title: Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors.
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.
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Robbins
authors.forename: Waibov A
authors.initials: WA
authors.lastname: Tembe
authors.forename: Angela
authors.initials: A
authors.lastname: Baker
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.forename: Tracy Y
authors.initials: TY
authors.lastname: Moses
authors.forename: Stephen
authors.initials: S
authors.lastname: Beckstrom-Sternberg
authors.forename: James
authors.initials: J
authors.lastname: Beckstrom-Sternberg
authors.forename: Michael
authors.initials: M
authors.lastname: Barrett
authors.forename: James
authors.initials: J
authors.lastname: Long
authors.forename: Arul
authors.initials: A
authors.lastname: Chinnaiyan
authors.forename: James
authors.initials: J
authors.lastname: Lowey
authors.forename: Edward
authors.initials: E
authors.lastname: Suh
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
mesh_terms: D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005091:Exons / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm