1. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer.
- Author
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Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, Mo F, Zoubeidi A, Anderson S, Bell RH, Haegert A, Shukin R, Wang Y, Fazli L, Hurtado-Coll A, Jones EC, Hach F, Hormozdiari F, Hajirasouliha I, Boutros PC, Bristow RG, Zhao Y, Marra MA, Fanjul A, Maher CA, Chinnaiyan AM, Rubin MA, Beltran H, Sahinalp SC, Gleave ME, Volik SV, and Collins CC
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma secondary, Adenocarcinoma therapy, Aged, Alternative Splicing, Biomarkers, Tumor blood, British Columbia, Cell Line, Tumor, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Cluster Analysis, Decision Support Techniques, Gene Dosage, Gene Fusion, Genetic Predisposition to Disease, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Grading, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Neoplasms, Hormone-Dependent therapy, Neuroendocrine Cells pathology, Nomograms, Patient Selection, Phenotype, Precision Medicine, Prognosis, Prostate-Specific Antigen blood, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, RNA Interference, Transfection, Adenocarcinoma genetics, Biomarkers, Tumor genetics, Cell Transformation, Neoplastic genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Neoplasms, Hormone-Dependent genetics, Neuroendocrine Cells metabolism, Oligonucleotide Array Sequence Analysis, Prostatic Neoplasms genetics
- Abstract
The current paradigm of cancer care relies on predictive nomograms which integrate detailed histopathology with clinical data. However, when predictions fail, the consequences for patients are often catastrophic, especially in prostate cancer where nomograms influence the decision to therapeutically intervene. We hypothesized that the high dimensional data afforded by massively parallel sequencing (MPS) is not only capable of providing biological insights, but may aid molecular pathology of prostate tumours. We assembled a cohort of six patients with high-risk disease, and performed deep RNA and shallow DNA sequencing in primary tumours and matched metastases where available. Our analysis identified copy number abnormalities, accurately profiled gene expression levels, and detected both differential splicing and expressed fusion genes. We revealed occult and potentially dormant metastases, unambiguously supporting the patients' clinical history, and implicated the REST transcriptional complex in the development of neuroendocrine prostate cancer, validating this finding in a large independent cohort. We massively expand on the number of novel fusion genes described in prostate cancer; provide fresh evidence for the growing link between fusion gene aetiology and gene expression profiles; and show the utility of fusion genes for molecular pathology. Finally, we identified chromothripsis in a patient with chronic prostatitis. Our results provide a strong foundation for further development of MPS-based molecular pathology., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2012
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