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HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts

Eriksson, Pontus LU ; Sjödahl, Gottfrid LU ; Chebil, Gunilla; Liedberg, Fredrik LU and Höglund, Mattias LU (2017) In Oncotarget 8(30). p.48905-48914
Abstract

We analyzed a cohort of 599 cases of urothelial carcinoma for EGFR, ERBB2, and ERBB3 gene expression and genomic alterations. The cohort consisted of a reference set (n = 292) comprising all stages and grades and one set (n = 307) of advanced tumors. All cases were previously classified into urothelial carcinoma molecular subtypes. Genomic amplifications were established by array-CGH or in-situ hybridization, and gene expression both at mRNA and protein levels. Clinical HER2 status was independently evaluated using standard clinical procedures. EGFR amplifications were observed in 14% and ERBB2 amplifications in 23% of the reference cohort. EGFR gains were enriched in the Basal/SCC-like and ERBB2 gains in the Genomically Unstable... (More)

We analyzed a cohort of 599 cases of urothelial carcinoma for EGFR, ERBB2, and ERBB3 gene expression and genomic alterations. The cohort consisted of a reference set (n = 292) comprising all stages and grades and one set (n = 307) of advanced tumors. All cases were previously classified into urothelial carcinoma molecular subtypes. Genomic amplifications were established by array-CGH or in-situ hybridization, and gene expression both at mRNA and protein levels. Clinical HER2 status was independently evaluated using standard clinical procedures. EGFR amplifications were observed in 14% and ERBB2 amplifications in 23% of the reference cohort. EGFR gains were enriched in the Basal/SCC-like and ERBB2 gains in the Genomically Unstable subtypes. The expression data suggests that the Genomically Unstable show high ERBB2/ERBB3 but low EGFR expression and that Basal/SCC-like tumors show high EGFR but low ERBB2/ERBB3 expression. Whereas the frequency of ERBB2 genomic amplification were similar for cases of the Genomically Unstable subtype in the two cohorts, the Urotheliallike subtype acquires ERBB2 amplifications and expression during progression. Even though a good correlation between gene amplification and ERBB2 gene expression was observed in the Urothelial-like and Genomically Unstable subtypes less than half of the Basal/SCC-like cases with ERBB2 amplification showed concomitant ERBB2 mRNA and protein expression. We conclude that clinical trials using ERBB2 (HER2) or EGFR as targets have not fully appreciated the molecular heterogeneity in which activated ERBB2 and EGFR systems operate. Proper tumor classification is likely to be critical for arriving at thorough conclusions regarding new HER2 and EGFR based treatment regimes.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amplification, EGFR, HER2, Molecular subtype, Urothelial carcinoma
in
Oncotarget
volume
8
issue
30
pages
10 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85025832208
  • wos:000406232400033
ISSN
1949-2553
DOI
10.18632/oncotarget.16554
language
English
LU publication?
yes
id
3abc4df5-020a-4005-a2c8-14f31c7169c6
date added to LUP
2017-08-30 13:16:49
date last changed
2017-09-18 11:43:33
@article{3abc4df5-020a-4005-a2c8-14f31c7169c6,
  abstract     = {<p>We analyzed a cohort of 599 cases of urothelial carcinoma for EGFR, ERBB2, and ERBB3 gene expression and genomic alterations. The cohort consisted of a reference set (n = 292) comprising all stages and grades and one set (n = 307) of advanced tumors. All cases were previously classified into urothelial carcinoma molecular subtypes. Genomic amplifications were established by array-CGH or in-situ hybridization, and gene expression both at mRNA and protein levels. Clinical HER2 status was independently evaluated using standard clinical procedures. EGFR amplifications were observed in 14% and ERBB2 amplifications in 23% of the reference cohort. EGFR gains were enriched in the Basal/SCC-like and ERBB2 gains in the Genomically Unstable subtypes. The expression data suggests that the Genomically Unstable show high ERBB2/ERBB3 but low EGFR expression and that Basal/SCC-like tumors show high EGFR but low ERBB2/ERBB3 expression. Whereas the frequency of ERBB2 genomic amplification were similar for cases of the Genomically Unstable subtype in the two cohorts, the Urotheliallike subtype acquires ERBB2 amplifications and expression during progression. Even though a good correlation between gene amplification and ERBB2 gene expression was observed in the Urothelial-like and Genomically Unstable subtypes less than half of the Basal/SCC-like cases with ERBB2 amplification showed concomitant ERBB2 mRNA and protein expression. We conclude that clinical trials using ERBB2 (HER2) or EGFR as targets have not fully appreciated the molecular heterogeneity in which activated ERBB2 and EGFR systems operate. Proper tumor classification is likely to be critical for arriving at thorough conclusions regarding new HER2 and EGFR based treatment regimes.</p>},
  author       = {Eriksson, Pontus and Sjödahl, Gottfrid and Chebil, Gunilla and Liedberg, Fredrik and Höglund, Mattias},
  issn         = {1949-2553},
  keyword      = {Amplification,EGFR,HER2,Molecular subtype,Urothelial carcinoma},
  language     = {eng},
  number       = {30},
  pages        = {48905--48914},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts},
  url          = {http://dx.doi.org/10.18632/oncotarget.16554},
  volume       = {8},
  year         = {2017},
}