title: Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer.
abstract: OBJECTIVE
  Genetic analysis of bladder cancer has revealed a number of frequently altered genes, including frequent alterations of the telomerase (TERT) gene promoter, although few altered genes have been functionally evaluated. Our objective is to characterize alterations observed by exome sequencing and sequencing of the TERT promoter, and to examine the functional relevance of histone lysine (K)-specific demethylase 6A (KDM6A/UTX), a frequently mutated histone demethylase, in bladder cancer.
  
  
  METHODS
  We analyzed bladder cancer samples from 54 U.S. patients by exome and targeted sequencing and confirmed somatic variants using normal tissue from the same patient. We examined the biologic function of KDM6A using in vivo and in vitro assays.
  
  
  RESULTS
  We observed frequent somatic alterations in BRCA1 associated protein-1 (BAP1) in 15% of tumors, including deleterious alterations to the deubiquitinase active site and the nuclear localization signal. BAP1 mutations contribute to a high frequency of tumors with breast cancer (BRCA) DNA repair pathway alterations and were significantly associated with papillary histologic features in tumors. BAP1 and KDM6A mutations significantly co-occurred in tumors. Somatic variants altering the TERT promoter were found in 69% of tumors but were not correlated with alterations in other bladder cancer genes. We examined the function of KDM6A, altered in 24% of tumors, and show depletion in human bladder cancer cells, enhanced in vitro proliferation, in vivo tumor growth, and cell migration.
  
  
  CONCLUSIONS
  This study is the first to identify frequent BAP1 and BRCA pathway alterations in bladder cancer, show TERT promoter alterations are independent of other bladder cancer gene alterations, and show KDM6A loss is a driver of the bladder cancer phenotype.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.affiliation: Department of Surgery, University of Colorado, Aurora, Colorado.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Dancik
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Im
authors.affiliation: Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Sevilay
authors.initials: S
authors.lastname: Turan
authors.affiliation: Ingenuity, Redwood City, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brown
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Christina
authors.initials: C
authors.lastname: Ruiz-Rodriguez
authors.affiliation: Department of Surgery, University of Colorado, Aurora, Colorado.
authors.forename: Charles
authors.initials: C
authors.lastname: Owens
authors.affiliation: Department of Pharmacology, University of Colorado, Aurora, Colorado.
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Guangwu
authors.initials: G
authors.lastname: Guo
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Tsang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Shenzhen Second People's Hospital, Shenzhen, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.affiliation: Department of Pathology, University of Colorado, Aurora, Colorado.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Lucia
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Surgery, University of Colorado, Aurora, Colorado. Department of Pharmacology, University of Colorado, Aurora, Colorado. University of Colorado Comprehensive Cancer Center, Aurora, Colorado. dan.theodorescu@ucdenver.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C400134:BAP1 protein, human; D019313:BRCA1 Protein; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; C509186:TERT protein, human; D019098:Telomerase; D043222:Ubiquitin Thiolesterase