Research Article

Evidence for association of SNPs in ABCB1 and CBR3, but not RAC2, NCF4, SLC28A3 or TOP2B, with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines

*Author for correspondence:

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Kelley M Kidwell

Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA

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Jacklyn N Thibert

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Christina Gersch

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Nicholas J Seewald

Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA

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Jeffrey Smerage

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Melvyn Rubenfire

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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N Lynn Henry

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Kathleen A Cooney

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

Department of Urology, University of Michigan Health System, Ann Arbor, MI 48109, USA

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Monika Leja

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Jennifer J Griggs

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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James M Rae

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Published Online:22 Jan 2016https://doi.org/10.2217/pgs.15.162

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Abstract

Aims: Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity. Patients & methods: A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis. Results: Previously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012). Conclusion: The associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Acknowledgements

The authors acknowledge the UM DNA Sequencing Core for performing the genotyping and the UM Comprehensive Cancer Center. The Michigan Institute for Clinical & Health Research Michigan Clinical Research Unit (MCRU) performed all of the sample collections for this study (2UL1TR000433–06).

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Financial & competing interests disclosure

This work was supported in part by The Breast Cancer Research Foundation (BCRF) (N003173 to JM Rae), the NIH (1RO1GM099143 to JM Rae), by a Pfizer Foundation Fellowship Award awarded to K Cooney to support M Caram, by the University of Michigan Cancer Research Committee Research Grant awarded to J Smerage and by the National Cancer Institute of the NIH under Award Number P30CA046592 by the use of the following Cancer Center Core: UM DNA Sequencing Core. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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