Abstract NG02: Ordered and selective patterns of cancer genome evolution revealed by lineage tracing of sporadic p53 loss

Abstract Inactivation of the tumor suppressor p53 is associated with molecular features such as genomic instability, polyploidy, and the emergence of heterogeneous tumors that acquire diverse copy number alterations (CNAs). Clinically, p53 loss is associated with aggressive disease, therapeutic resistance, and poor prognosis. However, precisely when specific molecular features are selected following p53 inactivation and their evolutionary contribution to the initiation and progression of heterogenous p53 mutant tumors, remains poorly understood. This is in part because cancer genomes are typically analyzed after tumor development and not as they transverse the benign to malignant spectrum. Here, we develop a mouse model of pancreatic ductal adenocarcinoma (PDAC) that reports sporadic p53 loss in vivo, irrespective of phenotype, enabling the identification, isolation and lineage tracing of incipient cancer cells as they evolve through the benign to malignant transition. Using functional, histopathological, and genomics-based approaches, we find that cells undergoing p53 loss gradually gain malignant potential as they acquire CNAs in highly ordered and selective patterns. Initially, distinct p53-deficient clones emerge and compete via the selective acquisition of recurrent chromosomal deletions in otherwise diploid cells. Following the accumulation of many genomic deletions in a diploid state, a subset of highly rearranged clones undergo genome doubling, entering polyploid, presumably an adaptation to excess loss of gene dosage. In a polyploid state, rampant genomic diversification ensues involving the acquisition of additional deletions and, now, widespread chromosomal gains and amplifications resulting in a heterogenous malignant tumor. Despite vast heterogeneity, chromosomal deletions are selectively fixed as truncal, homogenous events in the tumor hierarchy. Retrospective analysis of whole genome, targeted-panel, and single-cell sequencing data of human PDAC corroborate these patterns in human disease. p53 was coined “guardian of the genome” 30 years ago upon the discovery that its inactivation prevents proliferative arrest following DNA damage, leading to genomic instability. However, the evolutionary relationship between p53 inactivation, associated genomic features, and the emergence of p53 tumors remains poorly understood. Leveraging a unique lineage tracing mouse model, we find that p53 inactivation results in a set of predictable evolutionary rules that are highly ordered and deterministic. These specific rules suggest stage dependent contributions of CNA events to malignant transformation and point to new strategies to target lethal, p53-deficient tumors. Citation Format: Timour Baslan. Ordered and selective patterns of cancer genome evolution revealed by lineage tracing of sporadic p53 loss. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr NG02.