Ordered and deterministic cancer genome evolution after p53 loss

Abstract

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. 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. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

A compendium of co-regulated mitoribosomal proteins in pan-cancer uncovers collateral defective events in tumor malignancy

“…It is noted that malignant properties enabled by p53 inactivation are acquired through a pattern of genome evolution that involves four sequential phases—TP53 loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications ( Baslan et al., 2022 ), indicating that accumulation of deletions is an important feature of cancer evolution. Recent studies suggest that heterozygous genetic alterations may cause genetic instability in a yeast model, which may mimic genetic instability during cancer evolution in mammals.…”

Chromosomal Instability, Selection and Competition: Factors That Shape the Level of Karyotype Intra-Tumor Heterogeneity

“…BRCA mutations in breast cancer are associated with a particular pattern of CNVs [ 111 ]. Similarly, mutations in both alleles of Trp53 shape the trajectory of tumor evolution, resulting in recurring patterns of aneuploidy in a mouse model of pancreatic ductal adenocarcinoma [ 112 ]. Moreover, whole-genome doubling increases CIN and, in particular, results in whole chromosome CNVs [ 43 ].…”

Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment

“…Moreover, we compared the cumulative mutated proportion of classic carcinogenic pathways (Supplementary Figure 4A), which showed that the TP53 signaling pathway ranked first among all variables. Baslan et al (38) demonstrated that the occurrence and development of cancer relied on an ordered determined genome evolution caused by the accumulation of TP53 inactivation. Combining the results in this study, we hypothesized that the cells lost precise regulation of the cell cycle and glutamine metabolism due to TP53 mutations.…”