Somatic Alterations Contributing to Metastasis of a Castration-Resistant Prostate Cancer

Authors

  • Michael L. Nickerson,

    Corresponding author
    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
    • Correspondence to: Michael L. Nickerson, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-21, Frederick, Maryland 21702. E-mail: nickersonml@mail.nih.gov; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: deanm@mail.nih.gov

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  • Kate M. Im,

    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • Kevin J. Misner,

    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
    Current affiliation:
    1. ImmunArray, Inc., Richmond, VA
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  • Wei Tan,

    1. Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • Hong Lou,

    1. Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • Bert Gold,

    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • David W. Wells,

    1. Genetics Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • Hector C. Bravo,

    1. Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, Maryland
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  • Karin M. Fredrikson,

    1. Roche Diagnostics Corporation, Indianapolis, Indiana
    Current affiliation:
    1. Life Technologies, Advanced Applications Group, Beverly, MA
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  • Timothy T. Harkins,

    1. Roche Diagnostics Corporation, Indianapolis, Indiana
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  • Patrice Milos,

    1. Helicos BioSciences Corporation, Cambridge, Massachusetts
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  • Berton Zbar,

    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • W. Marston Linehan,

    1. Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Meredith Yeager,

    1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Thorkell Andresson,

    1. Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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  • Michael Dean,

    Corresponding author
    1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
    • Correspondence to: Michael L. Nickerson, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-21, Frederick, Maryland 21702. E-mail: nickersonml@mail.nih.gov; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: deanm@mail.nih.gov

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  • G. Steven Bova

    1. Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
    2. Institute of Biomedical Technology, University of Tampere, Tampere, Finland
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  • Contract grant sponsors: NIH; The National Cancer Institute Center for Cancer Research; National Institutes of Health funding (CA92234, HHSN26120080001E); John and Kathe Dyson; The American Cancer Society; and the Association for the Cure of Cancer of the Prostate.

  • Communicated by Bruce R. Gottlieb

ABSTRACT

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease, and molecular markers that differentiate indolent from aggressive subtypes are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index case with mCRPC to identify lesions associated with disease progression and metastasis. An Ashkenazi Jewish (AJ) germline founder mutation, del185AG in BRCA1, was observed and AJ ancestry was confirmed. Sixty-two somatic variants altered proteins in tumors, including cancer-associated genes, TMPRSS2-ERG, PBRM1, and TET2. The majority (n = 53) of somatic variants were present in all metastases and only a subset (n = 31) was observed in the primary tumor. Integrating tumor next-generation sequencing and DNA copy number showed somatic loss of BRCA1 and TMPRSS2-ERG. We sequenced 19 genes with deleterious mutations in the index case in additional mCRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNPs in TET2. In summary, genetic analysis of metastases from an index case permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of somatic lesions. The role of TET2 in mCRPC deserves additional analysis and may define a subset of metastatic disease.

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