title: HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts.
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.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Gottfrid
authors.initials: G
authors.lastname: Sjödahl
authors.affiliation: Unilabs, Helsingborg Hospital, Helsingborg, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Chebil
authors.affiliation: Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Liedberg
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Höglund
mesh_terms: D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics*; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009367:Neoplasm Staging; D020893:Receptor, ErbB-3 / Q000235:genetics; D014571:Urologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3
keywords: EGFR; HER2; amplification; molecular subtype; urothelial carcinoma