title: Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.
abstract: Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wu
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Anna V
authors.initials: AV
authors.lastname: Lapuk
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: McConeghy
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Sonal
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Robert
authors.initials: R
authors.lastname: Shukin
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.forename: Estelle
authors.initials: E
authors.lastname: Li
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: Yaron S
authors.initials: YS
authors.lastname: Butterfield
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: Steven Jm
authors.initials: SJ
authors.lastname: Jones
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
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* / Q000556:secondary / Q000628:therapy; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000032:analysis; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: D004273:DNA, Neoplasm; C438151:MSI2 protein, human; D016601:RNA-Binding Proteins