NAD(P)H:quinone oxidoreductase 1 NQO1☆2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
NAD(P)H:quinone oxidoreductase 1 NQO1☆2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
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DOI：
10.1038/ng.155
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发表时间：
2008-07-01
期刊：
影响因子：
30.8
通讯作者：
Nevanlinna, Heli
中科院分区：
文献类型：
--
作者：
Fagerholm, Rainer;Hofstetter, Barbara;Nevanlinna, Heli
NQO1可以防止氧化应激和致癌，稳定p53。我们发现一个纯合的常见错义变异（NQO1*2, rs1800566(T), NM_000903.2:c）。在两个独立的乳腺癌女性患者中，禁用nq01强烈预测生存率差（P = 0.002, N = 1005; P = 0.005, N = 1162），在蒽环类药物辅助化疗表阿霉素后（P = 7.52 × 10(-6)）和p53异常肿瘤（P = 6.15 × 10(-5)），这种影响尤其明显。NQO1*2纯合子的转移后生存率降低，进一步暗示NQO1缺失与癌症进展和治疗耐药有关。在体外实验中，NQO1*2纯合子乳腺癌细胞对表柔比星的应答也同样受损，这反映了NQO1与p53相关和与p53无关的作用。我们提出了NQO1缺失的乳腺肿瘤中蒽环类药物反应缺陷的模型，以及活性氧（ROS）升高导致的基因组不稳定性增加，并表明NQO1基因型是乳腺癌的预后和预测标志物。
NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1*2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1*2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1*2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.