title: Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy.
abstract: OBJECTIVE
  A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer.
  
  
  METHODS
  Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models.
  
  
  RESULTS
  The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2.
  
  
  CONCLUSIONS
  This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, UK. david.jamieson@newcastle.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.forename: Nicola
authors.initials: N
authors.lastname: Cresti
authors.forename: Johanne
authors.initials: J
authors.lastname: Bray
authors.forename: Julieann
authors.initials: J
authors.lastname: Sludden
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Griffin
authors.forename: Nahed M
authors.initials: NM
authors.lastname: Hawsawi
authors.forename: Eve
authors.initials: E
authors.lastname: Famie
authors.forename: Emily V A
authors.initials: EV
authors.lastname: Mould
authors.forename: Mark W
authors.initials: MW
authors.lastname: Verrill
authors.forename: Felicity E B
authors.initials: FE
authors.lastname: May
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D011110:Polymorphism, Genetic; D011808:Quinone Reductases / Q000235:genetics*; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D013629:Tamoxifen; D004317:Doxorubicin; D003520:Cyclophosphamide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases