Abstract
BackgroundGenomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization.ResultsTen tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype.ConclusionsThe multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0426-y) contains supplementary material, which is available to authorized users.
Highlights
Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, at the individual tumor level
Ten tumors were exposed to neo-adjuvant hormone therapy (NHT) for 1 to 9 months, and global transcript profiling demonstrated a marked split between these samples and the untreated tumors (Figure 1B; Additional file 1: Table S4; Additional file 2: Figure S1)
Downregulated genes in NHT tumours (DESeq comparison; Benjamini-Hochberg P
Summary
Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, at the individual tumor level. The glut of genomic and epigenomic aberrations accrued during progression continue to converge on characteristic ‘prostate cancer pathways’ with scant regard to molecular subtype: leading to a highly heterogeneous transcriptomic landscape, centered on an overactive androgen receptor (AR) signaling axis. This heterogeneity confounds attempts to advance beyond clinically-based nomograms for patient prognostication and to accurately stratify tumors for precision medicine. Since driver mechanisms within individual prostate tumors are highly diverse (as evidenced by lack of highly recurrent mutations), specific events are in many tumors likely to be unique
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