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Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer
- Source :
- Asian Journal of Andrology, Genome Biology
- Publication Year :
- 2014
-
Abstract
- Background 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, 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. Results Ten 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. Conclusions The 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 material The online version of this article (doi:10.1186/s13059-014-0426-y) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Invited Research Highlight
Antineoplastic Agents, Hormonal
Oncogene Proteins, Fusion
Biology
Genome
Transcriptome
Prostate cancer
Genetic Heterogeneity
medicine
Humans
Genetics
Proto-Oncogene Proteins c-ets
Genetic heterogeneity
Sequence Analysis, RNA
Research
Gene Expression Profiling
Genetic Variation
High-Throughput Nucleotide Sequencing
Prostatic Neoplasms
Chromoplexy
medicine.disease
Phenotype
Human genetics
3. Good health
Gene Expression Regulation, Neoplastic
Fusion transcript
Chemotherapy, Adjuvant
Drug Resistance, Neoplasm
Cancer research
Subjects
Details
- ISSN :
- 1474760X
- Volume :
- 15
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Genome biology
- Accession number :
- edsair.doi.dedup.....110f38b6f6b79c429fbe153458027218