Comprehensive molecular characterization of urothelial bladder carcinoma.

TitleComprehensive molecular characterization of urothelial bladder carcinoma.
Publication TypeJournal Article
Year of Publication2014
Corporate AuthorsCancer Genome Atlas Research Network
JournalNature
Volume507
Issue7492
Pagination315-22
Date Published2014 Mar 20
ISSN1476-4687
KeywordsCell Cycle, Chromatin, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Molecular Targeted Therapy, Oxidative Stress, Phosphatidylinositol 3-Kinases, Protein Kinases, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, TOR Serine-Threonine Kinases, Urinary Bladder Neoplasms, Virus Integration
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.

DOI10.1038/nature12965
Alternate JournalNature
PubMed ID24476821
Grant ListP01 CA120964 / CA / NCI NIH HHS / United States
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