Cited by 1,317Cancer Genomics and DiagnosticsPancreatic and Hepatic Oncology ResearchChromatin Remodeling and Cancer

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The patterns and dynamics of genomic instability in metastatic pancreatic cancer

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Campbell, Peter J., Yachida, Shinichi, Mudie, Laura J., Stephens, Philip J., Pleasance, Erin D., Stebbings, Lucy A., Morsberger, Laura A., Latimer, Calli, McLaren, Stuart, Lin, Meng-Lay, McBride, David J., Varela, Ignacio, Nik-Zainal, Serena A., Leroy, Catherine, Jia, Mingming, Menzies, Andrew, Butler, Adam P., Teague, Jon W., Griffin, Constance A., Burton, John, Swerdlow, Harold, Quail, Michael A., Stratton, Michael R., Iacobuzio-Donahue, Christine, Futreal, P. Andrew·2010·Nature

DOI 10.1038/nature09460PMC PMC3137369

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Abstract

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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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: Campbell, Peter J.
Yachida, Shinichi
Pleasance, Erin D.
Latimer, Calli
McLaren, Stuart
McBride, David J.
Varela, Ignacio
Jia, Mingming
Menzies, Andrew
Teague, Jon W.
Swerdlow, Harold
Quail, Michael A.
Stratton, Michael R.
Futreal, P. Andrew
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2010-10
Volume: 467
Issue: 7319
Pages: 1109-1113
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09460
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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The patterns and dynamics of genomic instability in metastatic pancreatic cancer

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