title: Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer.
abstract: We completed targeted exome sequencing of the tumors of 50 patients with pTis-pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival. Compared with The Cancer Genome Atlas, we found higher mutation rates in genes encoding products involved in epigenetic regulation and cell cycle regulation. Of the pathways examined, PI3K/mTOR and Cell Cycle/DNA Repair exhibited the greatest frequencies of mutation. RB1 and TP53, as well as NF1 and PIK3CA were frequently comutated. We identified no association between mutations in specific genes and key clinical outcomes of interest when corrected for multiple testing. Discovery phase analysis of the somatic mutations in 50 high-risk bladder cancer patients revealed novel mutations and mutational patterns, which may be useful for developing targeted therapy regimens or new biomarkers for patients at very high risk of disease metastasis and death.
  
  
  
  In this report we found known, as well as previously unreported, genetic mutations in the tumors of patients with high-risk bladder cancer. These mutations, if validated, may serve as actionable targets for new trials.
authors: Division of Urology, Department of Surgery, Duke University, Durham, NC, USA.
authors: Thomas
authors: T
authors: Longo
authors: Division of Urology, Department of Surgery, Duke University, Durham, NC, USA.
authors: Kathleen F
authors: KF
authors: McGinley
authors: Division of Oncology, Department of Medicine, Duke University, Durham, NC, USA.
authors: Jennifer A
authors: JA
authors: Freedman
authors: Division of Urology, Department of Surgery, Duke University, Durham, NC, USA.
authors: Wiguins
authors: W
authors: Etienne
authors: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
authors: Yuan
authors: Y
authors: Wu
authors: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
authors: Alexander
authors: A
authors: Sibley
authors: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
authors: Kouros
authors: K
authors: Owzar
authors: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
authors: Jeremy
authors: J
authors: Gresham
authors: Janssen Pharmaceuticals Inc., Raritan, NJ, USA.
authors: Christopher
authors: C
authors: Moy
authors: GlaxoSmithKline, Zebulon, NC, USA.
authors: Stephen
authors: S
authors: Szabo
authors: Novartis, Holly Springs, NC, USA.
authors: Joel
authors: J
authors: Greshock
authors: GlaxoSmithKline, Zebulon, NC, USA.
authors: Hui
authors: H
authors: Zhou
authors: GlaxoSmithKline, Zebulon, NC, USA.
authors: Yuchen
authors: Y
authors: Bai
authors: Division of Urology, Department of Surgery, Duke University, Durham, NC, USA. Electronic address: brant.inman@duke.edu.
authors: Brant A
authors: BA
authors: Inman
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D020360:Neoadjuvant Therapy / Q000379:methods*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D014481:United States; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D000970:Antineoplastic Agents
keywords: Bladder cancer; GOLGA5; IKZF1; epigenetics; somatic mutations