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Open Access 01-11-2021 | Cystectomy | Topic Paper

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

Authors: Veronika Weyerer, Robert Stoehr, Simone Bertz, Fabienne Lange, Carol I. Geppert, Sven Wach, Helge Taubert, Danijel Sikic, Bernd Wullich, Arndt Hartmann, Markus Eckstein

Published in: World Journal of Urology | Issue 11/2021

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.

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Burger M et al (2013) Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 63(2):234–241CrossRef

Humphrey PA et al (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol 70(1):106–119CrossRef

Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15(1):25–41CrossRef

Cancer Genome Atlas Research, N (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492):315–322CrossRef

Choi W et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25(2):152–165CrossRef

Damrauer JS et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111(8):3110–3115CrossRef

Lindgren D et al (2010) Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 70(9):3463–3472CrossRef

Robertson AG et al (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171:540 CrossRef

Sjodahl G et al (2012) A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 18(12):3377–3386CrossRef

10.

Kamoun A et al (2020) A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol 77(4):420–433CrossRef

11.

Seiler R et al (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72(4):544–554CrossRef

12.

Taber A et al (2020) Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat Commun 11(1):4858CrossRef

13.

Rinaldetti S et al (2018) Subclassification, survival prediction and drug target analyses of chemotherapy-naive muscle-invasive bladder cancer with a molecular screening. Oncotarget 9(40):25935–25945CrossRef

14.

Eckstein M et al (2018) mRNA-expression of KRT5 and KRT20 defines distinct prognostic subgroups of muscle-invasive urothelial bladder cancer correlating with histological variants. Int J Mol Sci 19(11):3396 CrossRef

15.

Eckstein M et al (2020) Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy. J Immunother Cancer 8(1):e000162. https://doi.org/10.1136/jitc-2019-000162CrossRefPubMedPubMedCentral

16.

Eckstein M et al (2020) CCL2 expression in tumor cells and tumor-infiltrating immune cells shows divergent prognostic potential for bladder cancer patients depending on lymph node stage. Cancers (Basel) 12(5):1253CrossRef

17.

Pfannstiel C et al (2019) The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes. Cancer Immunol Res 7(6):923–938CrossRef

18.

Wullweber A et al (2021) Bladder tumor subtype commitment occurs in carcinoma in situ driven by key signaling pathways including ECM remodeling. Cancer Res 81(6):1552–1566CrossRef

19.

Weyerer V et al (2021) TERT promoter mutation analysis of whole-organ mapping bladder cancers. Genes (Basel) 12(2):230CrossRef

20.

Weyerer V et al (2019) Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma. Histopathology 75(6):865–875CrossRef

21.

Weyerer V et al (2020) Pure large nested variant of urothelial carcinoma (LNUC) is the prototype of an FGFR3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype. Cancers (Basel) 12(3):763CrossRef

22.

Lerner SP et al (2016) Bladder cancer molecular taxonomy: summary from a consensus meeting. Bladder Cancer 2(1):37–47CrossRef

23.

Felsenstein KM, Theodorescu D (2018) Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy. Nat Rev Urol 15(2):92–111CrossRef

24.

Tan TZ et al (2019) Molecular subtypes of urothelial bladder cancer: results from a meta-cohort analysis of 2411 tumors. Eur Urol 75(3):423–432CrossRef

25.

Tan TZ et al (2019) Reply to Pontus Eriksson and Gottfrid Sjodahl’s letter to the editor re: Tuan Zea Tan, Mathieu Rouanne, Kien Thiam Tan, Ruby Yun-Ju Huang, Jean-Paul Thiery. Molecular subtypes of urothelial bladder cancer: results from a meta-cohort analysis of 2411 tumors. Eur Urol 2019;75:423–32. Eur Urol 75(4):e108–e109CrossRef

26.

Kollberg P et al (2019) Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival. Urol Oncol 37(10):791–799CrossRef

27.

Guo CC et al (2020) Assessment of luminal and basal phenotypes in bladder cancer. Sci Rep 10(1):9743CrossRef

28.

Matulay JT, Nrayan VM, Kamat AM (2019) Clinical and genomic considerations for variant histology in bladder cancer. Curr Oncol Rep 21(3):23CrossRef

29.

Zinnall U et al (2018) Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype. Hum Pathol 80:55–64CrossRef

Title: Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort
Authors: Veronika Weyerer
Robert Stoehr
Simone Bertz
Fabienne Lange
Carol I. Geppert
Sven Wach
Helge Taubert
Danijel Sikic
Bernd Wullich
Arndt Hartmann
Markus Eckstein
Publication date: 01-11-2021
Publisher: Springer Berlin Heidelberg
Keyword: Cystectomy
Published in: World Journal of Urology / Issue 11/2021
Print ISSN: 0724-4983
Electronic ISSN: 1433-8726
DOI: https://doi.org/10.1007/s00345-021-03788-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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