ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
复制标题
DOI：
10.1056/nejmoa1214271
复制
发表时间：
2013-03-21
期刊：
影响因子：
--
通讯作者：
Soria JC
中科院分区：
文献类型：
--
作者：
Friboulet L;Olaussen KA;Pignon JP;Shepherd FA;Tsao MS;Graziano S;Kratzke R;Douillard JY;Seymour L;Pirker R;Filipits M;André F;Solary E;Ponsonnailles F;Robin A;Stoclin A;Dorvault N;Commo F;Adam J;Vanhecke E;Saulnier P;Thomale J;Le Chevalier T;Dunant A;Rousseau V;Le Teuff G;Brambilla E;Soria JC
切除修复交叉互补组1（ERCC1）蛋白是非小细胞肺癌（NSCLC）顺铂化疗疗效的潜在预后生物标志物。虽然一些正在进行的试验正在评估ERCC1的表达水平，但尚未就评估方法达成共识。我们使用8F1抗体通过免疫组织化学分析的方法测量ERCC 1蛋白的表达水平，该方法在两个独立的3期试验（加拿大国家癌症研究所临床试验组JBR. 10和癌症和白血病组B 9633试验，来自肺辅助顺铂评估生物学项目）的494名患者的验证样本组中进行。我们比较了在国际辅助肺癌试验生物学研究中从589名患者获得的整个原始样本组的重复染色结果，这导致了ERCC1表达缺失和铂反应之间的初步相关性，与我们以前在相同肿瘤中的结果。我们绘制了16个市售ERCC1抗体识别的表位，并研究了不同ERCC1亚型修复铂诱导的DNA损伤的能力。我们无法验证ERCC1蛋白免疫染色的预测效果。ERCC1染色结果的不一致性表明自2006年以来8F1抗体的性能发生了变化。我们发现，16种抗体中没有一种能够区分四种ERCC1蛋白亚型，而只有一种亚型产生的蛋白具有完全的核苷酸切除修复和顺铂抗性能力。使用目前可用的ERCC1抗体的免疫组织化学分析没有特异性地检测到独特的功能性ERCC1亚型。因此，它在指导治疗决策方面的有用性有限。（由Eli Lilly和其他公司资助。
The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non–small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.)