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Nature Genetics 40, 844–853 (1 July 2008) | doi:10.1038/ng.155

NAD(P)H:quinone oxidoreductase 1 NQO1|[ast]|2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

Rainer Fagerholm , Barbara Hofstetter , Johanna Tommiska , Kirsimari Aaltonen , Radek Vrtel , Kirsi Syrj|[auml]|koski , Anne Kallioniemi , Outi Kilpivaara , Arto Mannermaa , Veli-Matti Kosma , Matti Uusitupa , Matti Eskelinen , Vesa Kataja , Kristiina Aittom|[auml]|ki , Karl von Smitten , P|[auml]|ivi Heikkil|[auml]| , Jiri Lukas , Kaija Holli , Jirina Bartkova , Carl Blomqvist , Jiri Bartek & Heli Nevanlinna

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1|[ast]|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 |[times]| 10|[minus]|6) and in p53-aberrant tumors (P = 6.15 |[times]| 10|[minus]|5). Survival after metastasis was reduced among NQO1|[ast]|2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1|[ast]|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.