NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
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.
Nature Genetics