title: DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors.
abstract: BACKGROUND
  To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease.
  
  
  METHODS
  Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients.
  
  
  RESULTS
  Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data.
  
  
  CONCLUSIONS
  The discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine.
authors.affiliation: Memorial Sloan Kettering Cancer Center/Weill Cornell Medical College, New York, USA. bamburyr@mskcc.org.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bambury
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Ami_Bhatt@DFCI.HARVARD.EDU.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Ami_Bhatt@DFCI.HARVARD.EDU.
authors.forename: Ami S
authors.initials: AS
authors.lastname: Bhatt
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. markus@jimmy.harvard.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. chandra@broadinstitute.org.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA. chandra@broadinstitute.org.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Fujiko@broadinstitute.org.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Fujiko@broadinstitute.org.
authors.forename: Fujiko
authors.initials: F
authors.lastname: Duke
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Joaquim_Bellmunt@DFCI.HARVARD.EDU.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. ecstack@gmail.com.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. lwerner@jimmy.harvard.edu.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. RachelS_Park@DFCI.HARVARD.EDU.
authors.forename: Rachel
authors.initials: R
authors.lastname: Park
authors.affiliation: Memorial Sloan Kettering Cancer Center/Weill Cornell Medical College, New York, USA. iyerg@mskcc.org.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Massimo_Loda@dfci.harvard.edu.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Massimo_Loda@dfci.harvard.edu.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Philip_Kantoff@dfci.harvard.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. michor@jimmy.harvard.edu.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA. Matthew_Meyerson@dfci.harvard.edu.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Matthew_Meyerson@dfci.harvard.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Memorial Sloan Kettering Cancer Center/Weill Cornell Medical College, New York, USA. rosenbj1@mskcc.org.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D002869:Chromosome Aberrations; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D050699:E2F3 Transcription Factor / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005787:Gene Frequency; D056426:Genetic Loci; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D059467:Transcriptome; D014571:Urologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D050699:E2F3 Transcription Factor