Article abstract

Nature Genetics 40, 844 - 853 (2008)
Published online: 30 May 2008 | doi:10.1038/ng.155

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

Rainer Fagerholm1,17, Barbara Hofstetter2,17, Johanna Tommiska1,17, Kirsimari Aaltonen1,3, Radek Vrtel2,16, Kirsi Syrjäkoski4, Anne Kallioniemi4, Outi Kilpivaara1, Arto Mannermaa5,6, Veli-Matti Kosma5,6, Matti Uusitupa7, Matti Eskelinen8, Vesa Kataja9,10, Kristiina Aittomäki11, Karl von Smitten12, Päivi Heikkilä13, Jiri Lukas2, Kaija Holli14, Jirina Bartkova2, Carl Blomqvist3,15, Jiri Bartek2,16 & Heli Nevanlinna1

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 times 10-6) and in p53-aberrant tumors (P = 6.15 times 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.

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  1. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
  2. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
  3. Department of Oncology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
  4. Laboratory of Cancer Genetics, Tampere University Hospital and Institute of Medical Technology, University of Tampere, FI-33014 Tampere, Finland.
  5. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, FI-70211 Kuopio, Finland.
  6. Department of Pathology, Kuopio University Hospital, FI-70211 Kuopio, Finland.
  7. Department of Public Health and Clinical Nutrition, Kuopio University Hospital, FI-70211 Kuopio, Finland.
  8. Department of Surgery, Kuopio University Hospital, FI-70211 Kuopio, Finland.
  9. Department of Oncology, Kuopio University Hospital, FI-70211 Kuopio, Finland.
  10. Department of Oncology, Vaasa Central Hospital, FI-651000 Vaasa, Finland.
  11. Department of Clinical Genetics, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
  12. Department of Surgery, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
  13. Department of Pathology, Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
  14. Medical School, University of Tampere, and Palliative Unit, Tampere University Hospital, FI-33014 Tampere, Finland.
  15. Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
  16. Laboratory of Genome Integrity, Palacky University, CZ-77515 Olomouc, Czech Republic.
  17. These authors contributed equally to this work.

Correspondence to: Heli Nevanlinna1 e-mail: heli.nevanlinna@hus.fi

Correspondence to: Jiri Bartek2,16 e-mail: jb@cancer.dk



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