Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Cancer Epidemiol Biomarkers Prev. 2010 Mar;19(3):811-21. doi: 10.1158/1055-9965.EPI-09-0871. Epub 2010 Mar 3.
Lung cancer is commonly treated with platinum compounds. The "glutathione pathway" participates in the metabolism of platinum compounds. We set out to test the hypotheses that single nucleotide polymorphisms (SNPs) or copy number polymorphisms for genes within the glutathione pathway might influence survival in lung cancer patients treated with these drugs.
Germline DNA samples from 973 lung cancer patients were genotyped for 290 glutathione pathway SNPs. GSTT1 copy number was also assayed. We determined the association of these polymorphisms with survival for lung cancer patients, followed by functional genomic validation.
We observed suggestive associations between survival and GSTT1 copy number (P = 0.017), and GSTA5, GSTM4, and ABCC4 SNPs, adjusted for covariates (P = 0.018, 0.002, and 0.002, respectively) or not (P = 0.005, 0.011, and 0.002). One hundred lymphoblastoid cell lines were then treated with cisplatin, and IC(50) values were significantly associated with the GSTM4 SNP (P = 0.019). Furthermore, GSTM4, GSTT1, and ABCC4 overexpression significantly decreased cisplatin sensitivity in lung cancer and HEK293T cell lines.
These results suggest that GSTM4 polymorphisms are biomarkers for the prediction of cisplatin response. ABCC4 polymorphisms, as well as GSTT1 copy number, may also help to predict cisplatin response, but further validation is required. These results represent a step toward the individualized chemotherapy of lung cancer.
肺癌通常采用铂类化合物进行治疗。“谷胱甘肽途径”参与铂类化合物的代谢。我们旨在检验以下假说，即谷胱甘肽途径中基因的单核苷酸多态性（SNP）或拷贝数多态性可能影响接受这些药物治疗的肺癌患者的生存。
对 973 例肺癌患者的种系 DNA 样本进行 290 个谷胱甘肽途径 SNP 的基因分型，并检测 GSTT1 拷贝数。我们确定了这些多态性与肺癌患者生存的相关性，随后进行了功能基因组验证。
我们观察到 GSTT1 拷贝数（P=0.017）、GSTA5、GSTM4 和 ABCC4 SNP 与生存之间存在提示性关联，这些 SNP 在经过协变量调整（P=0.018、0.002 和 0.002）或未经调整（P=0.005、0.011 和 0.002）后均具有显著相关性。随后，我们用顺铂处理 100 个淋巴母细胞系，IC50 值与 GSTM4 SNP 显著相关（P=0.019）。此外，GSTM4、GSTT1 和 ABCC4 的过表达显著降低了肺癌和 HEK293T 细胞系对顺铂的敏感性。
这些结果表明，GSTM4 多态性是预测顺铂反应的生物标志物。ABCC4 多态性以及 GSTT1 拷贝数也可能有助于预测顺铂反应，但需要进一步验证。这些结果标志着朝着肺癌个体化化疗迈出了一步。
