title: Identification of ALK gene alterations in urothelial carcinoma.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome.
  
  
  METHODS
  Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case.
  
  
  RESULTS
  70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5'ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease.
  
  
  CONCLUSIONS
  ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America; Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Shamini
authors.initials: S
authors.lastname: Selvarajah
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Salido
authors.affiliation: Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: de Muga
authors.affiliation: Hospital Parc Tauli, Sabadell, Spain.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Costa
authors.affiliation: Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.affiliation: Biostatistics and Computational Biology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mullane
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Brien
authors.affiliation: Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany; Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: André E
authors.initials: AE
authors.lastname: Minoche
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Montagut
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Heinz
authors.initials: H
authors.lastname: Himmelbauer
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Kantoff
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014571:Urologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
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