Correlation between HER2 Gene Amplification and Protein Expression in Micropapillary Urothelial Carcinoma (MPC)
CB Ching, MB Amin, R Tubbs, DE Hansel. The Cleveland Clinic, Cleveland, OH; Cedars-Sinai Medical Center, Los Angeles, CA
Background: HER2 is a well known growth promoting factor in oncogenesis and has been found to be up-regulated in urothelial carcinoma, both in regards to gene amplification and protein over-expression. In particular, it has been previously found to be upregulated in a small sampling of micropapillary bladder carcinomas, a rare but highly aggressive variant of urothelial carcinoma (UC). We looked at an expanded number of micropapillary UC samples to confirm these previous findings and directly compare HER2 gene amplification with HER2 protein expression.
Design: We evaluated 20 patients with MPC on radical cystectomy using 3-4 1.0 mm cores represented on tissue microarray (TMA). HER2 gene amplification was determined by chromogenic in situ hybridization (CISH). The centromeric probe CEP17 served as a control and was used to evaluate ploidy. A single reviewer (CBC) evaluated each TMA to determine ploidy as well as HER2 gene levels. Only cells with evidence of at least 2 CEP17 copies were included for review. A ratio of HER2:CEP17 of >2.2 was considered evident of gene amplification. HER2 protein expression was evaluated by IHC by a single reviewer (DEH), and scored according to standard criteria as 0 (no staining), 1+ (faint partial staining in >10% of cells), 2+ (weak staining in >10% of cancer cells), and 3+ (intense staining in >10% of cancer cells). Protein over-expression was considered to be present at IHC scores of 2+ and 3+.
Results: Thirteen of 20 specimens demonstrated HER2 protein over-expression (65%). HER2 gene amplification was present in 11/20 (55%) of samples with all 11 samples also demonstrating 2-3+ protein expression for a 100% correlation between gene amplification and increased protein expression. We found 2 samples with protein over-expression without gene amplification, although one sample had a ratio of 3:2 of HER2 and CEP17 expression. We found that polyploidy was demonstrated in 9/20 (45%) of samples, with 5 of the 9 samples demonstrating increased gene amplification.
Conclusions: We found a positive correlation between HER2 gene amplification and protein over-expression in MPC. Direct correlation between gene amplification and protein over-expression suggests that HER2-targeted therapy may be successful in patients with this aggressive variant of UC for which there is currently limited therapy. In addition, a large proportion of patients demonstrated polypoidy within tumor specimens, suggesting an inherent genomic instability in these patients.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 98, Tuesday Afternoon