Comprehensive molecular characterization of urothelial bladder carcinoma
Year: 2019
Type: article
Study design: Observational Study
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.
DOI: 10.17615/za09-dk57
Author: Perou, Charles
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: SRA International, Brigham and Women's Hospital, University of Miami, Massachusetts Institute of Technology, Memorial Sloan-Kettering Cancer Center, Harvard University, University of Chicago, Cleveland Clinic, Cleveland Clinic Foundation, Nationwide Children's Hospital, University of Texas Southwestern Medical Center, University of Pittsburgh, Dan L. Duncan Cancer Center, Baylor College of Medicine, Broad Institute, Sylvester Comprehensive Cancer Center, University of Miami Health Systems, National Institutes of Health, University of Texas MD Anderson Cancer Center, University of North Carolina at Chapel Hill, University of California, San Diego, School of Medicine, Indiana University, Research Institute, Nationwide Children's Hospital, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Dental and Craniofacial Research, National Center for Advancing Translational Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Awards: G1083213090, G111615301, G137804012, G139585312, G1570266655, G1609525565, G1671744939, G2049268772, G2659503640, G2664783788, G272783259, G2851467072, G2857508635, G2894286751, G3331582980, G3746653997, The Human Genome Sequencing Center, Harvard Genome Characterization Center, G5005221876, Cancer transcriptome characterization using massively parallel DNA sequencing, G5181012032, G5546132601, G5711250986, G7097003521, G884570035, G9000018409, G9000019010, G9000022338, G9000022781, G9000033506, G9000048103, G9000052705, G9000062434, G9000079746, G9000086836, G9000148096, G9000176922, G9000179146, G9000186802, G9000193931, G9000244592, G9000305565, G9000332944, Cancer Center Support Grant, Pre-doctoral Training Program in Integrative Vascular Biology, Cancer Center Support Grant, G987024288
OpenAlex ID: W4298025629