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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Gene Expression Omnibus
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.
Supplementary Figs. 1–14, Supplementary Tables 1–11 and Supplementary Methods