The patterns and dynamics of genomic instability in metastatic pancreatic cancer (original) (raw)

Accession codes

Data deposits

Genome sequence data have been deposited at the European Genome-Phenome Archive (EGA, http://www.ebi.ac.uk/ega/), which is hosted by the European Bioinformatics Institute (EBI), under accession number EGAS00000000064.

References

1. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)
   Article ADS CAS Google Scholar
2. Harada, T. et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27, 1951–1960 (2008)
   Article CAS Google Scholar
3. Fu, B., Luo, M., Lakkur, S., Lucito, R. & Iacobuzio-Donahue, C. A. Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma. Cancer Biol. Ther. 7, 1593–1601 (2008)
   Article CAS Google Scholar
4. Kimmelman, A. C. et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc. Natl Acad. Sci. USA 105, 19372–19377 (2008)
   Article ADS CAS Google Scholar
5. Gisselsson, D. et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA 98, 12683–12688 (2001)
   Article ADS CAS Google Scholar
6. Klein, C. A. Parallel progression of primary tumours and metastases. Nature Rev. Cancer 9, 302–312 (2009)
   Article CAS Google Scholar
7. Kuukasjarvi, T. et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res. 57, 1597–1604 (1997)
   CAS PubMed Google Scholar
8. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010)
   Article ADS CAS Google Scholar
9. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009)
   Article CAS Google Scholar
10. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010)
    Article ADS CAS Google Scholar
11. Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010)
    Article ADS CAS Google Scholar
12. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009)
    Article ADS CAS Google Scholar
13. Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008)
    Article CAS Google Scholar
14. Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009)
    Article ADS CAS Google Scholar
15. McLintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 (1941)
    Google Scholar
16. Bignell, G. R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007)
    Article CAS Google Scholar
17. O’Hagan, R. C. et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2, 149–155 (2002)
    Article Google Scholar
18. Bardeesy, N. & DePinho, R. A. Pancreatic cancer biology and genetics. Nature Rev. Cancer 2, 897–909 (2002)
    Article CAS Google Scholar
19. Maser, R. S. et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447, 966–971 (2007)
    Article ADS CAS Google Scholar
20. Sahin, E. & Depinho, R. A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010)
    Article ADS CAS Google Scholar
21. Blow, J. J. & Gillespie, P. J. Replication licensing and cancer—a fatal entanglement? Nature Rev. Cancer 8, 799–806 (2008)
    Article CAS Google Scholar
22. Hashimoto, Y., Murakami, Y. & Uemura, K. et al. Telomere shortening and telomerase expression during multistage carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. J. Gastrointest. Surg. 12, 17–29 (2008)
    Article Google Scholar
23. Campbell, P. J. et al. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc. Natl Acad. Sci. USA 105, 13081–13086 (2008)
    Article ADS CAS Google Scholar
24. Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature Med. 15, 559–565 (2009)
    Article CAS Google Scholar
25. Nguyen, D. X. & Massague, J. Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007)
    Article CAS Google Scholar
26. Klein, C. A. et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360, 683–689 (2002)
    Article CAS Google Scholar
27. Embuscado, E. E. et al. Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy. Cancer Biol. Ther. 4, 548–554 (2005)
    Article CAS Google Scholar
28. Quail, M. A. et al. A large genome center’s improvements to the Illumina sequencing system. Nature Methods 5, 1005–1010 (2008)
    Article ADS CAS Google Scholar
29. Li, H., Ruan, J. & Durbin, R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 18, 1851–1858 (2008)
    Article CAS Google Scholar
30. Flohr, T. et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 22, 771–782 (2008)
    Article CAS Google Scholar

Download references

Acknowledgements

This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. is funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). S.Y. has support from the Uehara memorial foundation. We would also like to acknowledge the financial support of the Skip Viragh Foundation and the Michael Rolphe Foundation for the autopsy programme, and funding from the National Institutes of Health (grants CA106610 and CA140599). I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. We would like to thank U. McDermott for discussions and a critical reading of the manuscript.

Author information

Author notes

1. Peter J. Campbell and Shinichi Yachida: These authors contributed equally to this work.

Authors and Affiliations

1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK,
   Peter J. Campbell, Laura J. Mudie, Philip J. Stephens, Erin D. Pleasance, Lucy A. Stebbings, Calli Latimer, Stuart McLaren, Meng-Lay Lin, David J. McBride, Ignacio Varela, Serena A. Nik-Zainal, Catherine Leroy, Mingming Jia, Andrew Menzies, Adam P. Butler, Jon W. Teague, John Burton, Harold Swerdlow, Michael A. Quail, Michael R. Stratton & P. Andrew Futreal
2. Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK,
   Peter J. Campbell
3. Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, USA
   Shinichi Yachida, Laura A. Morsberger, Constance A. Griffin & Christine Iacobuzio-Donahue
4. Institute for Cancer Research, Sutton, Surrey SM2 5NG, UK,
   Michael R. Stratton

Authors

1. Peter J. Campbell
   You can also search for this author inPubMed Google Scholar
2. Shinichi Yachida
   You can also search for this author inPubMed Google Scholar
3. Laura J. Mudie
   You can also search for this author inPubMed Google Scholar
4. Philip J. Stephens
   You can also search for this author inPubMed Google Scholar
5. Erin D. Pleasance
   You can also search for this author inPubMed Google Scholar
6. Lucy A. Stebbings
   You can also search for this author inPubMed Google Scholar
7. Laura A. Morsberger
   You can also search for this author inPubMed Google Scholar
8. Calli Latimer
   You can also search for this author inPubMed Google Scholar
9. Stuart McLaren
   You can also search for this author inPubMed Google Scholar
10. Meng-Lay Lin
    You can also search for this author inPubMed Google Scholar
11. David J. McBride
    You can also search for this author inPubMed Google Scholar
12. Ignacio Varela
    You can also search for this author inPubMed Google Scholar
13. Serena A. Nik-Zainal
    You can also search for this author inPubMed Google Scholar
14. Catherine Leroy
    You can also search for this author inPubMed Google Scholar
15. Mingming Jia
    You can also search for this author inPubMed Google Scholar
16. Andrew Menzies
    You can also search for this author inPubMed Google Scholar
17. Adam P. Butler
    You can also search for this author inPubMed Google Scholar
18. Jon W. Teague
    You can also search for this author inPubMed Google Scholar
19. Constance A. Griffin
    You can also search for this author inPubMed Google Scholar
20. John Burton
    You can also search for this author inPubMed Google Scholar
21. Harold Swerdlow
    You can also search for this author inPubMed Google Scholar
22. Michael A. Quail
    You can also search for this author inPubMed Google Scholar
23. Michael R. Stratton
    You can also search for this author inPubMed Google Scholar
24. Christine Iacobuzio-Donahue
    You can also search for this author inPubMed Google Scholar
25. P. Andrew Futreal
    You can also search for this author inPubMed Google Scholar

Contributions

P.J.C. undertook the analysis of the sequencing data assisted by P.J.S., E.D.P., L.A.S., M.-L.L., D.J.M., I.V., S.A.N.-Z., C.L., M.J., A.M., A.P.B. and J.W.T. Sample collection, processing, establishment of cell lines, DNA extraction and cytogenetic studies were performed by S.Y., L.A.M., C.A.G. and C.I.-D. PCR genotyping, capillary sequencing and downstream validation studies were performed by L.J.M. with assistance from C.L. and S.M. J.B., H.S. and M.A.Q. were responsible for generating libraries and running sequencers. P.J.C., S.Y., M.R.S., C.I.-D. and P.A.F. directed the research and wrote the manuscript, which all authors have approved.

Corresponding authors

Correspondence toChristine Iacobuzio-Donahue or P. Andrew Futreal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Results comprising Effects of rearrangements on protein-coding genes, Fold-back inversions, Patterns and dynamics of genomic amplification and Signatures of DNA repair, Supplementary References, Supplementary Figures 1-11 with legends and Supplementary Tables 4 and 5 (see separate files for Supplementary Tables 1-3 and 6-7). (PDF 1706 kb)

Supplementary Table 1

This table shows clinical and pathology characteristics of patients and samples studied by massively parallel, paired-end sequencing. (XLS 19 kb)

Supplementary Table 2

This table shows somatically acquired genomic rearrangements in 13 patients with pancreatic cancer. All structural variants have been confirmed by PCR across the breakpoint, with bidirectional sequencing confirming the segments involved. Most have had the breakpoint annotated to base-pair resolution (‘Seq’ in the Evidence column): for the others, we provide a range of genomic positions encompassing the breakpoints (‘PCR across bkpt’). Length and sequence of either microhomology or non-templated sequence at the junction are shown. (XLS 107 kb)

Supplementary Table 3

This table shows the germline genomic rearrangements in 13 patients with pancreatic cancer. All structural variants have been confirmed by PCR across the breakpoint, with bidirectional sequencing confirming the segments involved. Length and sequence of either microhomology or non templated sequence at the junction are shown. (XLS 53 kb)

Supplementary Table 6

The table shows the genes involved at both breakpoints for each of the somatically acquired genomic rearrangements. (XLS 129 kb)

Supplementary Table 7

This table shows the presence or absence of each somatically acquired genomic rearrangement across the available metastasis and primary tumour samples for 10 patients (1 = present by PCR; 0 = absent by PCR). (XLS 87 kb)

PowerPoint slides

Rights and permissions

About this article

Cite this article

Campbell, P., Yachida, S., Mudie, L. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature 467, 1109–1113 (2010). https://doi.org/10.1038/nature09460

Download citation

• Received: 07 May 2010
• Accepted: 24 August 2010
• Published: 27 October 2010
• Issue Date: 28 October 2010
• DOI: https://doi.org/10.1038/nature09460