TCGA Bladder Urothelial Carcinoma (2014)

Overview

The blca_tcga_pub dataset is the inaugural comprehensive multi-platform molecular characterization of muscle-invasive, high-grade urothelial bladder carcinoma produced by The Cancer Genome Atlas (TCGA) Research Network, published in Nature in 2014. It profiled 131 chemotherapy-naive tumors (stages T2–T4a, Nx, Mx) from 19 tissue source sites using six integrated data platforms: whole-exome sequencing, low-pass whole-genome sequencing, RNA-seq, miRNA-seq, DNA methylation arrays, reverse-phase protein arrays (RPPA), and Affymetrix SNP 6.0 copy-number arrays. The study established bladder cancer as the epithelial cancer with the highest frequency of chromatin-regulator mutations and identified potential therapeutic targets in 69% of tumors.

Composition

  • 131 chemotherapy-naive, muscle-invasive, high-grade urothelial bladder carcinomas (T2–T4a, Nx, Mx); matched peripheral blood (n=118) and/or tumor-adjacent normal bladder tissue (n=23).
  • Tumor purity threshold: ≥60% tumor nuclei, ≤20% necrosis, ≤50% variant histology.
  • Cancer type: BLCA (urothelial carcinoma of the bladder).
  • Samples from 19 tissue source sites across the United States.
  • Mean/median somatic mutation rates: 7.7 / 5.5 mutations per Mb; average 302 exonic mutations, 204 segmental copy-number alterations, and 22 genomic rearrangements per sample.
  • 72% of patients had current or past smoking history.

Assays / panels (linked)

  • whole-exome-seq — 130 tumor/normal pairs; 186,260 exons across 18,091 genes; mean coverage 100× (≥82% target bases covered ≥30×).
  • whole-genome-seq — low-pass paired-end sequencing of 114 tumors at 6–8× coverage for structural variant detection.
  • rna-seq — all tumors (n=129 used for mRNA subtype clustering); also miRNA-seq.
  • affymetrix-snp6 — somatic copy-number alteration profiling.
  • hm450-methylation-array — DNA methylation profiling; identified CIMP subgroup (34% of tumors).
  • rppa — protein and phosphoprotein expression profiling.
  • Analytic tools: mutect for somatic point mutations, mutsig (MutSig 1.5) for significantly mutated genes, gistic (GISTIC 2.0) for focal CNAs.

Papers using this cohort

  • PMID:24476821 — TCGA Research Network, Nature (2014): Comprehensive molecular characterization of urothelial bladder carcinoma.
  • PMID:26901067 — Al-Ahmadie et al., Nat Genet 2016: CDH1 mutations absent in 127 NOS tumors from this cohort; used as comparator for plasmacytoid-variant bladder cancer.
  • PMID:27749842 — Faltas et al., Nat Genet 2016: Used as mutation-frequency benchmark for the Weill Cornell chemotherapy-evolution cohort; clonal enrichment of L1CAM and integrin signaling mutations in post-chemotherapy tumors was compared against this TCGA baseline.
  • PMID:28583311 — Pietzak et al., JCO 2017: 98 TCGA MIBC specimens with no prior history of NMIBC used as a muscle-invasive comparator cohort to contextualize gene-alteration frequencies (e.g., FGFR3, STAG2, TP53/MDM2) and mutational burden in the MSK NMIBC cohort. PMID:28583311

Notable findings derived from this cohort

  • 32 significantly mutated genes by MutSig 1.5 (FDR < 0.1), including 9 not previously reported as significantly mutated in any cancer: CDKN1A, ERCC2, RXRA, ELF3, KLF5, FOXQ1, RHOB, PAIP1, and BTG2. PMID:24476821
  • TP53 mutated in 49%; TP53 pathway inactivated (mutation + MDM2 amplification or overexpression) in 76% of tumors. PMID:24476821
  • 76% of tumors (99/131) had an inactivating mutation in at least one chromatin regulatory gene; 41% had at least two. Four epigenetic regulators were MutSig-significant: KMT2D, ARID1A, KDM6A, EP300. KMT2D and KDM6A mutations were mutually exclusive. PMID:24476821
  • Recurrent in-frame activating FGFR3–TACC3 fusions identified in 3 of 114 WGS tumors; enriched in the papillary-like mRNA subtype (cluster I). PMID:24476821
  • Four mRNA expression subtypes defined (n=129): papillary-like (cluster I, enriched for FGFR3 mutation/amplification), basal/squamous-like (cluster III, expressing KRT14/KRT5/KRT6A and EGFR), and two luminal-like clusters resembling luminal A breast cancer with high GATA3 and FOXA1. PMID:24476821
  • APOBEC mutagenesis: 51% of all mutations were TpC → (T/G), attributed to APOBEC3B activity; APOBEC3B was highly expressed across all tumors. PMID:24476821
  • Potential therapeutic targets identified in 69% of tumors: 42% in PI(3)K/AKT/mTOR pathway (including PIK3CA 17%, TSC1/TSC2 9%); 45% in RTK/MAPK pathway (including FGFR3 17%, ERBB2 9%). PMID:24476821
  • CDKN2A focal deletion in 47% of samples (most common focal deletion); RXRA S427 hotspot mutations in 7 of 12 RXRA-mutant tumors (5 S427F, 2 S427Y) associated with elevated adipogenesis/lipid-metabolism gene expression. PMID:24476821
  • Comprehensive molecular characterization of 131 muscle-invasive urothelial carcinomas revealed APOBEC mutagenesis, chromatin remodeling alterations, and immune pathway enrichment PMID:25096233
  • Used as comparator for plasmacytoid-variant bladder cancer: CDH1 truncating mutations were absent in 127 urothelial carcinoma NOS tumors from this cohort, establishing CDH1 mutation as specific to the plasmacytoid variant PMID:26901067
  • Used as mutation-frequency benchmark for matched pre/post-chemotherapy WES of 72 UC tumors from 32 patients at Weill Cornell; copy-number landscape stability and APOBEC mutagenesis prevalence in this cohort provided the reference distribution for evolution analyses in the Cornell dataset PMID:27749842
  • Used as MIBC comparator in the MSK NMIBC NGS study: FGFR3 alteration rates in this TCGA MIBC cohort (16%) vs LGTa NMIBC (83%) supported the interpretation that FGFR3 alterations decrease progressively with stage; STAG2 truncating mutation rate (15% in TCGA MIBC) confirmed enrichment of STAG2 truncations in low-grade NMIBC (39%) vs advanced disease PMID:28583311
  • Superseded by the expanded 412-tumor blca_tcga_pub_2017 cohort (Robertson et al. 2017); the 2014 131-tumor set is retained as the historical baseline for the original TCGA BLCA molecular characterization PMID:28988769

Sources

  • TCGA data portal / GDC
  • cBioPortal study ID: blca_tcga_pub

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