TCGA Bladder Urothelial Carcinoma (2017, 412-tumor)

Overview

Robertson et al. (TCGA bladder analysis working group) report the comprehensive molecular characterization of the full TCGA cohort of 412 chemotherapy-naive muscle-invasive bladder cancers (BLCA). This dataset supersedes the earlier 131-tumor blca_tcga_pub (2014) cohort and integrates whole-exome, SNP6 copy-number, RNA-seq, miRNA-seq, DNA methylation, and RPPA profiling. The study identifies 58 significantly mutated genes (34 novel vs the 131-tumor cohort), defines five mRNA expression subtypes including a newly recognized neuronal subtype, and confirms APOBEC3A/3B-driven mutagenesis as the dominant mutational source. Published in Cell (2017).

Composition

  • 412 chemotherapy-naive, invasive, high-grade urothelial tumors (T1–T4a, N0–3, M0–1) from 36 tissue source sites; 4 expert genitourinary pathologists re-reviewed all cases.
  • Histology: 52 (13%) had urothelial carcinoma with variant histology — 42 squamous, 4 small cell/neuroendocrine, 2 micropapillary, 4 plasmacytoid.
  • Complete clinical data for 406; 35 patients had received prior intravesical BCG; at last follow-up 230 alive, 163 recurred, 182 died (≥122/67% cancer-related); median follow-up 20.9 months for the alive.
  • Cancer type: Bladder Urothelial Carcinoma (BLCA).

Assays / panels (linked)

Papers using this cohort

  • PMID:28988769 — Robertson et al., Cell (2017): Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Notable findings derived from this cohort

  • 58 significantly mutated genes by MutSig 2CV (q < 0.1); 34 novel vs the 131-tumor cohort; 7 new SMGs mutated in >10% of samples: KMT2C (18%), ATM (14%), FAT1 (12%), CREBBP (12%), ERBB2 (12%), SPTAN1 (12%), KMT2A (11%). PMID:28988769
  • APOBEC mutagenesis dominates — APOBEC-a and APOBEC-b signatures account for 67% of all SNVs; 64% of APOBEC mutations are clonal, implying early activity in bladder cancer development. PMID:28988769
  • APOBEC-high (MSig1) tumors have the best survival (75% 5-year OS); low-mutation-burden MSig2 tumors have worst (22% 5-year OS). PMID:28988769
  • Five mRNA expression subtypes (NMF consensus clustering, n=408): luminal-papillary (35%), luminal-infiltrated (19%), luminal (6%), basal-squamous (35%), neuronal (5%); survival association p = 4×10⁻⁴. PMID:28988769
  • Neuronal subtype (n=20) is newly recognized, includes tumors without neuroendocrine histology (17/20), enriched for TP53+RB1 co-mutation or E2F3 amplification (85%), and has the poorest survival of all five subtypes. PMID:28988769
  • Luminal-papillary subtype enriched for FGFR3 mutations (42/57; p < 10⁻⁹), amplification, and FGFR3–TACC3 fusions (8/10); best candidate for pan-FGFR inhibitors. PMID:28988769
  • Luminal-infiltrated subtype has highest CD274 (PD-L1) and PDCD1 (PD-1) expression; proposed checkpoint-immunotherapy-responsive subset. PMID:28988769
  • p53/cell-cycle pathway inactivated in 89% of tumors; chromatin-modifier mutations pervasive and predominantly inactivating in 10 of 39 SMGs. PMID:28988769
  • FGFR3–TACC3 fusion is the most common recurrent gene fusion (n=10) and is enriched in the luminal-papillary subtype. PMID:28988769
  • Neoantigen load predicts survival independently of age, AJCC stage, and squamous differentiation (p = 8×10⁻⁴). PMID:28988769
  • PPARG recurrently fused (6 fusions; 4 TSEN2-PPARG, 2 MKRN2-PPARG), implicated as a luminal driver alongside GATA3 and FOXA1. PMID:28988769
  • RPPA proteomic clusters 1 and 2 (HER2-high) are candidates for trastuzumab or ado-trastuzumab-emtansine; cluster 3 (EGFR-high proliferative) for EGFR inhibitors. PMID:28988769

Sources

  • cBioPortal study ID: blca_tcga_pub_2017
  • Supersedes blca_tcga_pub (131-tumor 2014 TCGA BLCA cohort)
  • TCGA data portal / GDC

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