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Signature DNA alterations in subtypes of bladder cancer

Presented by
Dr Andrew Thomas Lenis, Memorial Sloan Kettering Cancer Centre, New York, USA
ASCO GU 2021
Attempts to identify a signature DNA alteration pathognomonic of differing histologic subtypes of bladder cancer have been unsuccessful to date.

Urothelial carcinomas encompass a vast array of histological morphologies, some of which are more aggressive than others. For this reason, the histomorphologic features of bladder cancer carry a prognostic significance, and different variants necessitate different treatment approaches. Dr Andrew Thomas Lenis (Memorial Sloan Kettering Cancer Centre, New York, USA) shared results from his team’s genomic sequencing of bladder cancers of varying histologies in an attempt to determine whether these urothelial cancer variants had pathognomonic genomic profiles [1].

Memorial Sloan Kettering Cancer Centre developed the MSK-IMPACT™ test (authorised by the FDA in 2017) to analyse tumours for >400 mutations known to play a role in cancer. They used this test to identify gene alterations across a prospectively generated institutional cohort of >2,000 samples of bladder cancer. The cohort included patients with pure urothelial carcinoma not otherwise specified (NOS) as well as multiple variants: squamous, small cell, adenocarcinoma and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid. The current study aimed to identify trends that corresponded to these variant subtypes.

MSK-IMPACT™ analysis revealed the following:

  • the mutations in squamous cell tumours were similar to those seen in urothelial carcinoma NOS;
  • nearly all small cell tumours had mutations in TP53, RB1, and TERT;
  • adenocarcinomas frequently had mutations in TP53, KRAS, and PIK3CA;
  • urothelial carcinomas with glandular differentiation resembled urothelial carcinoma NOS;
  • micropapillary variants often showed ERBB2 amplifications;
  • nested variants often showed RHOA mutations and FOXA1 amplifications; and
  • plasmacytoid variants demonstrated pathognomonic CDH1

They also used single-cell RNA sequencing (scRNA-seq) on a subset of specimens to compare immune cell heterogeneity. This analysis identified distinct tumour cell clusters along with varying collections of immune cells in each bladder cancer subtype.

The analysis could not identify a pathognomonic DNA alternation that corresponded to the different variants of bladder cancer. However, they speculate that scRNA-seq carried out on larger cohorts may identify different immune cell profiles characteristic of different subtypes. Dr Lenis and his team will also utilise whole-exome sequencing and mutational signatures to further explore and characterise urothelial cancer variants.

  1. Lenis A. Genomic characterization of bladder cancer with variant histology. Abstract 470, ASCO Genitourinary Cancers Symposium, 11–13 February 2021.


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