Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors

  • Robbins C
  • Tembe W
  • Baker A
 et al. 
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Abstract

Advanced prostate cancer can progress to systemic metastatic tumors, which are generally androgen insensitive and ultimately lethal. Here, we report a comprehensive genomic survey for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancer-related genes using next generation sequencing. Focal homozygous deletions were detected at 8p22, 10q23.31, 13q13.1, 13q14.11, and 13q14.12. Key genes mapping within these deleted regions include PTEN, BRCA2, C13ORF15, and SIAH3. Focal high-level amplifications were detected at 5p13.2-p12, 14q21.1, 7q22.1, and Xq12. Key amplified genes mapping within these regions include SKP2, FOXA1, and AR. Furthermore, targeted mutational analysis of normal-tumor pairs has identified somatic mutations in genes known to be associated with prostate cancer including AR and TP53, but has also revealed novel somatic point mutations in genes including MTOR, BRCA2, ARHGEF12, and CHD5. Finally, in one patient where multiple independent metastatic tumors were available, we show common and divergent somatic alterations that occur at both the copy number and point mutation level, supporting a model for a common clonal progenitor with metastatic tumor-specific divergence. Our study represents a deep genomic analysis of advanced metastatic prostate tumors and has revealed candidate somatic alterations, possibly contributing to lethal prostate cancer. [Supplemental material is available for this article. The array CGH data from this study have been submitted to NCI's caArray (https://array.nci.nih.gov/caarray) under experiment ID carpt-00469. The sequencing data from this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/Traces/sra/sra.cgi) under accession no. SRP003897 and will be available in dbGaP.] Prostate cancer still remains the most common male-specific ma-lignancy diagnosed in the United States. In 2009 there were an es-timated 192,280 newly diagnosed cases of prostate cancer with 27,360 deaths attributed to this disease (Jemal et al. 2009). Although we have seen slight decreases in incidence rates, primarily due to new methods in estimating new cancer cases by the American Cancer Society, death rates have remained fairly constant between 2007 (27,050) and 2009 (27,360) (Jemal et al. 2007, 2008, 2009). In most cases, these deaths are associated with androgen-insensi-tive systemic metastatic prostate disease. In light of this incredible clinical problem, there is a growing need to understand the mo-lecular makeup of these lethal tumors. In order to uncover the ge-nomic characteristics of systemic lethal metastatic prostate tumors,

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Authors

  • Christiane M Robbins

  • Waibov A Tembe

  • Angela Baker

  • Shripad Sinari

  • Tracy Y Moses

  • Stephen Beckstrom-Sternberg

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