HER‐2 and TOP2A coamplification in urinary bladder cancer

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Abstract
HER‐2/NEU is one of the most frequently amplified oncogenes and a potential therapeutic target in bladder cancer. In breast cancer, the adjacent TOP2A gene, the molecular target for several anticancer drugs, is frequently coamplified together with HER‐2. To study the amplification and expression of TOP2A and HER‐2 and associations with tumor phenotype and clinical outcome in bladder cancer, a tissue microarray containing 2,317 bladder tumor samples was analyzed by FISH and immunohistochemistry. Overall amplification frequencies were 6.3% for HER‐2 and 1.5% for TOP2A. Amplifications were most frequently seen in advanced‐stage (pT2–4) tumors (HER‐2 13.8%, TOP2A 3.4%). Of HER‐2‐amplified tumors, 56% also had alterations of TOP2A, including 14.7% coamplifications, 33.3% gains and 8% deletions. Only 17.6% of TOP2A amplifications occurred independently of HER‐2 alterations. Both HER‐2 and TOP2A amplifications were significantly associated with advanced tumor stage (HER‐2 p < 0.0001, TOP2A p = 0.0218), high grade (p < 0.0001 for both) and protein overexpression (p < 0.0001 for both). TOP2A amplification and overexpression were linked to shortened survival in muscle‐invasive tumors (p = 0.0042 and 0.0077, respectively). In summary, our data suggest that HER‐2 amplifications are frequently linked to alterations of the TOP2A gene in bladder cancer. The anatomy of the 17q12‐q21 amplicon may be important for response to therapies targeting HER‐2 or TOP2A.