This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Udler, M. Articles by Pharoah, P. Search for Related Content PubMed PubMed Citation Articles by Udler, M. Articles by Pharoah, P.

Common Germline Genetic Variation in Antioxidant Defense Genes and Survival After Diagnosis of Breast Cancer

Miriam Udler, Ana-Teresa Maia, Arancha Cebrian, Clement Brown, David Greenberg, Mitul Shah, Carlos Caldas, Alison Dunning, Douglas Easton, Bruce Ponder, Paul Pharoah

From the Department of Public Health and Primary Care and the Department of Oncology, University of Cambridge; Cambridge Research Institute; and Eastern Cancer Registration and Information Centre, Unit C, Cambridge, United Kingdom

Address reprint requests to Miriam Udler, MPhil, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, United Kingdom; e-mail: miriam.udler{at}srl.cam.ac.uk

Purpose: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer.

Patients and Methods: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer.

Results: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r² = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes.

Conclusion: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.

Supported by a program grant from Cancer Research UK. B.P. is a Gibb Fellow, D.E. is a Principal Research Fellow, and P.P. is a Senior Clinical Research Fellow of Cancer Research UK.

M.U. and A.-T.M. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

This article has been cited by other articles:

				U. Peters, N. Chatterjee, R. B. Hayes, R. E. Schoen, Y. Wang, S. J. Chanock, and C. B. Foster Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1144 - 1154. [Abstract] [Full Text] [PDF]