A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
Open accessAbstract
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
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The disease progression model proposed based on observed co-mutation patterns was early KRAS mutation followed by CDKN2A then loss of TP53 and SMAD4.
“the disease progression model proposed based on observed co-mutation patterns was early KRAS mutation followed by CDKN2A then loss of TP53 and SMAD447,48”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [48]
Co-occurrence of other mutations was common in PDAC.
“Co-occurrence of other mutations were common in PDAC”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [48]
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- Authors
- Notta, F., Chan-Seng-Yue, M., Lemire, M., Li, Y., Wilson, G. W., Connor, A. A., Denroche, R. E., Liang, S.-B., Brown, A. M. K., Kim, J. C., Wang, T., Simpson, J. T., Beck, T., Borgida, A., Buchner, N., Chadwick, D., Hafezi-Bakhtiari, S., Dick, J. E., Heisler, L., Hollingsworth, M. A., Ibrahimov, E., Jang, G. H., Johns, J., Jorgensen, L. G. T., Law, C., Ludkovski, O., Lungu, I., Ng, K., Pasternack, D., Petersen, G. M., Shlush, L. I., Timms, L., Tsao, M.-S., Wilson, J. M., Yung, C. K., Zogopoulos, G., Bartlett, J. M. S., Alexandrov, L. B., Real, F. X., Cleary, S. P., Roehrl, M. H., McPherson, J. D., Stein, L. D., Hudson, T. J., Campbell, P. J., & Gallinger, S.
- Affiliations
- Ontario Institute for Cancer Research (CA)
- Wellcome Sanger Institute (GB)
- University Health Network (CA)
- University of Toronto (CA)
- Nebraska Medical Center (US)
- Sunnybrook Health Science Centre (CA)
- Mayo Clinic (US)
- Research Institute of the McGill University Health Centre (CA)
- Los Alamos National Laboratory (US)
- Spanish National Cancer Research Centre (ES)
- Mount Sinai Hospital (CA)
- University of Cambridge (GB)
- Corresponding author
- Notta, Faiyaz
- Hudson, Thomas J.
- ORCID
- Notta, Faiyaz
- Lemire, Mathieu
- Li, Yilong
- Wilson, Gavin W.
- Connor, Ashton A.
- Denroche, Robert E.
- Liang, Sheng-Ben
- Brown, Andrew M. K.
- Kim, Jaeseung C.
- Wang, Tao
- Simpson, Jared T.
- Borgida, Ayelet
- Dick, John E.
- Heisler, Lawrence
- Hollingsworth, Michael A.
- Jang, Gun Ho
- Law, Calvin
- Lungu, Ilinca
- Ng, Karen
- Petersen, Gloria M.
- Shlush, Liran I.
- Tsao, Ming-Sound
- Wilson, Julie M.
- Yung, Christina K.
- Zogopoulos, George
- Bartlett, John M. S.
- Alexandrov, Ludmil B.
- Real, Francisco X.
- Cleary, Sean P.
- Roehrl, Michael H.
- McPherson, John D.
- Stein, Lincoln D.
- Hudson, Thomas J.
- Campbell, Peter J.
- Venue
- Nature
- Published
- 2016-10-12
- Volume
- 538
- Issue
- 7625
- Pages
- 378-382
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5446075
- OpenAlex
- W2531887049
- Cited by
- 528
- References
- 30
- Citations by year
- 2026: 26 · 2025: 43 · 2024: 37 · 2023: 42 · 2022: 38 · 2021: 66 · 2020: 77 · 2019: 57 · 2018: 77 · 2017: 59 · 2016: 5 · 2015: 1
- FWCI
- 27.48
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-11-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (103858/Z/14/Z)
- Hebrew University of Jerusalem
- Hospital for Sick Children
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- Ontario Ministry of Research and Innovation
- National Cancer Institute (CA102701, P50CA102701, R01CA097075, P30CA008748, P30CA015083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- tumor evolution, chromothripsis, complex genomic rearrangements, punctuated equilibrium, carcinogenesis, pancreatic intraepithelial neoplasia, DNA copy number alterations, metastatic pancreatic cancer, KRAS, CDKN2A, TP53, SMAD4, mitotic errors, tumor progression, clonal evolution, tumor heterogeneity, tumor suppressor
- MeSH terms
- Chromothripsis, Carcinoma in Situ, Female, Humans, Male, Mitosis, Models, Biological, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Pancreatic Neoplasms, Polyploidy, Precancerous Conditions, Gene Rearrangement, Genome, Human, Mutagenesis, Disease Progression, Evolution, Molecular, Genes, Neoplasm, DNA Copy Number Variations, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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