Simon Ronald, Atefy Ramin, Wagner Urs, Forster Thomas, Fijan André, Bruderer James, Wilber Kim, Mihatsch Michael J, Gasser Thomas, Sauter Guido
Institute for Pathology and Urologic Clinics, University of Basel, Basel, Switzerland.
Int J Cancer. 2003 Dec 10;107(5):764-72. doi: 10.1002/ijc.11477.
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.
HER-2/NEU是膀胱癌中最常扩增的致癌基因之一，也是一个潜在的治疗靶点。在乳腺癌中，相邻的TOP2A基因是几种抗癌药物的分子靶点，它经常与HER-2共同扩增。为了研究TOP2A和HER-2在膀胱癌中的扩增、表达及其与肿瘤表型和临床结局的关系，我们通过荧光原位杂交（FISH）和免疫组化分析了一个包含2317个膀胱肿瘤样本的组织芯片。HER-2的总体扩增频率为6.3%，TOP2A为1.5%。扩增最常见于晚期（pT2-4）肿瘤（HER-2为13.8%，TOP2A为3.4%）。在HER-2扩增的肿瘤中，56%也有TOP2A改变，包括14.7%的共同扩增、33.3%的增加和8%的缺失。只有17.6%的TOP2A扩增独立于HER-2改变发生。HER-2和TOP2A扩增均与肿瘤晚期（HER-2 p<0.0001，TOP2A p = 0.0218）、高级别（两者均p<0.0001）和蛋白过表达（两者均p<0.0001）显著相关。TOP2A扩增和过表达与肌肉浸润性肿瘤的生存期缩短有关（分别为p = 0.0042和0.0077）。总之，我们的数据表明，在膀胱癌中HER-2扩增常与TOP2A基因改变有关。17q12-q21扩增子的结构对于针对HER-2或TOP2A的治疗反应可能很重要。
