Genetic Variants in Oxidative Stress-Related Genes Predict Chemoresistance in Primary Breast Cancer: A Prospective Observational Study and Validation
Genetic Variants in Oxidative Stress-Related Genes Predict Chemoresistance in Primary Breast Cancer: A Prospective Observational Study and Validation
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氧化应激相关基因的遗传变异预测原发性乳腺癌的化疗耐药性：一项前瞻性观察研究和验证。
DOI：
10.1158/0008-5472.can-11-2998
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发表时间：
2012-01-15
期刊：
影响因子：
11.2
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
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作者：
Yu, Ke-Da;Huang, A-Ji;Shao, Zhi-Ming
原发性乳腺癌患者的化疗反应难以预测，宿主遗传因素的作用尚未得到彻底研究。我们假设氧化应激（OS）相关基因（包括雌激素-醌代谢酶NQO 2和GSTM 1 -5）的多态性可能影响疾病进展和治疗反应。在这项前瞻性观察性研究中，对806例原发性乳腺癌患者的19个标记候选基因已知变异的多态性进行了基因分型和分析。在体外和离体实验中显示影响基因表达水平的三种功能多态性改变了化疗对无病生存的影响。化疗与个体多态性或组合基因型（指定为遗传评分）之间存在显著的相互作用。与未接受化疗的低遗传评分患者相比，高遗传评分患者的疾病进展风险降低了75（HR = 0.25，95% CI：0.10-0.63，P = 0.005）;但是，在此情况下，与接受化疗时遗传评分较低的患者相比，（相互作用的HR = 4.60，95% CI：1.63-13.3，P = 0.004）。这些结果在另一人群（n = 339）中得到验证。总之，OS相关基因的生殖系多态性影响乳腺癌患者的化疗敏感性。虽然OS水平降低可能会阻止乳腺癌进展，但它们可能会损害辅助化疗的有效性。我们的研究结果还表明，宿主相关因素必须考虑个体化化疗。
Chemotherapy response in patients with primary breast cancer is difficult to predict and the role of host genetic factors has not been thoroughly investigated. We hypothesized that polymorphisms in oxidative stress (OS)-related genes, including estrogen-quinone metabolizing enzymes NQO2 and GSTM1-5, may influence disease progression and treatment response. In this prospective observational study, nineteen polymorphisms tagging known variations in candidate genes were genotyped and analyzed in 806 patients with primary breast cancer. Three functional polymorphisms, which were shown to affect gene expression levels in experiments in vitro and ex vivo, modified the effect of chemotherapy on disease-free survival. There were significant interactions between chemotherapy and individual polymorphisms or combined genotypes (designated as genetic score). Patients harboring high genetic score had a 75% reduction in the hazard of disease progression compared with patients with low genetic score when no chemotherapy was administered (HR = 0.25, 95% CI: 0.10-0.63, P = 0.005); however, they received much less survival benefit from adjuvant chemotherapy compared with patients with low genetic score when chemotherapy was administered (HR = 4.60 for interaction, 95% CI: 1.63-13.3, P = 0.004). These findings were validated in another population (n = 339). In conclusion, germline polymorphisms in OS-related genes affect chemotherapy sensitivity in breast cancer patients. Although reduced OS levels might prevent breast cancer progression, they probably compromise the effectiveness of adjuvant chemotherapy. Our findings also indicate that host-related factors must be considered for individualized chemotherapy.