Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort

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Abstract

Purpose

Recently discovered molecular classifications for urothelial bladder cancer appeared to be promising prognostic and predictive biomarkers. The present study was conducted to evaluate the prognostic impact of molecular subtypes assessed by two different methodologies (gene and protein expression), to compare these two approaches and to correlate molecular with histological subtypes in a consecutively collected, mono-institutional muscle-invasive bladder cancer (MIBC) cohort.

Methods

193 MIBC were pathologically re-evaluated and molecular subtypes were assessed on mRNA (NanoString technology, modified 21-gene-containing MDACC approach) and protein levels (immuno-histochemical [IHC] analysis of CK5, CK14, CD44, CK20, GATA3 and FOXA1). Descriptive statistical methods and uni-/multi-variable survival models were employed to analyze derived data.

Results

Neither gene expression nor protein-based subtyping showed significant associations with disease-specific (DSS) or recurrence-free survival (RFS). Agreement between mRNA (reference) and protein-based subtyping amounted 68.6% for basal, 76.1% for luminal and 50.0% for double-negative tumors. Histological subtypes associated with RFS in uni-variable ( P = 0.03), but not in multivariable survival analyses. Tumors with variant histology predominantly showed luminal subtypes (gene expression subtyping: 36/55 cases, 65.5%; protein subtyping: 44/55 cases, 80.0%). Squamous differentiation significantly associated with basal subtypes (gene expression subtyping: 44/45 squamous cases, 97.8%; protein subtyping: 36/45 cases, 80.0%).

Conclusion

In our consecutive cystectomy cohort, neither gene, protein expression-based subtyping, nor histological subtypes associated with DSS or RFS in multi-variably adjusted survival analyses. Application of a limited IHC subtyping marker panel showed high concordance of 83.9% with gene expression-based subtyping, thus underlining the utility for subtyping in pathological routine diagnostics. In addition, histological MIBC subtypes are strong indicators for intrinsic subtypes.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00345-021-03788-1.

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Most cited references 29

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Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

Benilton de Sa Carvalho, Vinicius Chagas, Karen L Mungall … (2017)

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

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Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

Nikolaus Schultz (2014)

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in miRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.

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A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

Aurélie Kamoun, Aurélien de Reyniès, Yves Allory … (2019)

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes. Design, setting, and participants: We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. Outcome measurements and statistical analysis: We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models. Results and limitations: We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample’s transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment. Conclusions: This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials. Patient summary: Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.

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Author and article information

Contributors

Veronika Weyerer: Veronika.Weyerer@uk-erlangen.de

Journal

Journal ID (nlm-ta): World J Urol

Journal ID (iso-abbrev): World J Urol

Title: World Journal of Urology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0724-4983

ISSN (Electronic): 1433-8726

Publication date (Electronic): 14 July 2021

Publication date PMC-release: 14 July 2021

Publication date (Print): 2021

Volume: 39

Issue: 11

Pages: 4011-4019

Affiliations

[1 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Institute of Pathology, , University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, ; Krankenhausstr. 8-10, 91054 Erlangen, Germany

[2 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Comprehensive Cancer Center Erlangen (CCC ER-EMN), , University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, ; Erlangen, Germany

[3 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Department of Urology and Pediatric Urology, , University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, ; Erlangen, Germany

Article

Publisher ID: 3788

DOI: 10.1007/s00345-021-03788-1

PMC ID: 8571152

PubMed ID: 34259899

SO-VID: 85372092-32cc-4934-a498-2ca8a95699c5

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 March 2021

Date accepted : 4 July 2021

Funding

Funded by: Universitätsklinikum Erlangen (8546)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Urology

Keywords: muscle-invasive bladder cancer,molecular subtypes,prognostic impact,histological variants

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ScienceOpen disciplines: Urology

Keywords: muscle-invasive bladder cancer, molecular subtypes, prognostic impact, histological variants

Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort

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Abstract

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Supplementary Information

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Most cited references 29

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

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