title: Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer.
abstract: Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Roman
authors.identifier: http://orcid.org/0000-0002-7592-6567
authors.initials: R
authors.lastname: Gulati
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzioni
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Bolouri
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: White
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Dumpit
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Navonil
authors.initials: N
authors.lastname: DeSarkar
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Celestia
authors.initials: C
authors.lastname: Higano
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.|Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Urology, University of Washington, Seattle, Washington, USA.|Department of Pathology, University of Washington, Seattle, Washington, USA.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.|Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D016190:Carboplatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins