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Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Open accessAbstract
Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
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“modeling studies performed on the mutational data have estimated that the timeline of multistep progression to invasive neoplasia in the pancreas likely spans multiple years and provides a theoretically wide window of opportunity for early detection27.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [27]
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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 [67]
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“It is now appreciated that most clinically relevant solid tumors are highly heterogeneous at the phenotypic, physiologic, and genomic levels (13–15) and that they continue to evolve over time.”
From Radiomics: Images Are More than Pictures, They Are Data (2016) · cites this paper as [13]
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Single-Cell Exome Sequencing and Monoclonal Evolution of a JAK2-Negative Myeloproliferative Neoplasm
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Mechanisms Governing Metastatic Dormancy and Reactivation
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Metadata
- Authors
- Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., Kamiyama, M., Hruban, R. H., Eshleman, J. R., Nowak, M. A., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., & Iacobuzio-Donahue, C. A.
- Affiliations
- Johns Hopkins University (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- ORCID
- Venue
- Nature
- Published
- 2010-10
- Volume
- 467
- Issue
- 7319
- Pages
- 1114-1117
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3148940
- OpenAlex
- W2169895148
- Cited by
- 2,502
- References
- 24
- Citations by year
- 2026: 73 · 2025: 84 · 2024: 76 · 2023: 105 · 2022: 122 · 2021: 165 · 2020: 157 · 2019: 147 · 2018: 176 · 2017: 218 · 2016: 208 · 2015: 237 · 2014: 224 · 2013: 182 · 2012: 197
- FWCI
- 50.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01ca121113-15)
- U.S. Public Health Service (A62924)
- National Cancer Institute (R01CA140599, CA 57345, R01-CA121113, CA-121113, CA43460, K08CA106610, R37CA043460, R01CA057345, CA106610, P50CA062924, R37CA057345)
- National Institute of General Medical Sciences (R01GM078986, GM078986)
- 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, distant metastasis, clonal evolution, tumor subclones, chromosomal rearrangements, genomic instability, early detection, tumor heterogeneity, therapeutic target
- MeSH terms
- Adenocarcinoma, Autopsy, Clone Cells, DNA Mutational Analysis, Humans, Liver Neoplasms, Lung Neoplasms, Models, Biological, Mutation, Neoplasm Metastasis, Pancreas, Pancreatic Neoplasms, Peritoneal Neoplasms, Time Factors, Disease Progression, Cell Lineage, Evolution, Molecular, Early Detection of Cancer
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