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.

Figure 1.

Circos plot illustrating copy number alterations and genes affected by somatic mutation. Regions affected by focal copy number events are plotted within the gray inner circle with deleted regions deviating below copy neutrality (toward center) and amplified regions deviating above copy neutrality. Key genes mapping within copy number alterations are annotated within the innermost portion of the plot. Genes affected by somatic nonsysnonymous mutation are shown at their proper map positions on the outermost area of the Circos plot.

Figure 2.

Illustration of high-level amplification at 5p13.2 in tumors from patient RA45. (A) Chromosome view in Agilent DNA Analytics software showing log₂ ratios for probes mapping along chromosome 5 for RA45M (left), RA45RM (middle), and RA45AT (right). Amplicon at 5p13.2 is depicted by the arrow. (B) Gene view in DNA Analytics showing log₂ ratios for probes mapping to 5p13.2 for RA45M (left), RA45RM (middle), and RA45AT (right). Arrow points to map position of the SKP2 gene locus.