Somatic Alterations Contributing to Metastasis of a Castration-Resistant Prostate Cancer
Corresponding Author
Michael L. Nickerson
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: [email protected]; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: [email protected]Search for more papers by this authorKate M. Im
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorKevin J. Misner
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorWei Tan
Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorHong Lou
Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorBert Gold
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorDavid W. Wells
Genetics Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorHector C. Bravo
Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, Maryland
Search for more papers by this authorKarin M. Fredrikson
Roche Diagnostics Corporation, Indianapolis, Indiana
Search for more papers by this authorTimothy T. Harkins
Roche Diagnostics Corporation, Indianapolis, Indiana
Search for more papers by this authorPatrice Milos
Helicos BioSciences Corporation, Cambridge, Massachusetts
Search for more papers by this authorBerton Zbar
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorW. Marston Linehan
Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Search for more papers by this authorMeredith Yeager
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Search for more papers by this authorThorkell Andresson
Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorCorresponding Author
Michael Dean
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: [email protected]; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: [email protected]Search for more papers by this authorG. Steven Bova
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
Institute of Biomedical Technology, University of Tampere, Tampere, Finland
Search for more papers by this authorCorresponding Author
Michael L. Nickerson
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: [email protected]; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: [email protected]Search for more papers by this authorKate M. Im
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorKevin J. Misner
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorWei Tan
Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorHong Lou
Basic Science Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorBert Gold
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorDavid W. Wells
Genetics Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorHector C. Bravo
Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, Maryland
Search for more papers by this authorKarin M. Fredrikson
Roche Diagnostics Corporation, Indianapolis, Indiana
Search for more papers by this authorTimothy T. Harkins
Roche Diagnostics Corporation, Indianapolis, Indiana
Search for more papers by this authorPatrice Milos
Helicos BioSciences Corporation, Cambridge, Massachusetts
Search for more papers by this authorBerton Zbar
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorW. Marston Linehan
Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Search for more papers by this authorMeredith Yeager
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Search for more papers by this authorThorkell Andresson
Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland
Search for more papers by this authorCorresponding Author
Michael Dean
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: [email protected]; or Michael Dean, Cancer and Inflammation Program, National Cancer Institute, Building #560, Room #21-89B, Frederick, Maryland 21702. E-mail: [email protected]Search for more papers by this authorG. Steven Bova
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
Institute of Biomedical Technology, University of Tampere, Tampere, Finland
Search for more papers by this authorContract 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.
Supporting Information
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