Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers
Open accessAbstract
Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development.
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TP53 mutational inactivation is a clonal and predominantly early event in established NSCLC that precedes genome doubling and subsequent branched evolution.
“This notion is further supported by identification of TP53 mutational inactivation as a clonal and predominantly early event in established NSCLC that precedes genome doubling and subsequent branched evolution74, 103.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [103]
Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%-12.5% of EGFR-mutant LUAD.
“Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%−12.5% of EGFR-mutant LUAD72, 73, 103, 117.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [103]
TP53 co-mutations impact the natural history of EGFR-mutant NSCLC at least partially by allowing tolerance of a greater degree of genomic instability that results in larger numbers of co-occurring truncal drivers and late sub-clonal diversification with focal emergence of high amplitude amplifications and deletions in mediators of therapeutic resistance.
“Therefore, TP53 co-mutations impact the natural history of EGFR-mutant NSCLC at least partially by allowing tolerance of a greater degree of genomic instability that results in both larger numbers of co-occurring truncal drivers as well as late sub-clonal diversification with focal emergence of high amplitude amplifications and deletions in mediators of therapeutic resistance103.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [103]
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Self-citation
- Authors
- Muzumdar, M. D., Dorans, K. J., Chung, K. M., Robbins, R., Tammela, T., Gocheva, V., Li, C. M.-C., & Jacks, T.
- Affiliations
- Harvard University (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- Venue
- Nature Communications
- Published
- 2016-09-02
- Volume
- 7
- Issue
- 1
- Pages
- 12685-12685
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5025814
- OpenAlex
- W2516559527
- Cited by
- 72
- References
- 44
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 9 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 8
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by)
- Nature
- Funders
- Howard Hughes Medical Institute
- Harvard University (KL2 TR001100)
- Harvard Catalyst (KL2 TR001100, TR001100)
- National Institutes of Health (KL2TR001100)
- Ludwig Center at Harvard
- National Cancer Institute (CA14051, P30CA014051, P30-CA-14051)
- National Center for Research Resources
- National Center for Advancing Translational Sciences (TR001100)
- 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 › Cancer Cells and Metastasis
- Keywords
- p53, loss of heterozygosity, clonal dynamics, lung adenocarcinoma, pancreatic intraepithelial neoplasia, subclonal evolution, p19ARF, tumor progression, tumor heterogeneity, lineage tracing
- MeSH terms
- Adenocarcinoma, Animals, Lung Neoplasms, Mice, Transgenic, Pancreatic Neoplasms, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Disease Progression, Cyclin-Dependent Kinase Inhibitor p16, Carcinoma, Pancreatic Ductal, Cell Proliferation, Mice, Carcinogenesis
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