Single-nucleus and Spatially Resolved Intratumor Subtype Heterogeneity in Bladder Cancer.
Intratumor heterogeneity
Muscle-invasive bladder cancer
Non–muscle-invasive bladder cancer
RNA sequencing
Single-nucleus RNA sequencing
Spatial transcriptomics
Subtyping
Journal
European urology open science
ISSN: 2666-1683
Titre abrégé: Eur Urol Open Sci
Pays: Netherlands
ID NLM: 101771568
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
accepted:
13
03
2023
medline:
16
5
2023
pubmed:
16
5
2023
entrez:
15
5
2023
Statut:
epublish
Résumé
Current bulk transcriptomic classification systems for bladder cancer do not consider the level of intratumor subtype heterogeneity. To investigate the extent and possible clinical impact of intratumor subtype heterogeneity across early and more advanced stages of bladder cancer. We performed single-nucleus RNA sequencing (RNA-seq) of 48 bladder tumors and additional spatial transcriptomics for four of these tumors. Total bulk RNA-seq and spatial proteomics data were available from the same tumors for comparison, along with detailed clinical follow-up of the patients. The primary outcome was progression-free survival for non-muscle-invasive bladder cancer. Cox regression analysis, log-rank tests, Wilcoxon rank-sum tests, Spearman correlation, and Pearson correlation were used for statistical analysis. We found that the tumors exhibited varying levels of intratumor subtype heterogeneity and that the level of subtype heterogeneity can be estimated from both single-nucleus and bulk RNA-seq data, with high concordance between the two. We found that a higher class 2a weight estimated from bulk RNA-seq data is associated with worse outcome for patients with molecular high-risk class 2a tumors. The sparsity of the data generated using the DroNc-seq sequencing protocol is a limitation. Our results indicate that discrete subtype assignments from bulk RNA-seq data may lack biological granularity and that continuous class scores may improve clinical risk stratification of patients with bladder cancer. We found that several molecular subtypes can exist within a single bladder tumor and that continuous subtype scores can be used to identify a subgroup of patients with poor outcomes. Use of these subtype scores may improve risk stratification for patients with bladder cancer, which can help in making decisions on treatment.
Sections du résumé
Background
UNASSIGNED
Current bulk transcriptomic classification systems for bladder cancer do not consider the level of intratumor subtype heterogeneity.
Objective
UNASSIGNED
To investigate the extent and possible clinical impact of intratumor subtype heterogeneity across early and more advanced stages of bladder cancer.
Design setting and participants
UNASSIGNED
We performed single-nucleus RNA sequencing (RNA-seq) of 48 bladder tumors and additional spatial transcriptomics for four of these tumors. Total bulk RNA-seq and spatial proteomics data were available from the same tumors for comparison, along with detailed clinical follow-up of the patients.
Outcome measurements and statistical analysis
UNASSIGNED
The primary outcome was progression-free survival for non-muscle-invasive bladder cancer. Cox regression analysis, log-rank tests, Wilcoxon rank-sum tests, Spearman correlation, and Pearson correlation were used for statistical analysis.
Results and limitations
UNASSIGNED
We found that the tumors exhibited varying levels of intratumor subtype heterogeneity and that the level of subtype heterogeneity can be estimated from both single-nucleus and bulk RNA-seq data, with high concordance between the two. We found that a higher class 2a weight estimated from bulk RNA-seq data is associated with worse outcome for patients with molecular high-risk class 2a tumors. The sparsity of the data generated using the DroNc-seq sequencing protocol is a limitation.
Conclusions
UNASSIGNED
Our results indicate that discrete subtype assignments from bulk RNA-seq data may lack biological granularity and that continuous class scores may improve clinical risk stratification of patients with bladder cancer.
Patient summary
UNASSIGNED
We found that several molecular subtypes can exist within a single bladder tumor and that continuous subtype scores can be used to identify a subgroup of patients with poor outcomes. Use of these subtype scores may improve risk stratification for patients with bladder cancer, which can help in making decisions on treatment.
Identifiants
pubmed: 37187723
doi: 10.1016/j.euros.2023.03.006
pii: S2666-1683(23)00131-3
pmc: PMC10175738
doi:
Types de publication
Journal Article
Langues
eng
Pagination
78-88Informations de copyright
© 2023 The Author(s).
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