EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target.
EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target.
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DOI：
10.1038/bjc.2011.222
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发表时间：
2011-07-26
影响因子：
8.8
通讯作者：
Miyazaki, K.
中科院分区：
文献类型：
--
作者：
Iida, K.;Nakayama, K.;Rahman, M. T.;Rahman, M.;Ishikawa, M.;Katagiri, A.;Yeasmin, S.;Otsuki, Y.;Kobayashi, H.;Nakayama, S.;Miyazaki, K.
关键词：
本研究的目的是研究宫颈鳞癌和腺癌/腺鳞癌中表皮生长因子受体(EGFR)的过度表达、EGFR基因扩增以及该基因酪氨酸激酶结构域是否存在激活突变。采用免疫组化法、荧光原位杂交法和聚合酶链式反应-单链构象多态性分析(PCR-SSCP)分别检测宫颈癌组织中EGFR的表达、扩增和突变情况，并与临床资料进行对照分析。通过用有效的抑制剂AG1478使宫颈癌细胞中的EGFR失活来进行功能评估。免疫组织化学分析显示，59例宫颈鳞癌中有6例(10.2%)有明显的EGFR基因扩增，而52例腺/鳞状细胞癌中无一例检测到EGFR扩增(P<；0.05)。宫颈鳞癌中表皮生长因子受体基因扩增与总生存期缩短显著相关(P=0.001)。多因素分析显示，EGFR基因扩增是影响总生存期的独立预后因素(P=0.011)。没有鳞状细胞癌(0%：32例中的0例)在EGFR外显子18至21中检测到致癌基因突变。KRAS和BRAF突变在鳞癌和腺/腺鳞状细胞癌中的频率都很低。宫颈癌细胞对AG1478的敏感性依赖于EGFR的过表达。在小鼠异种移植模型中，AG1478诱导的EGFR过表达细胞系的EGFR失活显著抑制了肿瘤的发展和进展。我们的数据表明，EGFR信号在子宫颈鳞癌中是重要的，抗EGFR治疗可能使在肿瘤中携带7p11.2扩增的患者受益。
The aim of this study was to investigate the patterns of epidermal growth factor receptor (EGFR) overexpression, EGFR gene amplification, and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the uterine cervix. The EGFR expression, amplification, and mutation in cervical carcinomas were assessed by immunohistochemistry, fluorescence in situ hybridisation, and PCR–SSCP, respectively, and correlated with clinical data collected by a retrospective chart review. A functional assessment was performed by inactivating EGFR in cervical cancer cells with the potent inhibitor AG1478. Immunohistochemical analysis revealed that 6 out of 59 (10.2%) cervical squamous cell carcinomas showed significant amplification of the EGFR locus, whereas none of the 52 adeno/adenosquamous cell carcinomas had detectable EGFR amplification (P<0.05). The EGFR amplification significantly correlated with shorter overall survival (P=0.001) in cervical squamous cell carcinomas. Multivariate analysis showed that EGFR gene amplification was an independent prognostic factor for overall survival (P=0.011). None of the squamous cell carcinomas (0%: 0 out of 32) had detectable oncogenic mutations in EGFR exons 18 through 21. The frequencies of KRAS and BRAF mutations were very low in both squamous and adeno/adenosquamous cell carcinomas. Sensitivity of cervical cancer cells to AG1478 depended on the presence of EGFR overexpression. AG1478-induced EGFR inactivation in cell lines with EGFR overexpression significantly suppressed tumour development and progression in a mouse xenograft model. Our data suggest that EGFR signalling is important in a subset of cervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11.2 amplicon in their tumours.
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