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Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci

The Pharmacogenomics Journal volume 24, Article number: 21 (2024) Cite this article

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Abstract

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

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Fig. 1: Regional genetic association with cardiotoxicity risk.
Fig. 2: Gene expression by doxorubicin exposure.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Funding support for this study was provided by the NIH through MD Anderson’s Cancer Center Support Grant CA016672, Cancer Prevention Research Institute (CPRIT) grant RP180166, Harry S. Moss Heart Trust funding, and from MD Anderson Cancer Center’s University Cancer Foundation and the Duncan Family Institute for Cancer Prevention and Risk Assessment via the Cancer Survivorship Research Seed Money Grants.

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Authors and Affiliations

  1. Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lily K. Stafford, Xiaohui Tang, Amanda Brandt & Michelle A. T. Hildebrandt

  2. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Jianzhong Ma & Alanna C. Morrison

  3. Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Jose Banchs

  4. Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. Andrew Livingston

  5. Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael E. Roth

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Contributions

LS and MATH wrote the paper, with edits and final approval from all authors; XT, AB, and JM performed the analysis; ACM, JB, JAL, MER, and MATH designed the study.

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Correspondence to Michelle A. T. Hildebrandt.

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This study was approved by the Institutional Review Board of MD Anderson Cancer Center (protocol PA15-0172) and written informed consent was obtained from all study participants.

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Stafford, L.K., Tang, X., Brandt, A. et al. Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci. Pharmacogenomics J 24, 21 (2024). https://doi.org/10.1038/s41397-024-00343-0

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