Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma
Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma
复制标题
DOI：
10.1007/s00109-006-0054-4
复制
发表时间：
2006-08-01
影响因子：
4.7
通讯作者：
Butzow, Ralf
中科院分区：
文献类型：
--
作者：
Lassus, Heini;Sihto, Harri;Butzow, Ralf
EGFR和erbB-2是特异性癌症治疗的靶点。本研究的目的是研究浆液性癌中EGFR和ERBB 2基因扩增、蛋白表达和突变的频率和临床病理相关性，浆液性癌是最常见和最具侵袭性的卵巢癌类型。用发色原位杂交（CISH）和免疫组织化学方法对398例癌组织芯片进行检测。对CISH扩增EGFR的病例进一步进行荧光原位杂交分析。采用变性高效液相色谱法和直接测序法分析了198份样本中EGFR外显子18、19或21以及ERBB 2外显子20的突变。EGFR扩增率为12%（41/333），低水平扩增率为43%（144/333），蛋白过度表达率为17%（66/379）。EGFR拷贝数增加和过度表达均与肿瘤分级高、患者年龄大、残留肿瘤大小大、增殖指数高、异常p53和患者预后差相关。此外，EGFR拷贝数增加与ERBB 2拷贝数增加相关。EGFR中未发现突变，而1例肿瘤在ERBB 2的外显子20中存在插入突变。浆液性卵巢癌中EGFR的扩增和蛋白过表达均存在，但EGFR拷贝数具有更强的预后价值。这使得EGFR扩增成为在检测EGFR抑制剂对浆液性卵巢癌的作用的临床试验中选择患者的潜在有用标准。
EGFR and erbB-2 are targets for specific cancer therapy. The purpose of this study was to examine the frequency and clinicopathological correlations of gene amplification, protein expression, and mutations of EGFR and ERBB2 in serous carcinoma, the most common and aggressive type of ovarian cancer. Tissue microarray constructed of 398 carcinomas was examined by chromogenic in situ hybridization (CISH) and by immunohistochemistry. Cases with amplification of EGFR by CISH were further analyzed by fluorescence in situ hybridization. One hundred ninety-eight samples were analyzed for mutations in exons 18, 19, or 21 of EGFR and in exon 20 of ERBB2 using denaturating high-performance liquid chromatography and direct sequencing. Amplification of EGFR was present in 12% (41/333), low-level gain in 43% (144/333), and protein overexpression in 17% (66/379) of the tumors. Both increased copy number and overexpression of EGFR were associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53, and poor patient outcome. Furthermore, increased copy number of EGFR was associated with increased copy number of ERBB2. No mutations were identified in EGFR, whereas one tumor had an insertion mutation in exon 20 of ERBB2. Both amplification and protein overexpression of EGFR occur in serous ovarian carcinoma, but EGFR copy number has a stronger prognostic value. This makes EGFR amplification a potentially useful criterion for selecting patients in clinical trials testing the effect of EGFR inhibitors in serous ovarian carcinoma.