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Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy.
Pharmacogenet Genomics. 2011 Dec; 21(12):808-19.PG

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 Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank).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.

Authors+Show Affiliations

Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, UK. david.jamieson@newcastle.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21946896

Citation

Jamieson, David, et al. "Two Minor NQO1 and NQO2 Alleles Predict Poor Response of Breast Cancer Patients to Adjuvant Doxorubicin and Cyclophosphamide Therapy." Pharmacogenetics and Genomics, vol. 21, no. 12, 2011, pp. 808-19.
Jamieson D, Cresti N, Bray J, et al. Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. Pharmacogenet Genomics. 2011;21(12):808-19.
Jamieson, D., Cresti, N., Bray, J., Sludden, J., Griffin, M. J., Hawsawi, N. M., Famie, E., Mould, E. V., Verrill, M. W., May, F. E., & Boddy, A. V. (2011). Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. Pharmacogenetics and Genomics, 21(12), 808-19. https://doi.org/10.1097/FPC.0b013e32834b6918
Jamieson D, et al. Two Minor NQO1 and NQO2 Alleles Predict Poor Response of Breast Cancer Patients to Adjuvant Doxorubicin and Cyclophosphamide Therapy. Pharmacogenet Genomics. 2011;21(12):808-19. PubMed PMID: 21946896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. AU - Jamieson,David, AU - Cresti,Nicola, AU - Bray,Johanne, AU - Sludden,Julieann, AU - Griffin,Melanie J, AU - Hawsawi,Nahed M, AU - Famie,Eve, AU - Mould,Emily V A, AU - Verrill,Mark W, AU - May,Felicity E B, AU - Boddy,Alan V, PY - 2011/9/28/entrez PY - 2011/9/29/pubmed PY - 2012/6/15/medline SP - 808 EP - 19 JF - Pharmacogenetics and genomics JO - Pharmacogenet Genomics VL - 21 IS - 12 N2 - 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. SN - 1744-6880 UR - https://www.unboundmedicine.com/medline/citation/21946896/Two_minor_NQO1_and_NQO2_alleles_predict_poor_response_of_breast_cancer_patients_to_adjuvant_doxorubicin_and_cyclophosphamide_therapy_ L2 - https://doi.org/10.1097/FPC.0b013e32834b6918 DB - PRIME DP - Unbound Medicine ER -