title: Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations.
abstract: BACKGROUND
  In the current study, the authors present a comprehensive genomic profile (CGP)-based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs).
  
  
  METHODS
  DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism-driven clinical trials.
  
  
  RESULTS
  All 295 patients assessed were classified with high-grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin-dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001).
  
  
  CONCLUSIONS
  Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702-711. © 2015 American Cancer Society.
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York.|Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Depinder
authors.initials: D
authors.lastname: Khaira
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York.
authors.forename: Huge A G
authors.initials: HA
authors.lastname: Fisher
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York.
authors.forename: Badar
authors.initials: B
authors.lastname: Mian
authors.affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College Albany, New York.
authors.forename: Tipu
authors.initials: T
authors.lastname: Nazeer
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Norma
authors.initials: N
authors.lastname: Palma
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Cancer Center, Duarte, California.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D016208:Databases, Factual; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D050939:Gene Fusion; D015321:Gene Rearrangement; D018734:Genes, erbB-2; D019942:Genes, p16; D016158:Genes, p53; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: bladder cancer; comprehensive genomic profiling; cyclin-dependent kinase inhibitor 2A (CDKN2A); fibroblast growth factor receptor (FGFR); metastatic; micropapillary