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The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Open accessAbstract
Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.
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“Pancreatic tumours are highly heterogeneous, both within and between individuals.66,67”
From Early detection of pancreatic cancer (2020) · cites this paper as [66]
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Metadata
- Authors
- Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A., Morsberger, L. A., Latimer, C., McLaren, S., Lin, M.-L., McBride, D. J., Varela, I., Nik-Zainal, S. A., Leroy, C., Jia, M., Menzies, A., Butler, A. P., Teague, J. W., Griffin, C. A., Burton, J., Swerdlow, H., Quail, M. A., Stratton, M. R., Iacobuzio-Donahue, C., & Futreal, P. A.
- Affiliations
- University of Cambridge (GB)
- Johns Hopkins University (US)
- Wellcome Sanger Institute (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Futreal, P. Andrew
- ORCID
- Venue
- Nature
- Published
- 2010-10
- Volume
- 467
- Issue
- 7319
- Pages
- 1109-1113
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3137369
- OpenAlex
- W2066254965
- Cited by
- 1,317
- References
- 30
- Citations by year
- 2026: 10 · 2025: 31 · 2024: 33 · 2023: 51 · 2022: 47 · 2021: 86 · 2020: 69 · 2019: 72 · 2018: 75 · 2017: 117 · 2016: 104 · 2015: 119 · 2014: 153 · 2013: 109 · 2012: 135
- FWCI
- 34.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Skip Viragh Foundation
- Uehara Memorial Foundation
- Wellcome Trust (077012/Z/05/Z, 088340, 093867, WT088340MA)
- National Institutes of Health
- National Cancer Institute (R01CA140599, K08CA106610, CA140599, CA106610)
- 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
- pancreatic cancer, metastasis, genomic instability, chromosomal rearrangements, clonal evolution, telomere dysfunction, G1/S checkpoint, copy number alterations, tumor progression, early detection, therapeutic target, interpatient heterogeneity, tumour dissemination, somatic mutations, GATA4, GATA3
- MeSH terms
- Adenocarcinoma, Cell Cycle, Clone Cells, DNA Mutational Analysis, Humans, Liver Neoplasms, Lung Neoplasms, Neoplasm Metastasis, Organ Specificity, Pancreatic Neoplasms, Mutagenesis, Telomere, Disease Progression, Cell Lineage, Evolution, Molecular, Genomic Instability, Genes, Neoplasm
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