Abstract
Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.
Highlights
Anthracyclines are the milestone of chemotherapy drugs used to treat a variety of tumors
About 47% of the native map7d1b transcript was disrupted in the GBT239 heterozygous and 99% was disrupted in the GBT239 homozygous mutant (Figure 1(f))
This study combined the power of forward genetic study in the zebrafish animal model and a genome-wide association study (GWAS) in humans to identify MAP7D1 as a clinical relevant susceptibility gene to doxorubicin-induced cardiomyopathy (DIC)
Summary
Anthracyclines are the milestone of chemotherapy drugs used to treat a variety of tumors. While some candidate-gene approaches focused on genes involving pharmacokinetics and/or metabolisms of doxorubicin that mostly affect the acute cardiomyopathy which are usually clinically manageable, multiple unbiased GWASs have been used to identify genes/variants associated with the chronic and irreversible side effects of DIC [4, 5]. These chronic DIC-associated genes usually exhibit abundant expression in the heart organ and play primary roles in cardiac remodelling. Genetic variants in cardiomyopathy-causative genes, such as truncation variants in the titin gene, significantly increased the risk of anthracycline drug-associated cardiomyopathy and adverse cardiac events [5, 6]
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