Ordered and deterministic cancer genome evolution after p53 loss
Open accessAbstract
Although p53 inactivation promotes genomic instability 1 and presents a route to malignancy for more than half of all human cancers 2,3 , 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.
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PDAC mouse models suggest TP53 mutations promote a patterned loss of genomic integrity rather than a chaotic process.
“PDAC mouse models have suggested TP53 mutations promote a patterned loss of genomic integrity as opposed to a chaotic process60.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [60]
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Song, M., Ma, S., Wang, G., Wang, Y., Yang, Z., Xie, B., Guo, T., Huang, X., & Zhang, L. (2025) · Briefings in Bioinformatics · doi:10.1093/bib/bbaf076 · Cited by 12 · see citing works
Convergent TP53 loss and evolvability in cancer
Mansur, M. B., & Greaves, M. F. (2023) · BMC Ecology and Evolution · doi:10.1186/s12862-023-02146-6 · Cited by 12 · see citing works
Reyes, J., Priore, I. S. D., Chaikovsky, A. C., Pasnuri, N., Elhossiny, A. M., Park, J., Weiler, P., Krause, T., Moorman, A. R., Snopkowski, C., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.032 · Cited by 11 · see citing works
Self-citationDiscovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53
Liu, Z., Yang, Y., Sun, X., Ma, R., Zhang, W., Wang, W., Yang, G., Wang, H., Zhang, J., Wang, Y., et al. (2024) · Molecules · doi:10.3390/molecules29030725 · Cited by 11 · see citing works
- Authors
- Baslan, T., Morris, J. P., Zhao, Z., Reyes, J., Ho, Y.-J., Tsanov, K. M., Bermeo, J., Tian, S., Zhang, S., Askan, G., Yavas, A., Lecomte, N., Erakky, A., Varghese, A. M., Zhang, A., Kendall, J., Ghiban, E., Chorbadjiev, L., Wu, J., Dimitrova, N., Chadalavada, K., Nanjangud, G. J., Bandlamudi, C., Gong, Y., Donoghue, M. T. A., Socci, N. D., Krasnitz, A., Notta, F., Leach, S. D., Iacobuzio-Donahue, C. A., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Ontario Institute for Cancer Research (CA)
- Cold Spring Harbor Laboratory (US)
- Technical University of Sofia (BG)
- Philips (United States) (US)
- Corresponding author
- Lowe, Scott W.
- ORCID
- Baslan, Timour
- Morris, John P.
- Zhao, Zhen
- Ho, Yu-Jui
- Tsanov, Kaloyan M.
- Bermeo, Jonathan
- Tian, Sha
- Zhang, Sean
- Yavas, Aslihan
- Lecomte, Nicolas
- Erakky, Amanda
- Varghese, Anna M.
- Zhang, Amy
- Wu, Jie
- Dimitrova, Nevenka
- Chadalavada, Kalyani
- Nanjangud, Gouri J.
- Bandlamudi, Chaitanya
- Gong, Yixiao
- Donoghue, Mark T. A.
- Socci, Nicholas D.
- Notta, Faiyaz
- Leach, Steve D.
- Iacobuzio-Donahue, Christine A.
- Lowe, Scott W.
- Venue
- Nature
- Published
- 2022-08-17
- Volume
- 608
- Issue
- 7924
- Pages
- 795-802
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9402436
- OpenAlex
- W4292122046
- Cited by
- 221
- References
- 73
- Citations by year
- 2026: 29 · 2025: 46 · 2024: 71 · 2023: 63 · 2022: 12
- FWCI
- 20.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute (P30 CA008748)
- Simons Foundation (519054)
- Damon Runyon Cancer Research Foundation (P30 CA008748)
- Pancreatic Cancer Action Network
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- Wellcome Trust
- Cold Spring Harbor Laboratory
- National Institutes of Health (CA008748, 5p30ca045508-35)
- Philips Research Americas
- National Cancer Institute (P01CA087497, CA008748, P30-CA045508, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- TP53 mutation, cancer genome evolution, pancreatic ductal adenocarcinoma, Trp53, genomic deletions, genome doubling, gene amplification, carcinogenesis, precancerous lesions, histological stage, single-cell genotyping, tumor heterogeneity
- MeSH terms
- Adenocarcinoma, Animals, Models, Genetic, Pancreatic Neoplasms, Genes, p53, Tumor Suppressor Protein p53, Genome, Gene Deletion, Disease Progression, Evolution, Molecular, Loss of Heterozygosity, Carcinoma, Pancreatic Ductal, Mice, Carcinogenesis
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