Department of Clinical Oncology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Mutat Res. 2014 Jan;759:37-44. doi: 10.1016/j.mrfmmm.2013.11.001. Epub 2013 Nov 9.
ERCC1 is involved in the repair of oxaliplatin-induced DNA damage. Studies for the association of the C118T SNP with clinical response to treatment with platinum drugs have rendered inconsistent results. We investigated the ERCC1 C118T SNP with respect to overall and progression-free survival in patients with advanced colorectal cancer (ACC) treated with oxaliplatin and in vitro DNA repair capacity after oxaliplatin exposure. In addition we discuss discrepancies from other studies concerning ERCC1 C118T.
Progression-free survival was determined in 145 ACC patients treated with oxaliplatin-based chemotherapy in a phase 3 trial. For the in vitro studies regarding ERCC1 functionality, we transfected an ERCC1 negative cell line with 118C or 118T ERCC1. Cellular sensitivity and DNA repair capacity after exposure to oxaliplatin was examined by Sulphorodamine B growth inhibition assay, COMET assay and Rad51 foci staining.
We found no association between ERCC1 C118T and progression-free or overall survival. In addition, transfection of either 118C or 118T restores DNA-repair capacity of UV20 cells to the same level and chemosensitivity to oxaliplatin was similar in ERCC1 118C and 118T transfected cells.
This study shows that the ERCC1 C118T variants are not associated with survival in ACC patients treated with oxaliplatin or the in vitro sensitivity and DNA-repair capacity in 118C and 118T transfected cell lines. Therefore, ERCC1 C118T genotyping seems of no value in individualizing oxaliplatin based chemotherapy in ACC.
ERCC1 参与奥沙利铂诱导的 DNA 损伤修复。研究 ERCC1 C118T 单核苷酸多态性与铂类药物治疗的临床反应之间的关系，结果不一致。我们研究了 ERCC1 C118T 单核苷酸多态性与接受奥沙利铂治疗的晚期结直肠癌（ACC）患者的总生存和无进展生存的关系，以及奥沙利铂暴露后体外 DNA 修复能力。此外，我们还讨论了与 ERCC1 C118T 有关的其他研究中的差异。
在一项 3 期临床试验中，对 145 例接受奥沙利铂为基础化疗的 ACC 患者进行了无进展生存的测定。为了研究 ERCC1 功能，我们用 118C 或 118T ERCC1 转染 ERCC1 阴性细胞系。通过 Sulphorodamine B 生长抑制试验、COMET 试验和 Rad51 焦点染色，检测细胞对奥沙利铂的敏感性和 DNA 修复能力。
我们没有发现 ERCC1 C118T 与无进展生存或总生存之间存在关联。此外，转染 118C 或 118T 均可将 UV20 细胞的 DNA 修复能力恢复到相同水平，而 ERCC1 118C 和 118T 转染细胞对奥沙利铂的化疗敏感性相似。
本研究表明，在接受奥沙利铂治疗的 ACC 患者中，ERCC1 C118T 变体与生存无关，在 118C 和 118T 转染细胞系中，体外敏感性和 DNA 修复能力也没有差异。因此，ERCC1 C118T 基因分型在奥沙利铂为基础的个体化化疗中似乎没有价值。
