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Molecular classification of urothelial carcinoma : global mRNA classification versus tumour-cell phenotype classification

Sjödahl, Gottfrid LU ; Eriksson, Pontus LU ; Liedberg, Fredrik LU and Höglund, Mattias LU (2017) In Journal of Pathology 242(1). p.113-125
Abstract

Global mRNA expression analysis is efficient for phenotypic profiling of tumours, and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non-tumour cells. This problem is particularly pertinent for analysis of advanced invasive tumours, which are known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour-cell phenotypes and compare classification by tumour-cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomized) both by genome gene expression analysis and by immunohistochemistry with antibodies for 28... (More)

Global mRNA expression analysis is efficient for phenotypic profiling of tumours, and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non-tumour cells. This problem is particularly pertinent for analysis of advanced invasive tumours, which are known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour-cell phenotypes and compare classification by tumour-cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomized) both by genome gene expression analysis and by immunohistochemistry with antibodies for 28 proteins. According to systematic analysis of gene and protein expression data, focusing on key molecular processes, we describe five tumour-cell phenotypes of advanced urothelial carcinoma: urothelial-like, genomically unstable, basal/SCC-like, mesenchymal-like, and small-cell/neuroendocrine-like. We provide molecular pathological definitions for each subtype. Tumours expressing urothelial differentiation factors show inconsistent and abnormal protein expression of terminal differentiation markers, suggesting pseudo-differentiation. Cancers with different tumour-cell phenotypes may co-cluster (converge), and cases with identical tumour-cell phenotypes may cluster apart (diverge), in global mRNA analyses. This divergence/convergence suggests that broad global commonalities related to the invasive process may exist between muscle-invasive tumours regardless of specific tumour-cell phenotype. Hence, there is a systematic disagreement in subtype classification determined by global mRNA profiling and by immunohistochemical profiling at the tumour-cell level. We suggest that a combination of molecular pathology (tumour-cell phenotype) and global mRNA profiling (context) is required for adequate subtype classification of muscle-invasive bladder cancer.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bladder cancer, molecular classification, pseudo-differentiation, tumour-cell phenotypes
in
Journal of Pathology
volume
242
issue
1
pages
13 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85017121084
  • wos:000399674800012
ISSN
0022-3417
DOI
10.1002/path.4886
language
English
LU publication?
yes
id
7ded0bf3-8c1e-48fa-82af-67a3e860fa95
date added to LUP
2017-05-04 16:13:47
date last changed
2018-04-22 04:28:34
@article{7ded0bf3-8c1e-48fa-82af-67a3e860fa95,
  abstract     = {<p>Global mRNA expression analysis is efficient for phenotypic profiling of tumours, and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non-tumour cells. This problem is particularly pertinent for analysis of advanced invasive tumours, which are known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour-cell phenotypes and compare classification by tumour-cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomized) both by genome gene expression analysis and by immunohistochemistry with antibodies for 28 proteins. According to systematic analysis of gene and protein expression data, focusing on key molecular processes, we describe five tumour-cell phenotypes of advanced urothelial carcinoma: urothelial-like, genomically unstable, basal/SCC-like, mesenchymal-like, and small-cell/neuroendocrine-like. We provide molecular pathological definitions for each subtype. Tumours expressing urothelial differentiation factors show inconsistent and abnormal protein expression of terminal differentiation markers, suggesting pseudo-differentiation. Cancers with different tumour-cell phenotypes may co-cluster (converge), and cases with identical tumour-cell phenotypes may cluster apart (diverge), in global mRNA analyses. This divergence/convergence suggests that broad global commonalities related to the invasive process may exist between muscle-invasive tumours regardless of specific tumour-cell phenotype. Hence, there is a systematic disagreement in subtype classification determined by global mRNA profiling and by immunohistochemical profiling at the tumour-cell level. We suggest that a combination of molecular pathology (tumour-cell phenotype) and global mRNA profiling (context) is required for adequate subtype classification of muscle-invasive bladder cancer.</p>},
  author       = {Sjödahl, Gottfrid and Eriksson, Pontus and Liedberg, Fredrik and Höglund, Mattias},
  issn         = {0022-3417},
  keyword      = {bladder cancer,molecular classification,pseudo-differentiation,tumour-cell phenotypes},
  language     = {eng},
  number       = {1},
  pages        = {113--125},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Pathology},
  title        = {Molecular classification of urothelial carcinoma : global mRNA classification versus tumour-cell phenotype classification},
  url          = {http://dx.doi.org/10.1002/path.4886},
  volume       = {242},
  year         = {2017},
}