Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node-Negative Cervical Cancer
Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node-Negative Cervical Cancer
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DOI：
10.1158/1078-0432.ccr-11-0297
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发表时间：
2011-08-15
影响因子：
11.5
通讯作者：
Lyng, Heidi
中科院分区：
文献类型：
--
作者：
Halle, Cathinka;Lando, Malin;Lyng, Heidi
目的：我们比较了表皮生长因子受体（EGFR）胞外域亚型（缺少酪氨酸激酶（TK）结构域）与全长受体及其自身磷酸化状态在常规放化疗治疗的宫颈癌中的预后意义。实验设计：在前瞻性收集的178例宫颈鳞状细胞癌患者中，用Western blotting和反转录PCR检测癌细胞中的DNA片段。邻位连接免疫组织化学分析用于评估EGFR特异性自身磷酸化。通过使用Illumina微珠阵列对110名患者进行基因表达分析，研究了与胞外域亚型表达相关的途径，并在41名患者的独立队列中进行了验证。单独胞外域亚型的膜表达，没有全长受体的共表达，显示出与不良临床结果的相关性，这在淋巴结阴性患者中非常显著。（局部控制，P = 0.0002;无进展生存，P < 0.0001;疾病特异性生存，在对数秩检验中P = 0.005）并且独立于临床变量。胞外域亚型主要是替代EGFR转录物的60 kD产物。它们的膜表达与致癌途径的转录调控相关，包括MYC和MAX的激活，这与不良结局显著相关。这种胞外域EGFR表达肿瘤的侵袭性表型在独立队列中得到证实。无论是总的还是全长EGFR蛋白水平，或自磷酸化状态，显示预后significant.Conclusion：膜表达的胞外域EGFR亚型，而不是TK激活，预测化疗后淋巴结阴性宫颈癌患者放疗效果不佳。临床癌症研究; 17（16）; 5501-12。（C）2011年《非洲标准化评论》。
Purpose: We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.Experimental Design: Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.Results: Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.Conclusion: Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer. Clin Cancer Res; 17(16); 5501-12. (C)2011 AACR.