title: From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer.
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.
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Lapuk
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wu
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: McConeghy
authors.forename: Sonal
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Robert
authors.initials: R
authors.lastname: Shukin
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: Edward C
authors.initials: EC
authors.lastname: Jones
authors.forename: Faraz
authors.initials: F
authors.lastname: Hach
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.forename: Iman
authors.initials: I
authors.lastname: Hajirasouliha
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.forename: S Cenk
authors.initials: SC
authors.lastname: Sahinalp
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Volik
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary / Q000628:therapy; D000368:Aged; D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001955:British Columbia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D003661:Decision Support Techniques; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D055099:Neuroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D049451:Nomograms; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen