Association of GSTM1 null variant with anthracycline‐related cardiomyopathy after childhood cancer—A Children's Oncology Group ALTE03N1 report

Abstract

BackgroundAnthracycline‐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.MethodsThe 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.ResultsA 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).ConclusionsThe current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline‐related cardiomyopathy.

Genetics of Anthracycline Cardiomyopathy in Cancer Survivors

“…The existing evidence has been used to construct the proposed pathophysiologic mechanism of anthracycline-related cardiomyopathy in the Central Illustration . Whereas some studies utilized childhood cancer ( 21 – 25 , 27 , 28 , 45 – 47 ) or adult-onset cancer populations ( 26 , 48 – 55 ), others included patients across the age spectrum ( 20 , 30 , 56 , 57 ). Several studies examined homogeneous cancer populations (leukemia, osteosarcoma, breast cancer, lymphoma), whereas others examined a mix of several cancers.…”

“…Twelve of the 26 studies (46%) reviewed here, did not attempt a replication of their salient findings. However, some of these studies were either examining a single SNP with targeted activity and established mechanism of cardiotoxicity ( 28 , 57 ) or had extended their findings by demonstrating differential gene expression ( 47 ) or by validating in preclinical mouse models ( 26 ). Furthermore, some of these studies replicated findings from previous studies ( 30 , 48 – 51 ).…”

“…A previous report indicates an association between the GSTM1 null genotype and iron-overload–related cardiomyopathy in patients with thalassemia ( 59 , 60 ). Singh et al ( 47 ) sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors. They examined the GSTM1 gene deletion in 75 survivors with clinically validated cardiomyopathy and 92 survivors without cardiomyopathy.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…MLH1 and MLH2 are genes playing a role in DNA repair and GSTs are detoxifying enzymes. Another recent study by Singh et al (2020) investigated the role of GSTM1 in chronic anthracycline-induced cardiotoxicity. They found that patients carrying GSTM1 null genotype (i.e.…”

Pharmacogenomics and Pharmacogenetics in Osteosarcoma: Translational Studies and Clinical Impact

“…A recent study carried out on 167 anthracycline-exposed childhood cancer survivors (75 cases and 92 matched controls with different diagnosis including 40 with bone tumors) reported that patients who had the GSTM1 null genotype had a significantly higher risk to develop cardiomyopathy [ 121 ]. GSTM1 expression downregulation in patients with the null phenotype in peripheral blood was confirmed by array and RNA-Seq analyses.…”