Plasmacytoid Bladder Carcinoma MSKCC 2016 (Al-Ahmadie et al.)

Overview

Multi-cohort study of 31 plasmacytoid-variant bladder carcinomas (SRCBC) profiled at MSKCC by whole-exome sequencing, targeted panel sequencing (MSK-IMPACT 341-gene panel), and bisulfite sequencing of the CDH1 promoter. Represents the defining genomic characterization of this aggressive histologic variant, establishing truncating somatic CDH1 mutations and E-cadherin loss as pathognomonic events. An additional prospective clinical outcome cohort of 53 MSKCC patients is linked. Registered in cBioPortal as blca_plasmacytoid_mskcc_2016. PMID:26901067

Composition

  • Discovery cohort: 6 plasmacytoid-variant tumors with matched normal, profiled by whole-exome sequencing (SureSelect XT Human All Exon V4, HiSeq 2500, ~63M read pairs/sample, 94.4% of targets at ≥30×).
  • Validation cohort: 19 additional plasmacytoid-variant tumors by a 300-gene exon-capture panel, plus 6 profiled with the CLIA-certified MSK-IMPACT 341-gene panel.
  • Prospective clinical cohort: 62 invasive bladder cancer patients prospectively sequenced at MSKCC; 6 plasmacytoid-variant and 56 urothelial carcinoma NOS.
  • Clinical outcome cohort: 53 MSKCC patients with predominantly plasmacytoid histology treated 7/1994–4/2014; 37 included in survival analyses. Compared against 978 patients with pure urothelial carcinoma, NOS (5/2001–3/2010). Median follow-up among survivors: 71.8 months.
  • Cancer type: SRCBC (plasmacytoid/signet-ring-cell bladder carcinoma), a variant of BLCA.
  • All molecular samples are single-institution (MSKCC pathology archive); centralized histologic review performed. PMID:26901067

Assays / panels (linked)

Papers using this cohort

  • PMID:26901067 — Al-Ahmadie et al., Nat Genet 2016: primary discovery study defining CDH1 mutations as the pathognomonic event in plasmacytoid-variant bladder cancer.

Notable findings derived from this cohort

  • CDH1 truncating mutations in 84% of plasmacytoid-variant tumors (vs. 0% in 127 TCGA urothelial NOS tumors from blca_tcga_pub); E-cadherin loss is universal across all 31 plasmacytoid tumors PMID:26901067.
  • Promoter hypermethylation accounts for 4/5 mutation-negative plasmacytoid cases; no germline CDH1 alterations detected PMID:26901067.
  • Multi-region exon capture of one mixed tumor demonstrated that CDH1 Y68fs is plasmacytoid-specific while CDKN1A (A45fs) and PIK3C2G (S48R) are truncal, supporting common precursor with urothelial NOS PMID:26901067.
  • Co-mutation profile beyond CDH1 resembles conventional urothelial carcinoma: recurrent TP53, RB1, ARID1A, ERBB2, PIK3CA, and TSC1 alterations flagged as clinically actionable PMID:26901067.
  • Plasmacytoid-variant patients have higher cumulative incidence of local recurrence and cancer-specific mortality than urothelial NOS; CRISPR/Cas9 CDH1 knockout in RT4 and MGHU4 cells enhanced migration, providing a mechanistic basis for the variant’s peritoneal spread pattern PMID:26901067.

Sources

  • cBioPortal study: blca_plasmacytoid_mskcc_2016
  • PMID:26901067 — Al-Ahmadie HA et al., “Truncating somatic alterations in the CDH1 gene define the plasmacytoid variant of urothelial carcinoma.” Nat Genet 2016.

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