Comprehensive molecular characterization of urothelial bladder carcinoma
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Abstract
Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far. This study of 131 high-grade muscle-invasive urothelial bladder carcinomas, part of The Cancer Genome Atlas (TCGA) project, reports recurrent mutations in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date. Recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of viruses associated with gene inactivation are also identified. Importantly, potential therapeutic targets are identified in 69% of the tumours.
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The record
- Venue
- Nature
- Topic
- Bladder and Urothelial Cancer Treatments
- Field
- Medicine
- Canadian institutions
- St. Joseph’s Healthcare HamiltonCanada's Michael Smith Genome Sciences CentreUniversity of British Columbia
- Funders
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillNational Center for Advancing Translational SciencesNational Cancer InstituteNational Human Genome Research InstituteMassachusetts Institute of TechnologyDan L. Duncan Cancer Center, Baylor College of MedicineSchool of Medicine, Indiana UniversityUniversity of California, San DiegoNational Heart, Lung, and Blood InstituteUniversity of Texas MD Anderson Cancer CenterNational Institutes of HealthSylvester Comprehensive Cancer Center, University of Miami Health SystemsBrigham and Women's HospitalUniversity of North Carolina at Chapel HillBroad InstituteNational Institute of Dental and Craniofacial ResearchResearch Institute, Nationwide Children's HospitalMemorial Sloan-Kettering Cancer CenterUniversity of Texas Southwestern Medical CenterCleveland Clinic FoundationCleveland ClinicUniversity of ChicagoHarvard UniversityUniversity of PittsburghNationwide Children's HospitalSRA InternationalUniversity of Miami
- Keywords
- Cancer researchBiologymicroRNAChromatinGeneTargeted therapyPI3K/AKT/mTOR pathwayCancerGeneticsSignal transduction
- Has abstract in OpenAlex
- yes