title: Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer.
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.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.forename: Kendric
authors.initials: K
authors.lastname: Wang
authors.forename: Brian
authors.initials: B
authors.lastname: McConeghy
authors.forename: Sonal
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Lina
authors.initials: L
authors.lastname: Jong
authors.forename: Devon M
authors.initials: DM
authors.lastname: Mitchell
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Johnston
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Estelle
authors.initials: E
authors.lastname: Li
authors.forename: Janet
authors.initials: J
authors.lastname: Liew
authors.forename: Jake
authors.initials: J
authors.lastname: Yeung
authors.forename: Raunak
authors.initials: R
authors.lastname: Shrestha
authors.forename: Anna V
authors.initials: AV
authors.lastname: Lapuk
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Robert
authors.initials: R
authors.lastname: Shukin
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bishop
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
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: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant / Q000379:methods; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets