Open Access

ARTICLE

Polymorphic Variations Associated With Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients

Valentina K. Todorova^*, Issam Makhoul^†, Ishwori Dhakal^‡, Jeanne Wei^§, Annjanette Stone^¶, Weleetka Carter^¶, Aaron Owen^*, V. Suzanne Klimberg^*

* Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
† Division of Medical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
‡ Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
§ Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
¶ Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA

Oncology Research 2017, 25(8), 1223-1229. https://doi.org/10.3727/096504017X14876245096439

Abstract

Doxorubicin (DOX) is a commonly used antineoplastic agent for the treatment of various malignancies, and its use is associated with unpredictable cardiotoxicity. Susceptibility to DOX cardiotoxicity is largely patient dependent, suggesting genetic predisposition. We have previously found that individual sensitivity to DOX cardiotoxicity was associated with differential expression of genes implicated in inflammatory response and immune trafficking, which was consistent with the increasing number of reports highlighting the important role of human leukocyte antigen (HLA) complex polymorphism in hypersensitivity to drug toxicity. This pilot study aimed to investigate DNA from patients treated with DOX-based chemotherapy for breast cancer and to correlate the results with the risk for DOX-associated cardiotoxicity. We have identified 18 SNPs in nine genes in the HLA region (NFKBIL1, TNF-α, ATP6V1G2-DDX39B, MSH5, MICA, LTA, BAT1, and NOTCH4) and in the psoriasis susceptibility region of HLA-C as potential candidates for association with DOX cardiotoxicity. These results, albeit preliminary and involving a small number of patients, are consistent with reports showing the presence of susceptibility loci within the HLA gene region for several inflammatory and autoimmune diseases, and with our previous findings indicating that the increased sensitivity to DOX cardiotoxicity was associated with dysregulation of genes implicated both in inflammation and autoimmune disorders.

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Keywords

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