PMID- 25083769
OWN - NLM
STAT- MEDLINE
DCOM- 20150423
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 8
DP  - 2014
TI  - Identification of ALK gene alterations in urothelial carcinoma.
PG  - e103325
LID - 10.1371/journal.pone.0103325 [doi]
LID - e103325
AB  - 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.
FAU - Bellmunt, Joaquim
AU  - Bellmunt J
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America; Hospital del Mar Research 
      Institute-IMIM, Barcelona, Spain.
FAU - Selvarajah, Shamini
AU  - Selvarajah S
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Rodig, Scott
AU  - Rodig S
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Salido, Marta
AU  - Salido M
AD  - Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, 
      Spain.
FAU - de Muga, Silvia
AU  - de Muga S
AD  - Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, 
      Spain.
FAU - Costa, Irmgard
AU  - Costa I
AD  - Hospital Parc Tauli, Sabadell, Spain.
FAU - Bellosillo, Beatriz
AU  - Bellosillo B
AD  - Department of Pathology, Hospital del Mar Research Institute-IMIM, Barcelona, 
      Spain.
FAU - Werner, Lillian
AU  - Werner L
AD  - Biostatistics and Computational Biology, Harvard Medical School, Dana-Farber 
      Cancer Institute, Boston, Massachusetts, United States of America.
FAU - Mullane, Stephanie
AU  - Mullane S
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Fay, Andre P
AU  - Fay AP
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - O'Brien, Robert
AU  - O'Brien R
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Barretina, Jordi
AU  - Barretina J
AD  - Broad Institute, Cambridge, Massachusetts, United States of America.
FAU - Minoche, Andre E
AU  - Minoche AE
AD  - Max Planck Institute for Molecular Genetics, Berlin, Germany; Centre for Genomic 
      Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
FAU - Signoretti, Sabina
AU  - Signoretti S
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Montagut, Clara
AU  - Montagut C
AD  - Hospital del Mar Research Institute-IMIM, Barcelona, Spain.
FAU - Himmelbauer, Heinz
AU  - Himmelbauer H
AD  - Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, 
      Barcelona, Spain.
FAU - Berman, David M
AU  - Berman DM
AD  - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United 
      States of America.
FAU - Kantoff, Philip
AU  - Kantoff P
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Choueiri, Toni K
AU  - Choueiri TK
AD  - Bladder Cancer Center, Dana-Farber Cancer Institute/Harvard Medical School, 
      Boston, Massachusetts, United States of America.
FAU - Rosenberg, Jonathan E
AU  - Rosenberg JE
AD  - Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New 
      York, United States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140801
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Aged
MH  - Anaplastic Lymphoma Kinase
MH  - Carcinoma/*genetics/metabolism/mortality/pathology
MH  - Chromosome Aberrations
MH  - Comparative Genomic Hybridization
MH  - DNA Copy Number Variations
MH  - Female
MH  - Gene Deletion
MH  - *Genetic Variation
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Neoplasm Staging
MH  - Prognosis
MH  - Receptor Protein-Tyrosine Kinases/*genetics/metabolism
MH  - Urologic Neoplasms/*genetics/metabolism/mortality/pathology
PMC - PMC4118868
COIS- Competing Interests: Toni K. Choueiri: Consultancy: Pfizer, Novartis; Advisory 
      board: Pfizer, Novartis, Aveo, GlaxoSmithKline, Exelixis; Research: Pfizer; No 
      Speakers bureau. All remaining authors have declared no conflicts of interest for 
      this work. This does not alter the authors' adherence to PLOS ONE policies on 
      sharing data and materials.
EDAT- 2014/08/02 06:00
MHDA- 2015/04/24 06:00
PMCR- 2014/08/01
CRDT- 2014/08/02 06:00
PHST- 2014/04/15 00:00 [received]
PHST- 2014/06/26 00:00 [accepted]
PHST- 2014/08/02 06:00 [entrez]
PHST- 2014/08/02 06:00 [pubmed]
PHST- 2015/04/24 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - PONE-D-14-16177 [pii]
AID - 10.1371/journal.pone.0103325 [doi]
PST - epublish
SO  - PLoS One. 2014 Aug 1;9(8):e103325. doi: 10.1371/journal.pone.0103325. eCollection 
      2014.