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Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy

Lookup NU author(s): Dr David Jamieson, Dr Nicola Cresti, Julieann Sludden, Melanie Griffin, Nahed Hawsawi, Emily Mould, Dr Mark Verrill, Dr Felicity May, Professor Alan Boddy

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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 Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank).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. Conclusion This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity. Pharmacogenetics and Genomics 21:808-819 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.


Publication metadata

Author(s): Jamieson D, Cresti N, Bray J, Sludden J, Griffin MJ, Hawsawi NM, Famie E, Mould EVA, Verrill MW, May FEB, Boddy AV

Publication type: Article

Publication status: Published

Journal: Pharmacogenetics and Genomics

Year: 2011

Volume: 21

Issue: 12

Pages: 808-819

Print publication date: 01/12/2011

ISSN (print): 1744-6872

ISSN (electronic): 1744-6880

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1097/FPC.0b013e32834b6918

DOI: 10.1097/FPC.0b013e32834b6918


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