Oncotarget

Research Papers:

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

Pontus Eriksson, Gottfrid Sjödahl, Gunilla Chebil, Fredrik Liedberg and Mattias Höglund _

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Oncotarget. 2017; 8:48905-48914. https://doi.org/10.18632/oncotarget.16554

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Abstract

Pontus Eriksson1, Gottfrid Sjödahl2, Gunilla Chebil3, Fredrik Liedberg2 and Mattias Höglund1

1Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden

2Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden

3Unilabs, Helsingborg Hospital, Helsingborg, Sweden

Correspondence to:

Mattias Höglund, email: mattias.hoglund@med.lu.se

Keywords: HER2, EGFR, amplification, urothelial carcinoma, molecular subtype

Received: November 15, 2016     Accepted: March 08, 2017     Published: March 24, 2017

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 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 Urothelial-like 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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