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Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women

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Abstract

Purpose

Cytochrome b 5 (encoded by CYB5A) and NADH cytochrome b 5 reductase (encoded by CYB5R3) detoxify aromatic and heterocyclic amine mammary carcinogens found in cigarette smoke. We hypothesized that CYB5A and CYB5R3 polymorphisms would be associated with breast cancer risk in women.

Methods

We characterized the prevalence of 18 CYB5A and CYB5R3 variants in genomic DNA from African American (AfrAm) and Caucasian (Cauc) women from the Carolina Breast Cancer Study population (1,946 cases and 1,747 controls) and determined their associations with breast cancer risk, with effect modification by smoking.

Results

A CYB5R3 variant, I1M+6T (rs8190370), was significantly more common in breast cancer cases (MAF 0.0238) compared with controls (0.0169, p = 0.039); this was attributable to a higher MAF in AfrAm cases (0.0611) compared with AfrAm controls (0.0441, p = 0.046; adjusted OR 1.41, CI 0.98–2.04; p = 0.062). When smoking was considered, I1M+6T was more strongly associated with breast cancer risk in AfrAm smokers (adjusted OR 2.10, 1.08–4.07; p = 0.028) compared with never smokers (OR = 1.21; 0.77–1.88; p for interaction = 0.176). I1M+6T and three additional CYB5R3 variants, -251T, I8-1676C, and *392C, as well as two CYB5A variants, 13G and I2-992T, were significantly more common in AfrAms compared with Caucs.

Conclusions

CYB5R3 I1M+6C>T should be considered in future molecular epidemiologic studies of breast cancer risk in AfrAms. Further, variants in CYB5A and CYB5R3 should be considered in the evaluation of other tumors in AfrAms that are associated with aromatic and heterocyclic amine exposures, to include prostate, bladder, and colon cancers.

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Acknowledgments

The authors thank Jessica Tse, at the Mammalian Genotyping Core at the University of North Carolina at Chapel Hill, for genotype analyses and Dr. Elim Lau at the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for performing pyrosequencing. The authors also acknowledge the kind assistance of Dr. Richard Weinshilboum, whose laboratory performed initial screening of selected allele frequencies in Coriell DNA samples from African American subjects. Finally, the PI thanks Dr. Andrew Olshan, who was instrumental in the completion of this manuscript following the unexpected death of Dr. Robert Millikan. This study was supported by a grant from the Prevent Cancer Foundation, and in part by R01 GM61753 from the National Institutes of Health. Kristina Blanke was supported by an NIH/NIEHS training grant in Molecular and Environmental Toxicology (T32 ES007015). The Carolina Breast Cancer Study was funded by the Specialized Program of Research Excellence (SPORE) in Breast Cancer at UNC (NIH/NCI P50-CA58223) and the Lineberger Comprehensive Cancer Center Core Grant (P30-CA16086). The University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) facilities are supported by NIH/NCI P30 CA014520. Dr. Richard Weinshilboum’s contributions to preliminary data were supported by NIH/NIGMS grant U19 GM061388.

Conflict of interest

The authors assert that they have no relationships that could be construed as resulting in an actual, potential, or perceived conflict of interest relative to the work in this manuscript.

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Authors and Affiliations

  1. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI, 53706-1102, USA

    Kristina L. Blanke, James C. Sacco & Lauren A. Trepanier

  2. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Robert C. Millikan & Andrew F. Olshan

  3. Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    Robert C. Millikan, Andrew F. Olshan & Jingchun Luo

Authors
  1. Kristina L. Blanke
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  2. James C. Sacco
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  3. Robert C. Millikan
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  4. Andrew F. Olshan
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  5. Jingchun Luo
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  6. Lauren A. Trepanier
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Corresponding author

Correspondence to Lauren A. Trepanier.

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Robert C. Millikan: Deceased.

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Blanke, K.L., Sacco, J.C., Millikan, R.C. et al. Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women. Cancer Causes Control 25, 1513–1521 (2014). https://doi.org/10.1007/s10552-014-0454-7

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