Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

Nature. 507: p315-322, 29 January 2014 10.1038/nature12965

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for 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 signaling pathways, as well as 9 genes not previously implicated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and squamous-like) were also evident in miRNA 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) associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.

Data in the GDC

• GDC Manifests
  • Open-Access Data - Download Manifest (27 Files)
  • Controlled-Access Data - Download Manifest (2 Files)

Supplemental Data

• Sample Lists - below are links to cumulative list of samples for the population
  • Cumulative Sample List [txt]
  • Cumulative Data Freeze List [txt]
• Mutations
  • Level 2 Data Archives - Somatic MAF file [maf] - Exome-based somatic mutations
  • Supplementary Data - BAM file list [txt] - Exome Sequence BAM File References
• Expression
  • unc.edu_BLCA.IlluminaHiSeq_RNASeqV2.Level_3.tar.gz [tar] - Level 3 RNA-seq expression data
  • unc.edu_BLCA.IlluminaHiSeq_RNASeqV2.mage-tab.1.9.0.tar.gz [tar] - mage-tab
  • BLCA_cluster-assign-k4.tsv [tsv] - mRNAseq Subtypes
  • BLCA_gnames.txt [txt] - Gene list (2,708 genes used for clustering the samples in Supplemental figure S4.1)
• Copy Number
  • hms.harvard.edu_BLCA.IlluminaHiSeq_DNASeqC.Level_3.tar.gz [tar.gz] - a collection of Level 3 archives derived from low-pass whole-genome sequencing using the Illumina HiSeq platform
  • hms.harvard.edu_BLCA.IlluminaHiSeq_DNASeqC.Level_2.tar.gz [tar.gz] - a collection of Level 2 archives containing structural aberrations derived from low-pass whole-genome sequencing using the Illumina HiSeq platform
  • hms.harvard.edu_BLCA.IlluminaHiSeq_DNASeqC.mage-tab.1.4.0.tar.gz [tar] - mage-tab archive
  • broad.mit.edu_BLCA.Genome_Wide_SNP_6.Level_3.tar.gz [tar] - a collection of Level 3 archives derived from Affymetrix SNP 6 platform
  • broad.mit.edu_BLCA.Genome_Wide_SNP_6.Level_2.tar.gz [tar] - a collection of Level 2 archives derived from Affymetrix SNP 6 platform
  • broad.mit.edu_BLCA.Genome_Wide_SNP_6.Level_1.tar.gz [tar] - a collection of Level 1 archives derived from Affymetrix SNP 6 platform
  • broad.mit.edu_BLCA.Genome_Wide_SNP_6.mage-tab.1.2009.0.tar.gz [tar] - mage-tab archive
• miRNA - below is a link to the Level 3 archive that contains miRNA data and analysis
  • bcgsc.ca_BLCA.Illumina_miRNASeq.tar.gz [tar]
• Methylation - below is a link to a file that contains Methylation data and analysis
  • jhu-usc.edu_BLCA.HumanMethylation450.Level_3.tar [tar] - Level 3 methylation data
  • jhu-usc.edu_BLCA.HumanMethylation450.Level_2.tar [tar] - Level 2 methylation data
  • jhu-usc.edu_BLCA.HumanMethylation450.Level_1.tar [tar] - Level 1 methylation data
  • jhu-usc.edu_BLCA.HumanMethylation450.mage-tab.1.9.0.tar.gz [tar] mage-tab archive
  • BLCA_DNA_methylation_clusters.csv [csv] methylation cluster data
• Clinical - below are links to supplemental clinical data for the publication
  • nationwidechildrens.org_BLCA.bio.Level_1 [tar] - XML files containing biospecimen processing and clinical data
• Reverse Phase Protein Array (RPPA)
  • mdanderson.org_BLCA.MDA_RPPA_Core.Level_1.1.tar.gz [tar.gz] - Level 1 RPPA data
  • mdanderson.org_BLCA.MDA_RPPA_Core.Level_2.1.tar.gz [tar.gz] - Level 2 RPPA data
  • mdanderson.org_BLCA.MDA_RPPA_Core.Level_3.1.tar.gz [tar.gz] - Level 3 RPPA data
  • mdanderson.org_BLCA.MDA_RPPA_Core.mage-tab.1.tar.gz [tar.gz] - MAGE-TAB for RPPA data
  • BLCA_RPPA_unsupervised_cluster_membership.txt [txt] - RPPA cluster membership
• Supplemental data
  • S1_S2_S6_S9_S12_DataFiles.zip - supplementary tables
  • BLCA.n131.miRNAseq.5-NMF_clusters.20130518.txt - miRNA cluster file

Additional Resources

• GDC Encyclopedia
• Descriptions of TCGA data are provided in the TCGA Barcode Encyclopedia Page
• Genomic Data Commons Portal