Department of Obstetrics and Gynecology, Shimane University School of Medicine, Enyacho 89-1, Izumo, Shimane 6938501, Japan.
Br J Cancer. 2011 Jul 26;105(3):420-7. doi: 10.1038/bjc.2011.222. Epub 2011 Jul 5.
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.
本研究旨在探讨表皮生长因子受体（EGFR）在子宫颈鳞癌和腺癌/腺鳞癌中的过度表达、EGFR 基因扩增以及酪氨酸激酶结构域的激活突变的模式。
通过免疫组织化学、荧光原位杂交和 PCR-SSCP 分别评估宫颈癌中 EGFR 的表达、扩增和突变，并通过回顾性病历回顾收集的临床数据进行相关性分析。通过用有效的抑制剂 AG1478 使宫颈癌细胞中的 EGFR 失活，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%）显示 EGFR 基因座的显著扩增，而 52 例腺癌/腺鳞癌中没有检测到 EGFR 扩增（P<0.05）。EGFR 扩增与宫颈鳞癌患者的总生存期显著缩短相关（P=0.001）。多因素分析显示，EGFR 基因扩增是总生存期的独立预后因素（P=0.011）。没有一例鳞癌（0%：32 例中无 1 例）在 EGFR 外显子 18 到 21 中检测到致癌突变。在鳞癌和腺癌/腺鳞癌中，KRAS 和 BRAF 突变的频率都非常低。AG1478 对宫颈癌细胞的敏感性取决于 EGFR 的过度表达。在 EGFR 过度表达的细胞系中，AG1478 诱导 EGFR 失活显著抑制了小鼠异种移植模型中的肿瘤发生和进展。
我们的数据表明，EGFR 信号在子宫颈鳞癌的一个亚组中很重要，并且针对 EGFR 的治疗可能会使携带肿瘤中 7p11.2 扩增子的患者受益。
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