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A quantitative polymerase chain reaction based method for molecular subtype classification of urinary bladder cancer—Stromal gene expressions show higher prognostic values than intrinsic tumor genes

Olah, Csilla ; Hahnen, Christina ; Nagy, Nikolett ; Musial, Joanna ; Varadi, Melinda ; Nyiro, Gabor ; Gyorffy, Balazs ; Hadaschik, Boris ; Rawitzer, Josefine and Ting, Saskia , et al. (2022) In International Journal of Cancer 150(5). p.856-867
Abstract

Transcriptome-based molecular subtypes of muscle-invasive bladder cancer (MIBC) have been shown to be both prognostic and predictive, but are not used in routine clinical practice. We aimed to develop a feasible, reverse transcription quantitative polymerase chain reaction (RT-qPCR)-based method for molecular subtyping. First, we defined a 68-gene set covering tumor intrinsic (luminal, basal, squamous, neuronal, epithelial-to-mesenchymal, in situ carcinoma) and stromal (immune, extracellular matrix, p53-like) signatures. Then, classifier methods with this 68-gene panel were developed in silico and validated on public data sets with available subtype class information (MD Anderson [MDA], The Cancer Genome Atlas [TCGA], Lund, Consensus).... (More)

Transcriptome-based molecular subtypes of muscle-invasive bladder cancer (MIBC) have been shown to be both prognostic and predictive, but are not used in routine clinical practice. We aimed to develop a feasible, reverse transcription quantitative polymerase chain reaction (RT-qPCR)-based method for molecular subtyping. First, we defined a 68-gene set covering tumor intrinsic (luminal, basal, squamous, neuronal, epithelial-to-mesenchymal, in situ carcinoma) and stromal (immune, extracellular matrix, p53-like) signatures. Then, classifier methods with this 68-gene panel were developed in silico and validated on public data sets with available subtype class information (MD Anderson [MDA], The Cancer Genome Atlas [TCGA], Lund, Consensus). Finally, expression of the selected 68 genes was determined in 104 frozen tissue samples of our MIBC cohort by RT-qPCR using the TaqMan Array Card platform and samples were classified by our newly developed classifiers. The prognostic value of each subtype classification system and molecular signature scores were assessed. We found that the reduced marker set combined with the developed classifiers were able to reproduce the TCGA II, MDA, Lund and Consensus subtype classification systems with an overlap of 79%, 76%, 69% and 64%, respectively. Importantly, we could successfully classify 96% (100/104) of our MIBC samples by using RT-qPCR. Neuronal and luminal subtypes and low stromal gene expressions were associated with poor survival. In conclusion, we developed a robust and feasible method for the molecular subtyping according to the TCGA II, MDA, Lund and Consensus classifications. Our results suggest that stromal signatures have a superior prognostic value compared to tumor intrinsic signatures and therefore underline the importance of tumor-stroma interaction during the progression of MIBC.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bladder cancer, molecular subtype classification, neuronal signature, stroma
in
International Journal of Cancer
volume
150
issue
5
pages
856 - 867
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85116308580
  • pmid:34536301
ISSN
0020-7136
DOI
10.1002/ijc.33809
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
id
52a30e29-7dd3-4716-93b3-37b841d53088
date added to LUP
2021-11-17 15:09:10
date last changed
2024-06-15 20:31:39
@article{52a30e29-7dd3-4716-93b3-37b841d53088,
  abstract     = {{<p>Transcriptome-based molecular subtypes of muscle-invasive bladder cancer (MIBC) have been shown to be both prognostic and predictive, but are not used in routine clinical practice. We aimed to develop a feasible, reverse transcription quantitative polymerase chain reaction (RT-qPCR)-based method for molecular subtyping. First, we defined a 68-gene set covering tumor intrinsic (luminal, basal, squamous, neuronal, epithelial-to-mesenchymal, in situ carcinoma) and stromal (immune, extracellular matrix, p53-like) signatures. Then, classifier methods with this 68-gene panel were developed in silico and validated on public data sets with available subtype class information (MD Anderson [MDA], The Cancer Genome Atlas [TCGA], Lund, Consensus). Finally, expression of the selected 68 genes was determined in 104 frozen tissue samples of our MIBC cohort by RT-qPCR using the TaqMan Array Card platform and samples were classified by our newly developed classifiers. The prognostic value of each subtype classification system and molecular signature scores were assessed. We found that the reduced marker set combined with the developed classifiers were able to reproduce the TCGA II, MDA, Lund and Consensus subtype classification systems with an overlap of 79%, 76%, 69% and 64%, respectively. Importantly, we could successfully classify 96% (100/104) of our MIBC samples by using RT-qPCR. Neuronal and luminal subtypes and low stromal gene expressions were associated with poor survival. In conclusion, we developed a robust and feasible method for the molecular subtyping according to the TCGA II, MDA, Lund and Consensus classifications. Our results suggest that stromal signatures have a superior prognostic value compared to tumor intrinsic signatures and therefore underline the importance of tumor-stroma interaction during the progression of MIBC.</p>}},
  author       = {{Olah, Csilla and Hahnen, Christina and Nagy, Nikolett and Musial, Joanna and Varadi, Melinda and Nyiro, Gabor and Gyorffy, Balazs and Hadaschik, Boris and Rawitzer, Josefine and Ting, Saskia and Sjödahl, Gottfrid and Hoffmann, Michéle J. and Reis, Henning and Szarvas, Tibor}},
  issn         = {{0020-7136}},
  keywords     = {{bladder cancer; molecular subtype classification; neuronal signature; stroma}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{856--867}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{A quantitative polymerase chain reaction based method for molecular subtype classification of urinary bladder cancer—Stromal gene expressions show higher prognostic values than intrinsic tumor genes}},
  url          = {{http://dx.doi.org/10.1002/ijc.33809}},
  doi          = {{10.1002/ijc.33809}},
  volume       = {{150}},
  year         = {{2022}},
}