The inactivation of the widely studied tumor suppressor TP53 leads to genomic instability that opens the door to malignancy for more than half of all human cancers. However, the tumor evolution triggered by loss of the gene and the protein p53 that it encodes isn't random but subject to predictable patterns that could potentially guide new cancer treatment strategies, according to a new study in this week's Nature. To investigate the ways through which TP53 mutant genomes emerge and influence tumorigenesis, a team led by scientists from Memorial Sloan Kettering Cancer Center used a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, enabling them to observe the evolutionary dynamics of cells undergoing stepwise progression to malignancy at single-cell resolution from the point of p53 inactivation. Single-cell sequencing and in situ genotyping of cells reveals four sequential phases for the cells: loss of heterozygosity of the gene encoding mouse p53, accumulation of deletions, genome doubling, and the emergence of gains and amplifications. Each phase is associated with specific histological stages across the premalignant and malignant spectrum, the study's authors write, and "despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations." The findings indicate that the loss of p53 "is not merely a gateway to genetic chaos but … can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumors."