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.
Highlights
Bladder cancer is the fifth most common malignancy in the Western world
We show that ERBB2 amplifications and expression, as well as clinically “HER2 positive” cases, may be of two fundamentally different molecular subtypes, of Uro or the Genomically Unstable (GU) subtypes, and that EGFR expression is associated with the SCC-like subtype
To clarify the molecular context in which ERBB2 and EGFR gene amplifications and overexpression occur we performed an in-depth study of EGFR, ERBB2, and ERBB3 alterations in relation to existing urothelial carcinoma molecular subtypes
Summary
Bladder cancer is the fifth most common malignancy in the Western world It is associated with a high rate of mortality in patients with advanced disease. Several studies have reported a low concordance between ERBB2 protein level and gene amplification in urothelial carcinomas [5, 6]. We have described three major molecular subtypes of bladder cancer, Urothelial-like (Uro) (previously termed Urobasal [9]), Genomically Unstable (GU) and Basal/SCC-like [9], that accommodates fundamental differences in their molecular biology [10,11,12,13,14]. We investigate EGFR, ERBB2 (HER2), and ERBB3 (HER3) genomic alterations and expression in relation urothelial carcinoma molecular subtypes. We show that ERBB2 amplifications and expression, as well as clinically “HER2 positive” cases, may be of two fundamentally different molecular subtypes, of Uro or the GU subtypes, and that EGFR expression is associated with the SCC-like subtype
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