期刊
CANCER
卷 126, 期 17, 页码 4051-4058出版社
WILEY
DOI: 10.1002/cncr.32948
关键词
anthracyclines; cardiomyopathy; childhood cancer survivors; gene expression; glutathione S-transferase 1 (GSTM1) null genotype
类别
资金
- American Cancer Society Institutional Research Grant [IRG-60-001-53-IRG]
- Kaul Pediatric Research Institute Research Grant
- Children's Oncology Group (COG) Chair [U10 CA98543]
- National Clinical Trials Network (NCTN) Operations Center grant [U10CA180886]
- COG Statistics and Data Center grant [U10CA098413]
- St Baldrick's Foundation [GM 115279, CA 21765]
- Leukemia and Lymphoma Society Translational Research Program [6093-08]
- NCTN Statistics and Data Center [U10CA180899]
- National Cancer Institute Community Oncology Research Program Research Base [UG1CA189955]
Background Anthracycline-related cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione S-transferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As free-radical scavengers, GSTs could play a role in oxidative damage-induced cardiomyopathy. Associations between the GST mu 1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia. Methods The authors sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative real-time polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSC-CMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels. Results A significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3-5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 +/- 0.57 vs 1.33 +/- 1.33, respectively; P = .049). hiPSC-CMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007). Conclusions The current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline-related cardiomyopathy.
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