Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer
Open accessAbstract
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.
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Artifacts can be identified by their presence in a large number of unrelated datasets, after excluding the possibility that they represent true recurrent fusions.
“When control datasets are not available, artifacts can be identified by their presence in a large number of unrelated datasets, after excluding the possibility that they represent true recurrent fusions [90, 91].”
From A survey of best practices for RNA-seq data analysis (2016) · cites this paper as [90]
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- Authors
- Wyatt, A. W., Mo, F., Wang, K., McConeghy, B., Brahmbhatt, S., Jong, L., Mitchell, D. M., Johnston, R. L., Haegert, A., Li, E., Liew, J., Yeung, J., Shrestha, R., Lapuk, A. V., McPherson, A., Shukin, R., Bell, R. H., Anderson, S., Bishop, J., Hurtado-Coll, A., Xiao, H., Chinnaiyan, A. M., Mehra, R., Lin, D., Wang, Y., Fazli, L., Gleave, M. E., Volik, S. V., & Collins, C. C.
- Affiliations
- University of British Columbia (CA)
- Michigan Center for Translational Pathology (US)
- BC Cancer Agency (CA)
- Corresponding author
- Collins, Colin C
- ORCID
- Venue
- Genome Biology
- Published
- 2014-08-26
- Volume
- 15
- Issue
- 8
- Pages
- 426-426
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC4169643
- OpenAlex
- W2109103692
- Cited by
- 82
- References
- 61
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 10 · 2017: 16 · 2016: 10 · 2015: 9 · 2014: 4
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- cIRcle (University of British Columbia) (submittedVersion, cc-by)
- Funders
- Prostate Cancer Foundation
- Prostate Cancer Canada
- Canadian Institutes of Health Research
- National Cancer Institute (U01CA157703)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- high-risk prostate cancer, intertumoral heterogeneity, transcriptome, hormone resistance, neuroendocrine transdifferentiation, genome rearrangement, tandem duplication, tumor stratification, translational regulation, immune regulation, cell cycle progression, precision oncology
- MeSH terms
- Humans, Male, Phenotype, Prostatic Neoplasms, Genetic Variation, Oncogene Proteins, Fusion, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Sequence Analysis, RNA, Genetic Heterogeneity, Antineoplastic Agents, Hormonal, Drug Resistance, Neoplasm, Gene Expression Profiling, Proto-Oncogene Proteins c-ets, High-Throughput Nucleotide Sequencing
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