Yu Dianke, Zhang Xuemei, Liu Ju, Yuan Peng, Tan Wen, Guo Yongli, Sun Tong, Zhao Dan, Yang Ming, Liu Junniao, Xu Binghe, Lin Dongxin
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Clin Cancer Res. 2008 May 1;14(9):2878-86. doi: 10.1158/1078-0432.CCR-07-1612.
The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC).
Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors.
We identified two functional variants in the ERCC1 5'-flanking region, -433T>C and 262G>T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the -433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262T allele.
These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs.
切除修复交叉互补基因1（ERCC1）在DNA修复中起关键作用，并且与预防致癌作用及对铂类抗癌药物的耐药性相关。我们测试了ERCC1基因中的遗传变异是否与肺癌易感性以及小细胞肺癌（SCLC）患者铂类化疗的疗效相关。
对30个个体的DNA样本进行测序以寻找单核苷酸多态性，并通过一系列生化测定研究变异的功能。对988例肺癌患者和986例对照者进行了病例对照研究。根据基因型，对162例SCLC患者的化疗结果进行了比较。通过针对临床因素进行调整的Cox模型计算总生存期。
我们在ERCC1 5'侧翼区域鉴定出两个功能性变异，-433T>C和262G>T，它们共同影响ERCC1的转录调控。262G等位基因与核蛋白结合的亲和力显著降低，并与ERCC1 RNA表达降低相关。病例对照分析表明，-433C和262G等位基因单独以及以基因-吸烟联合效应的方式与肺癌易感性增加相关。相反，SCLC患者化疗结果分析显示，与262T等位基因相比，262G等位基因与更好的药物反应和更长的生存时间相关。
这些发现与DNA修复在癌症中是一把双刃剑的观点一致，并表明ERCC1中的功能性单核苷酸多态性可能作为基于铂类抗癌药物的个体化化疗的简单且侵入性较小的生物标志物。
