CNA) upon p53 loss of heterozygosity (LOH). By tracking cells acquiring LOH from their emergence in pre-malignant tissue, we directly visualize patterns by which conserved, cancer associated CNAs are acquired and selected. Distinct, competing LOH clones begin evolving largely via the selective acquisition of chromosomal deletion events in diploid cells. Highly rearranged diploid clones then undergo endoreduplication followed by rapid genomic diversification involving the acquisition of additional further deletions, but also chromosomal gains and amplifications. Despite vast heterogeneity, chromosomal deletions are selectively fixed as truncal events, a pattern also reflected in human PDAC. These results reveal non-random principles that underly distinct phases of malignant evolution following p53 loss and have implications for the therapeutic targeting of p53 mutant cancers.