p53 Inactivation Leads to a Predictable Pattern of Genome Evolution

TP53 encodes a tumor suppressor that can respond to a myriad of cellular stress signals by promoting a multifaceted transcriptional program that protects cells from genome instability and malignant transformation. TP53 is inactivated in most human cancers, but the mechanism by which genomic instability develops following p53 inactivation is not well understood due to a lack of markers that distinguish cells immediately after p53 inactivation. Baslan, Morris, Zhao, and colleagues studied the evolution of p53-inactivated cancer genomes by developing a murine model of pancreatic ductal adenocarcinoma (PDAC), initiated by Kras^G12D and monoallelic inactivation of Trp53, in which premalignant cells were double-positive (DP) for green and red fluorescent proteins. Given that one of these markers was on the same chromosome as the remaining wild-type Trp53 allele, this model allowed lineage tracing of cells that became single-positive (SP) following sporadic biallelic Trp53 inactivation. Immunohistochemistry analysis of pancreata demonstrated that, whereas DP cells displayed premalignant histopathology, SP cells emerged within DP structures and formed highly proliferative PDAC tumors. Comparison of DP and SP cells within PDAC-bearing pancreata revealed that Trp53 loss of heterozygosity (LOH) first led to recurrent copy-number gains and losses that reflected conserved copy-number alterations observed in human PDAC, including deletions on chromosome 4 and gains on chromosome 6, which respectively harbor Cdkn2a and Kras. Notably, breakpoint-based phylogenetic analysis of single-cell sequencing of DP and SP cells identified four distinct, ordered phases of genome evolution: Trp53 LOH, recurrent chromosomal deletions, genome doubling, and widespread chromosomal gains and focal amplifications. This sequential transformation of nonrearranged, diploid DP genomes to highly rearranged, polyploid SP genomes was confirmed in human PDAC tumors, supporting conservation of this evolutionary pattern. In summary, this work reveals how p53 inactivation enables malignant transformation by initiating an ordered and deterministic pattern of cancer genome evolution.

Baslan T, Morris JP 4th, Zhao Z, Reyes J, Ho YJ, Tsanov KM, et al. Ordered and deterministic cancer genome evolution after p53 loss. Nature 2022;608:795–802.

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