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Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System

Eriksson, Pontus LU ; Cotillas, Elena Aramendía LU ; Mattsson, Carl Adam ; Zadoroznyj, Aymeric LU ; Bernardo, Carina LU orcid ; Sjödahl, Gottfrid LU orcid ; Edsjö, Anders LU orcid ; Heidenblad, Markus LU orcid ; Liedberg, Fredrik LU and Höglund, Mattias LU (2026) In Modern Pathology 39(6).
Abstract

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage... (More)

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non–muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell–intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bladder cancer, Lund Taxonomy, molecular subtypes, RNA sequencing, UROSCANSEQ, urothelial carcinoma
in
Modern Pathology
volume
39
issue
6
article number
100997
publisher
Nature Publishing Group
external identifiers
  • pmid:41936844
  • scopus:105038450120
ISSN
0893-3952
DOI
10.1016/j.modpat.2026.100997
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Authors
id
524c869f-3064-4ba0-92d0-ac0981dadcb5
date added to LUP
2026-06-12 09:07:12
date last changed
2026-06-26 09:51:04
@article{524c869f-3064-4ba0-92d0-ac0981dadcb5,
  abstract     = {{<p>Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non–muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell–intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.</p>}},
  author       = {{Eriksson, Pontus and Cotillas, Elena Aramendía and Mattsson, Carl Adam and Zadoroznyj, Aymeric and Bernardo, Carina and Sjödahl, Gottfrid and Edsjö, Anders and Heidenblad, Markus and Liedberg, Fredrik and Höglund, Mattias}},
  issn         = {{0893-3952}},
  keywords     = {{bladder cancer; Lund Taxonomy; molecular subtypes; RNA sequencing; UROSCANSEQ; urothelial carcinoma}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Modern Pathology}},
  title        = {{Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System}},
  url          = {{http://dx.doi.org/10.1016/j.modpat.2026.100997}},
  doi          = {{10.1016/j.modpat.2026.100997}},
  volume       = {{39}},
  year         = {{2026}},
}