ASCO GU 2021: Genomic Characterization of Bladder Cancer with Variant Histology

( While the preponderance of patients with bladder tumors have urothelial histology, up to 25% of tumors are of pure variant or mixed urothelial and variant histology. These variant histologies are associated with more advanced stage at presentation and worse response to systemic therapy. In a poster presentation at the 2021 ASCO GU Cancers Symposium, Dr. Andrew Lenis and colleagues presented a genomic analysis of bladder cancers with variant histology.

To do so, the authors examined a prospectively accrued single-center institutional cohort of the molecularly profiled bladder and upper tract tumors. Among over 2,000 samples in the cohort, the author identified nearly 300 primary bladder tumor samples from patients with variant histology. The authors performed targeted sequencing with MSK-IMPACT to identify alterations in cancer-associated genes and to describe trends across variant subtypes. Further, in a subset analysis, the authors used single-cell RNA sequencing (scRNA-seq) to explore and compare tumor and immune cell heterogeneity.

The authors included patients with pure urothelial carcinoma not otherwise specified (NOS), squamous, small cell, pure adenocarcinoma, and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid variants. Mutational patterns varied on the basis of the variant histology.

Utilizing urothelial carcinoma NOS as the referent, the following associations between variant histology and genomic alterations were noted:
  • small cell tumors: nearly all with mutations in TP53, RB1, and TERT
  • squamous tumors: similar mutational frequencies to urothelial NOS
  • pure adenocarcinoma: frequent mutations in TP53, KRAS, and PIK3CA, resembling colorectal adenocarcinomas
  • urothelial carcinoma with glandular differentiation: similar mutational frequencies to urothelial NOS
  • micropapillary variant: enriched with ERBB2 amplifications
  • nested variant: enriched with RHOA mutations and FOXA1 amplification
  • plasmacytoid variants: nearly all with pathognomonic alterations in CDH1.
Using single-cell RNA sequencing, the authors examined four samples from patients with urothelial carcinoma NOS, squamous, micropapillary, and nested variants, showing distinct tumor cell clusters and varying contributions of immune cells from each variant.

The authors conclude that, despite differing mutational patterns, pathognomonic DNA alterations were not identified for most variant subtypes of bladder cancer. Thus, further analysis is required, potentially focusing on immune cell population infiltrates, exome sequencing, and mutational signatures.

Presented by: Andrew Thomas Lenis, MD, MS, Memorial Sloan Kettering Cancer Center

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021