Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Pharmacogenet Genomics. 2011 Dec;21(12):808-19. doi: 10.1097/FPC.0b013e32834b6918.
A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer.
Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models.
The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2.
This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.
NQO1 基因中的 SNP 与乳腺癌患者对含蒽环类药物方案的反应有关。NQO1 和其同源物 NQO2 有许多共同的底物，但保留了明显的功能差异，NQO2 是一种更宽容的电子接受底物的分子。我们旨在确定功能性 NQO2 变体是否与辅助阿霉素和环磷酰胺治疗（无论是否使用他莫昔芬）治疗乳腺癌的反应改变相关。
对 227 例早期乳腺癌患者的基因组 DNA 样本进行 NQO1 和 NQO2 多态性的基因分型。所有参与者均接受 AC 辅助治疗方案治疗。在体外异位表达模型中验证了 NQO2 多态性的功能意义。
NQO1 SNP（rs1800566）与较差的预后和治疗延迟的可能性降低相关。ER 和 PR 阴性疾病且 NQO1 和 NQO2 SNP（rs1143684）均为野生型的患者，5 年总生存率为 100%，而携带一个次要等位基因的患者为 88%，携带两个或更多次要等位基因的患者为 70%（P=0.018，对数秩）。三等位 NQO2 启动子多态性的小等位基因携带者因不耐受而提前退出他莫昔芬治疗的可能性更高（P=0.009，对数秩）。通过 NQO2 的异位表达，MCF-7 细胞对阿霉素和 4OH 他莫昔芬的生长抑制更敏感，但对环磷酰胺不敏感。
本研究表明，NQO1 和 NQO2 均调节 AC 治疗的疗效，并且 NQO2 与他莫昔芬毒性相关。
