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Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer

Nature Medicine volume 15, pages 559–565 (2009)Cite this article

An Erratum to this article was published on 01 July 2009

This article has been updated

Abstract

Many studies have shown that primary prostate cancers are multifocal1,2,3 and are composed of multiple genetically distinct cancer cell clones4,5,6. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis7 and recent single-locus genetic data in prostate and other metastatic cancers8,9,10, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.

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Figure 1: DNA copy number changes in mulitple anatomically separate prostate cancer samples from JHASPC subjects cluster together by subject.
Figure 2: Allele-specific DNA copy number analysis in JHASPC subject 17 reveals clonal and subclonal changes.
Figure 3: Allele-specific DNA copy number analysis in JHASPC subject 34 reveals clonal and subclonal changes.
Figure 4: Potential patterns of metastatic prostate cancer spread.

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Gene Expression Omnibus

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  • 07 July 2009

    In the version of this article initially published, some of the sample identifiers were missing from Figure 1e. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the participating men and their families who suffered through metastatic prostate cancer and nonetheless gave the gift of participation so that others might benefit. We also thank V. Sinibaldi, T.B. Smyth and G.J. Mamo for oncologic and urologic clinical support, the Johns Hopkins Pathology Autopsy Service, including B. Crain and G. Hutchins, and A. Alkula, S. Kuivanen, T. Vilkkilä-Qwick, M. Vakkuri, D. Jay, X. Yi, S. H. Hahm, K. Jeffers Keiger, S. H. Chen, P. Powers, M. Taylor, C. Kang and Partek Customer Support for technical assistance. This work, commenced in 1994, was supported in part by Pirkanmaa Cancer Foundation, Maud Kuistila Foundation, Finnish Medical Foundation, the Medical Research Fund of Tampere University Hospital, Academy of Finland, Cancer Society of Finland, Reino Lahtikari Foundation, Sigrid Juselius Foundation, CaPCURE Foundation, John and Kathe Dyson, David Koch, the US National Institutes of Health National Cancer Institute (CA92234), the Prostate Cancer Research and Education Foundation, the US Department of Defense Congressionally Directed Prostate Cancer Research Program, the Grove Foundation and the American Cancer Society.

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Author notes

  1. Wennuan Liu and Sari Laitinen: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

    Wennuan Liu & Jianfeng Xu

  2. Laboratory of Cancer Genetics Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

    Sari Laitinen & Tapio Visakorpi

  3. Laboratory of Bioinformatics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

    Sofia Khan & Mauno Vihinen

  4. Department of Oncology Biostatistics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Jeanne Kowalski

  5. Department of Electrical and Computer Engineering, Computational Bioinformatics and Bio-imaging Laboratory, Virginia Polytechnic Institute and State University, Arlington, Virginia, USA

    Guoqiang Yu, Li Chen & Yue Wang

  6. Department of Urology Genetic Medicine and Health Sciences Informatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Charles M Ewing, Jun Luo, William B Isaacs & G Steven Bova

  7. Department of Oncology, Genetic Medicine and Health Sciences Informatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Mario A Eisenberger, Michael A Carducci, William G Nelson, Srinivasan Yegnasubramanian, Jun Luo, William B Isaacs & G Steven Bova

  8. Departments of Pathology, Project to Eliminate Lethal Prostate Cancer Laboratory, Genetic Medicine and Health Sciences Informatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    G Steven Bova

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  1. Wennuan Liu
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Contributions

W.L. performed and analyzed Affy6 assays and contributed to the manuscript and direction of study; S.L. performed and analyzed cCGH assays and contributed to the manuscript; S.K. performed statistical analysis of cCGH data and contributed to the manuscript; M.V. supervised statistical analysis of cCGH data and contributed to the manuscript; J.K. supervised and directed statistical analysis of cCGH and Affy6 data and contributed to the manuscript; G.Y. and L.C. performed statistical analysis of cCGH and Affy6 data and contributed to the manuscript; C.M.E. performed TMPRSS2-ERG transcript assays and contributed to the manuscript; M.A.E. and M.A.C. provided clinical support for the study; W.G.N. contributed to the manuscript and the analysis of chemotherapy data; S.Y. contributed to the manuscript and the direction of the study; J.L. contributed to the TMPRSS2-ERG transcript analysis and contributed to the manuscript; Y.W. supervised and directed cCGH and Affy6 data analysis and contributed to the manuscript; J.X. supervised Affy6 data collection and analysis and contributed to the direction of the study; W.B.I. supervised TMPRSS2-ERG transcript analysis and contributed to the manuscript and the direction of the study; T.V. supervised and interpreted cCGH data collection and contributed to the manuscript and the direction of the study; and G.S.B. founded and directed the autopsy project, directed the study, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to G Steven Bova.

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Supplementary Figs. 1–14, Supplementary Tables 1–11 and Supplementary Methods (PDF 902 kb)

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Liu, W., Laitinen, S., Khan, S. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 15, 559–565 (2009). https://doi.org/10.1038/nm.1944

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