Comprehensive molecular characterization of urothelial bladder carcinoma Journal Article
| Author: | The Cancer Genome Atlas Research Network |
| Contributors: | Al-Ahmadie, H. A.; Reuter, V. E.; Rosenberg, J. E.; Bajorin, D. F.; Bochner, B. H.; Solit, D. B.; Schultz, N.; Ramirez, R. |
| Article Title: | Comprehensive molecular characterization of urothelial bladder carcinoma |
| 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. © 2014 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; protein kinase b; clinical article; human tissue; protein expression; unclassified drug; gene mutation; gene sequence; somatic mutation; missense mutation; mutation; histopathology; cancer staging; molecular genetics; cancer grading; chromosome; cell cycle; protein bcl 2; microrna; hepatocyte nuclear factor 3alpha; transcription factor gata 3; gene expression; protein kinases; basal cell carcinoma; epidermal growth factor receptor 2; down-regulation; enzyme activity; protein tyrosine kinase; fibroblast growth factor receptor 3; phosphatidylinositol 3 kinase; uvomorulin; dna methylation; urinary bladder neoplasms; gene expression regulation, neoplastic; messenger rna; rna, messenger; chromatin; mammalian target of rapamycin; proto-oncogene proteins c-akt; gene fusion; molecular analysis; chromosome translocation; rhoa guanine nucleotide binding protein; genome; dna sequence; gene inactivation; oxidative stress; mutation rate; cyclin dependent kinase inhibitor 1a; gene dosage; papillary carcinoma; micrornas; point mutation; bladder carcinoma; cell cycle regulation; transitional cell carcinoma; virus; cell organelle; phosphoprotein; cytomegalovirus; chromatin assembly and disassembly; rna sequence; wart virus; tissue characterization; signal; virus dna; copy number variation; e1a associated p300 protein; transcription factor e2f3; chromosome 4; molecular targeted therapy; microrna 125b; phosphatidylinositol 3-kinases; regulator gene; human papillomavirus type 16; mixed lineage leukemia protein; splicing defect; muscle invasive bladder cancer; tor serine-threonine kinases; indel mutation; kruppel like factor 5; virus integration; xeroderma pigmentosum group d protein; estrogen receptor beta; bk virus; microrna 99a; cancer; humans; human; male; female; priority journal; article; human herpesvirus 6; microrna 100; microrna 145; mll2 protein; protein bcl 2 l1; rhob guanine nucleotide binding protein; thioredoxin interacting protein |
| Journal Title: | Nature |
| Volume: | 507 |
| Issue: | 7492 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-03-20 |
| Start Page: | 315 |
| End Page: | 322 |
| Language: | English |
| DOI: | 10.1038/nature12965 |
| PUBMED: | 24476821 |
| PROVIDER: | scopus |
| PMCID: | PMC3962515 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: NATUA -- Source: Scopus |
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