Ordered and deterministic cancer genome evolution after p53 loss

Timour Baslan, John P. Morris, Zhen Zhao, Jose Reyes, Yu-Jui Ho, Kaloyan M. Tsanov, Jonathan Bermeo, Sha Tian, Sean Zhang, Gokce Askan, Aslihan Yavas, Nicolas Lecomte, Amanda Erakky, Anna M. Varghese, Amy Zhang, Jude Kendall, Elena Ghiban, Lubomir Chorbadjiev, Jie Wu, Nevenka Dimitrova, Kalyani Chadalavada, Gouri J. Nanjangud, Chaitanya Bandlamudi, Yixiao Gong, Mark T. A. Donoghue, Nicholas D. Socci, Alex Krasnitz, Faiyaz Notta, Steve D. Leach, Christine A. Iacobuzio-Donahue and Scott W. Lowe ()
Additional contact information
Timour Baslan: Memorial Sloan Kettering Cancer Center
John P. Morris: Memorial Sloan Kettering Cancer Center
Zhen Zhao: Memorial Sloan Kettering Cancer Center
Jose Reyes: Memorial Sloan Kettering Cancer Center
Yu-Jui Ho: Memorial Sloan Kettering Cancer Center
Kaloyan M. Tsanov: Memorial Sloan Kettering Cancer Center
Jonathan Bermeo: Memorial Sloan Kettering Cancer Center
Sha Tian: Memorial Sloan Kettering Cancer Center
Sean Zhang: Memorial Sloan Kettering Cancer Center
Gokce Askan: Memorial Sloan Kettering Cancer Center
Aslihan Yavas: Memorial Sloan Kettering Cancer Center
Nicolas Lecomte: Memorial Sloan Kettering Cancer Center
Amanda Erakky: Memorial Sloan Kettering Cancer Center
Anna M. Varghese: Memorial Sloan Kettering Cancer Center
Amy Zhang: Ontario Institute for Cancer Research
Jude Kendall: Cold Spring Harbor Laboratory
Elena Ghiban: Cold Spring Harbor Laboratory
Lubomir Chorbadjiev: Technical University of Sofia
Jie Wu: Oncology Informatics and Genomics
Nevenka Dimitrova: Oncology Informatics and Genomics
Kalyani Chadalavada: Memorial Sloan Kettering Cancer Center
Gouri J. Nanjangud: Memorial Sloan Kettering Cancer Center
Chaitanya Bandlamudi: Memorial Sloan Kettering Cancer Center
Yixiao Gong: Memorial Sloan Kettering Cancer Center
Mark T. A. Donoghue: Memorial Sloan Kettering Cancer Center
Nicholas D. Socci: Memorial Sloan Kettering Cancer Center
Alex Krasnitz: Cold Spring Harbor Laboratory
Faiyaz Notta: Ontario Institute for Cancer Research
Steve D. Leach: Memorial Sloan Kettering Cancer Center
Christine A. Iacobuzio-Donahue: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 608, issue 7924, 795-802

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05082-5

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