Singh P, Wang X, Hageman L, Chen Y, Magdy T, Landier W, Ginsberg JP, Neglia JP, Sklar CA, Castellino SM, Dreyer ZE, Hudson MM, Robison LL, Blanco JG, Relling MV, Burridge P, Bhatia S. Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children’s Oncology Group ALTE03N1 report. Cancer. 2020 Sep 1;126(17):4051-4058. doi: 10.1002/cncr.32948. Epub 2020 May 15. PubMed PMID: 32413235; PubMed Central PMCID: PMC7423633.
Study ID Citation
Abstract
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 GSTμ1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia. 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.