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- Title
NAD(P)H:quinone oxidoreductase 1 NQO1<sup>*</sup>2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer.
- Authors
Fagerholm, Rainer; Hofstetter, Barbara; Tommiska, Johanna; Aaltonen, Kirsimari; Vrtel, Radek; Syrjäkoski, Kirsi; Kallioniemi, Anne; Kilpivaara, Outi; Mannermaa, Arto; Kosma, Veli-Matti; Uusitupa, Matti; Eskelinen, Matti; Kataja, Vesa; Aittomäki, Kristiina; von Smitten, Karl; Heikkilä, Päivi; Lukas, Jiri; Holli, Kaija; Bartkova, Jirina; Blomqvist, Carl
- Abstract
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 × 10−6) and in p53-aberrant tumors (P = 6.15 × 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.
- Subjects
BREAST cancer; CARCINOGENESIS; DRUG therapy; CANCER invasiveness; TUMORS
- Publication
Nature Genetics, 2008, Vol 40, Issue 7, p844
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.155