title: Polymorphic Variations Associated With Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.
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.
authors.forename: Valentina K
authors.initials: VK
authors.lastname: Todorova
authors.forename: Issam
authors.initials: I
authors.lastname: Makhoul
authors.forename: Ishwori
authors.initials: I
authors.lastname: Dhakal
authors.forename: Jeanne
authors.initials: J
authors.lastname: Wei
authors.forename: Annjanette
authors.initials: A
authors.lastname: Stone
authors.forename: Weleetka
authors.initials: W
authors.lastname: Carter
authors.forename: Aaron
authors.initials: A
authors.lastname: Owen
authors.forename: V Suzanne
authors.initials: VS
authors.lastname: Klimberg
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000150:complications* / Q000473:pathology; D066126:Cardiotoxicity / Q000209:etiology*; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin