Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy.
Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy.
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DOI：
10.1158/1055-9965.epi-09-0871
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发表时间：
2010-03
期刊：
影响因子：
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通讯作者：
Weinshilboum RM
中科院分区：
文献类型：
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作者：
Moyer AM;Sun Z;Batzler AJ;Li L;Schaid DJ;Yang P;Weinshilboum RM
肺癌通常用铂化合物治疗。“谷胱甘肽途径”参与铂化合物的代谢。我们开始测试的假设，单核苷酸多态性（SNP）或谷胱甘肽通路内的基因拷贝数变异可能会影响肺癌患者的生存与这些药物治疗。对973例肺癌患者的生殖系DNA样本进行了290个谷胱甘肽途径SNP的基因分型。还测定了GSTT1拷贝数。我们确定了这些多态性与肺癌患者生存率的相关性，随后进行了功能基因组验证。我们观察到生存率与GSTT1拷贝数（p=0.017），GSTA5，GSTM4和ABCC4 SNP之间的暗示性关联，调整协变量（分别为p=0.018，0.002，0.002）或不调整（p=0.005，0.011，0.002）。然后用顺铂处理100个淋巴母细胞样细胞系，并且IC 50值与GSTM 4 SNP显著相关（p=0.019）。此外，GSTM4、GSTT1和ABCC4过表达显著降低了肺癌和HEK293T细胞系中顺铂的敏感性。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。这些结果为肺癌的个体化化疗迈出了一步。
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 variation 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, 0.002, respectively) or not (p=0.005, 0.011, 0.002). One hundred lymphoblastoid cell lines were then treated with cisplatin, and IC50 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.