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Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases

Sjödahl, Gottfrid LU ; Eriksson, Pontus LU ; Lövgren, Kristina LU ; Marzouka, Nour Al Dain LU ; Bernardo, Carina LU ; Nordentoft, Iver; Dyrskjøt, Lars; Liedberg, Fredrik LU and Höglund, Mattias LU (2018) In Modern Pathology 31(12). p.1869-1881
Abstract

Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle-invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28... (More)

Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle-invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28 matched lymph-node metastases. Full section immunohistochemistry was performed to assess intra-tumor subtype heterogeneity in discordant cases, and exome sequencing was performed for 20 sample pairs. Discordant subtype classification between the bladder tumor and lymph-node metastasis was generally rare (12/67, 18%), but most (7/12, 58%) involved the Basal/Squamous-like subtype. Discordant Basal/Squamous-like tumors showed either Urothelial-like or Genomically Unstable, luminal-like phenotype in the lymph-node metastasis. Full section immunohistochemistry revealed intra-tumor subtype heterogeneity for six discordant cases including four involving the Basal/Squamous-like subtype. Subtype concordance for non- Basal/Squamous-like tumors was 91%. RNA-based classification agreed with immunohistochemistry classification but quantitative assessment is necessary to avoid false detection of subtype shifts. Most high confidence cancer mutations were shared between samples (n = 93, 78%), and bladder tumor private mutations (n = 20, 17%) were more frequent than those private to the lymph-node metastasis (n = 7, 6%). We conclude that bladder tumors and lymph-node metastases have overall similar molecular subtype, biomarker expression, and cancer mutations. The main exception was tumors of the Basal/Squamous-like subtype where most cases showed discordant classification, some with evidence of intra-tumor heterogeneity. The data are of relevance for neoadjuvant treatment stratification and raises questions on the dynamics of molecular subtypes during bladder cancer progression.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Modern Pathology
volume
31
issue
12
pages
1869 - 1881
publisher
Nature Publishing Group
external identifiers
  • scopus:85049555033
ISSN
0893-3952
DOI
10.1038/s41379-018-0096-5
language
English
LU publication?
yes
id
c46404f9-52a0-4799-9b63-6ff7f678a519
date added to LUP
2018-07-23 11:48:00
date last changed
2019-03-24 04:47:42
@article{c46404f9-52a0-4799-9b63-6ff7f678a519,
  abstract     = {<p>Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle-invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28 matched lymph-node metastases. Full section immunohistochemistry was performed to assess intra-tumor subtype heterogeneity in discordant cases, and exome sequencing was performed for 20 sample pairs. Discordant subtype classification between the bladder tumor and lymph-node metastasis was generally rare (12/67, 18%), but most (7/12, 58%) involved the Basal/Squamous-like subtype. Discordant Basal/Squamous-like tumors showed either Urothelial-like or Genomically Unstable, luminal-like phenotype in the lymph-node metastasis. Full section immunohistochemistry revealed intra-tumor subtype heterogeneity for six discordant cases including four involving the Basal/Squamous-like subtype. Subtype concordance for non- Basal/Squamous-like tumors was 91%. RNA-based classification agreed with immunohistochemistry classification but quantitative assessment is necessary to avoid false detection of subtype shifts. Most high confidence cancer mutations were shared between samples (n = 93, 78%), and bladder tumor private mutations (n = 20, 17%) were more frequent than those private to the lymph-node metastasis (n = 7, 6%). We conclude that bladder tumors and lymph-node metastases have overall similar molecular subtype, biomarker expression, and cancer mutations. The main exception was tumors of the Basal/Squamous-like subtype where most cases showed discordant classification, some with evidence of intra-tumor heterogeneity. The data are of relevance for neoadjuvant treatment stratification and raises questions on the dynamics of molecular subtypes during bladder cancer progression.</p>},
  author       = {Sjödahl, Gottfrid and Eriksson, Pontus and Lövgren, Kristina and Marzouka, Nour Al Dain and Bernardo, Carina and Nordentoft, Iver and Dyrskjøt, Lars and Liedberg, Fredrik and Höglund, Mattias},
  issn         = {0893-3952},
  language     = {eng},
  number       = {12},
  pages        = {1869--1881},
  publisher    = {Nature Publishing Group},
  series       = {Modern Pathology},
  title        = {Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases},
  url          = {http://dx.doi.org/10.1038/s41379-018-0096-5},
  volume       = {31},
  year         = {2018},
}