Bladder Urothelial Carcinoma (BLCA)

Overview

Urothelial carcinoma arising in the bladder; OncoTree code BLCA under the bladder/urinary tract lineage. Spans non-muscle-invasive (NMIBC), muscle-invasive (MIBC), and metastatic disease states with distinct genomic landscapes (PMID:37682528).

Cohorts in the corpus

  • bladder_msk_2023 — 1,421 patients / 1,507 urothelial carcinoma tumors sequenced at MSK, including 504 NMIBC and 526 MIBC bladder specimens alongside upper-tract and metastatic cases (PMID:37682528).

Recurrent alterations

  • FGFR3 — oncogenic alterations in 39% (199/504) of NMIBC and 14% (75/526) of MIBC bladder tumors; S249C is the dominant hotspot, and R248C is less frequent in bladder (11%, 37/333) than upper-tract disease (PMID:37682528).
  • ERBB2 — co-altered in 11% of FGFR3-altered MIBC (vs 2.5% in NMIBC) (PMID:37682528).
  • TP53, RB1 — inversely associated with FGFR3 alterations in urothelial carcinoma (PMID:37682528).
  • PIK3CA, TSC1, AKT1 — PI3K pathway co-alterations in 37% of FGFR2/3-altered tumors (PMID:37682528).
  • CDKN2A, CDKN2B, KDM6A — frequently co-altered with FGFR3 (PMID:37682528).
  • Bladder cancer patients harboring FGFR3 alterations showed differential responses to erdafitinib in a clinical cohort analysis PMID:36543146
  • UC-GENOME study (n=218 metastatic urothelial carcinoma) found Stroma-rich molecular subtype enrichment in metastatic vs non-metastatic disease (Mantel-Haenszel p=1.86e-10), TP53 E285K hotspot enrichment (10.8% vs 5.9% in TCGA-BLCA), APOBEC SBS13 low similarity predicting worse outcomes on both chemotherapy (HR 2.50, p=0.013) and ICI (HR 2.19, p=0.011), and a 25-predictor elastic net model achieving AUC=0.84 for ICI response prediction vs TMB alone (AUC=0.68, p=0.038) PMID:36333289
  • Integrated genomic analysis of 97 high-grade urothelial tumors found 61% carried a potentially actionable alteration; most prevalent somatic mutations were TP53 (34%), PIK3CA (18%), and FGFR3 (13%); RTK-RAS-RAF and PI3K/AKT/mTOR pathway lesions were largely mutually exclusive; ERBB2 focally amplified in 6.2% with HER2 overexpression PMID:23897969.
  • Whole-exome/genome sequencing of 99 Chinese transitional cell carcinoma (TCC) cases identified 37 significantly mutated genes including novel driver STAG2 (16% combined mutation/deletion frequency); 32% of tumors harbored alterations in sister chromatid cohesion and segregation genes; STAG2 alterations associated with significantly worse survival and higher aneuploidy; recurrent FGFR3-TACC3 fusion detected in 5% by RNA-seq PMID:24121792.
  • TCGA multi-platform analysis of 131 muscle-invasive urothelial carcinomas identified 32 significantly mutated genes, chromatin-regulator mutations in 76% of tumors (highest frequency among TCGA epithelial cancers), APOBEC3B as a dominant mutagen (51% of mutations), and potential therapeutic targets in 69% of cases — including FGFR3–TACC3 fusions, ERBB2 alterations (9%), and PI3K/mTOR pathway activation (42%) PMID:24476821.
  • SMARCA4 inactivating mutations occur in 5–8% of bladder carcinoma (TCGA data) PMID:24658004
  • MSK-IMPACT targeted sequencing of 109 high-grade urothelial carcinomas: PIK3CA mutations (21%) associated with improved RFS/CSS post-cystectomy (HR 0.35, P=0.014); CDKN2A alterations independently predict worse outcomes (RFS HR 5.76, P<0.001); TP53 mutation (57%) not prognostic after stage adjustment; chromatin-modifying genes mutated in 83% but not prognostic PMID:25092538
  • Whole-exome sequencing of 50 muscle-invasive urothelial carcinoma patients (25 cisplatin responders vs 25 non-responders) identified somatic ERCC2 mutations exclusively in responders (9/25, 36%; q=0.007), proposing ERCC2 as a predictive biomarker for neoadjuvant cisplatin-based chemotherapy response. PMID:25096233
  • UTUC and BLCA share recurrent FGFR3 alterations; targeted sequencing of upper-tract urothelial carcinoma cohort identified FGFR3 mutations in a subset with bladder cancer comparisons PMID:26278805
  • Plasmacytoid-variant bladder cancer (SRCBC) arises within the context of urothelial carcinoma; CDH1 truncating mutations are pathognomonic for the plasmacytoid subtype (84% frequency, vs 0% in 127 TCGA urothelial NOS tumors), and E-cadherin loss is universal; co-mutation profile otherwise overlaps with conventional urothelial carcinoma (TP53, RB1, ERBB2, PIK3CA) PMID:26901067
  • WES of 72 urothelial tumors from 32 patients (16 matched pre/post-chemotherapy sets + 2 rapid autopsies) at Weill Cornell showed only 28.4% of mutations shared between matched pre- and post-chemotherapy samples; post-chemotherapy tumors showed clonal enrichment of L1CAM/integrin-signaling pathway mutations and dominant APOBEC3A mutagenesis, supporting repeat biopsy and L1CAM/FAK inhibition as candidate strategies in chemotherapy-resistant BLCA PMID:27749842.
  • Single case of EWSR1::BEND2 fusion sarcoma (small round cell) of the urinary bladder; initial misdiagnosis as Ewing sarcoma (CD99+, EWSR1 FISH+) corrected by RNA-seq revealing EWSR1 exon 10::BEND2 exon 2 in-frame fusion; PTEN loss co-occurring on 10q deletion PMID:28199314
  • In the MSK-IMPACT pan-cancer cohort, BLCA had the highest TERT promoter mutation rate of any principal tumor type at 70%; MSI BLCA patients showed responses to immune checkpoint blockade; BLCA was included among 62 principal tumor types in msk_impact_2017. PMID:28481359
  • MSK-IMPACT targeted sequencing of 105 nonmuscle invasive bladder cancer (NMIBC) tumors (blca_nmibc_2017) found TERT promoter mutations in 73% across all grade/stage groups; chromatin-modifying gene alterations in 69% (KDM6A 38%, ARID1A 21%); ERBB2 and FGFR3 alterations in 57% of high-grade NMIBC in a mutually exclusive pattern; DDR gene alterations in 30% of high-grade NMIBC; ARID1A mutations associated with 3.14-fold higher BCG-recurrence risk (HR=3.14, 95% CI 1.51-6.51, P=0.002). PMID:28583311
  • TCGA expanded comprehensive molecular characterization of 412 chemotherapy-naive muscle-invasive bladder cancers integrating WES, RNA-seq, miRNA-seq, DNA methylation, SNP6, and RPPA; defined five mRNA subtypes (luminal-papillary, luminal-infiltrated, luminal, basal-squamous, neuronal), identified 58 SMGs, and linked APOBEC-dominated mutagenesis (67% of SNVs) paradoxically to best survival PMID:28988769
  • In the SUMMIT basket trial (n=16 bladder), HER2-mutant bladder urothelial carcinoma showed no RECIST responses to neratinib despite S310 hotspot predominance, demonstrating lineage-based intrinsic resistance to single-agent pan-HER kinase inhibition PMID:29420467
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included BLCA; BLCA concordance with the legacy PanCan12 MAF exceeded 90% PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) identified FGFR3–TACC3 in 2.0% of BLCA samples as a top recurrent intra-cancer fusion; FGFR3 was annotated as a druggable target in BLCA across 15 cancer types PMID:29617662
  • Pan-cancer aneuploidy study (10,522 TCGA tumors) included BLCA in the pan-cancer cohort; BLCA was not highlighted as an outlier for aneuploidy score PMID:29622463

Subtypes

  • NMIBC vs MIBC disease states show markedly different FGFR3 alteration frequencies (39% vs 14%), supporting distinct molecular biology (PMID:37682528).
  • FGFR3-fusion tumors carry lower TMB than FGFR3-mutant tumors (median 5 vs 9 mut/Mb, p=0.0006) (PMID:37682528).

Therapeutic landscape

  • erdafitinib — real-world ORR 40%, median PFS 2.8 months, OS 6.6 months in 32 metastatic FGFR3-altered urothelial carcinoma patients; tolerability-limited with 38% dose reductions (PMID:37682528).
  • Immune checkpoint blockade outcomes did not differ by FGFR3 status (n=26 altered vs 155 wildtype) (PMID:37682528).
  • BRAF fusions were identified as acquired resistance mechanisms to EGFR TKIs in BLCA patients PMID:38922339.
  • ctDNA detection (MSK-ACCESS) was associated with higher VTE risk in BLCA patients, though the association was not significant for BLCA specifically PMID:39147831.
  • enfortumab-vedotin and next-generation FGFR3-selective inhibitors (e.g., TYRA300, LOXO435) cited as alternative options given erdafitinib’s modest durability (PMID:37682528).
  • ROBIN GenRad center (U54 CA274513; Cleveland Clinic and Emory University) RAD-SG trial (NCT05833867) evaluates RT + sacituzumab-govitecan for bladder preservation in locally advanced muscle-invasive BLCA (MIBC); preliminary results show feasibility with only grade-1 toxicities. Flow cytometry-based immune profiling demonstrates extensive myeloid-lineage accumulation during RT+ADC treatment, with distinct profiles from ICI-treated patients. Comprehensive genomics, serum proteomics, imaging, and ctDNA analyses are underway. PMID:41941260

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29420467

This page was processed by entity-page-writer on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15. - PMID:29622463

This page was processed by wiki-cli on 2026-05-15.