Risk of Anthracycline-induced Cardiac Dysfunction in Adolescent and Young Adult (AYA) Cancer Survivors: Role of Genetic Susceptibility Loci

Overview

Journal Pharmacogenomics J

Specialties Genetics
Molecular Biology
Pharmacology

Date 2024 Jul 1

PMID 38951505

Authors

Lily K Stafford

Xiaohui Tang

Amanda Brandt

Jianzhong Ma

Jose Banchs

J Andrew Livingston

Michael E Roth

Alanna C Morrison

Michelle A T Hildebrandt

Affiliations

Soon will be listed here.

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.

References

Hildebrandt M, Reyes M, Wu X, Pu X, Thompson K, Ma J . Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Sci Rep. 2017; 7(1):9698. PMC: 5575079. DOI: 10.1038/s41598-017-09517-2. View

Allenby G, Bocquel M, Saunders M, Kazmer S, Speck J, Rosenberger M . Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993; 90(1):30-4. PMC: 45593. DOI: 10.1073/pnas.90.1.30. View

Armenian S, Ding Y, Mills G, Sun C, Venkataraman K, Wong F . Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br J Haematol. 2013; 163(2):205-13. PMC: 3795883. DOI: 10.1111/bjh.12516. View

Magdy T, Jiang Z, Jouni M, Fonoudi H, Lyra-Leite D, Jung G . RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy. Cell Stem Cell. 2021; 28(12):2076-2089.e7. PMC: 8642268. DOI: 10.1016/j.stem.2021.08.006. View

Lipshultz S, Adams M, Colan S, Constine L, Herman E, Hsu D . Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. 2013; 128(17):1927-95. DOI: 10.1161/CIR.0b013e3182a88099. View

Huang H, Christidi E, Shafaattalab S, Davis M, Tibbits G, Brunham L . RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Reports. 2022; 17(4):756-765. PMC: 9023798. DOI: 10.1016/j.stemcr.2022.03.002. View

Semsei A, Erdelyi D, Ungvari I, Csagoly E, Hegyi M, Kiszel P . ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol Int. 2011; 36(1):79-86. DOI: 10.1042/CBI20110264. View

Ruiz-Pinto S, Pita G, Patino-Garcia A, Alonso J, Perez-Martinez A, Carton A . Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer. Pharmacogenet Genomics. 2017; 27(12):445-453. DOI: 10.1097/FPC.0000000000000309. View

Aminkeng F, Bhavsar A, Visscher H, Rassekh S, Li Y, Lee J . A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015; 47(9):1079-84. PMC: 4552570. DOI: 10.1038/ng.3374. View

10.

Berkman A, Lakoski S . Treatment, behavioral, and psychosocial components of cardiovascular disease risk among survivors of childhood and young adult cancer. J Am Heart Assoc. 2015; 4(4). PMC: 4579959. DOI: 10.1161/JAHA.115.001891. View

11.

Volkova M, Russell 3rd R . Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2012; 7(4):214-20. PMC: 3322439. DOI: 10.2174/157340311799960645. View

12.

Visscher H, Ross C, Rassekh S, Sandor G, Caron H, van Dalen E . Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr Blood Cancer. 2013; 60(8):1375-81. DOI: 10.1002/pbc.24505. View

13.

Bleyer A, Barr R, Hayes-Lattin B, Thomas D, Ellis C, Anderson B . The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer. 2008; 8(4):288-98. DOI: 10.1038/nrc2349. View

14.

Christidi E, Huang H, Shafaattalab S, Maillet A, Lin E, Huang K . Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes. Sci Rep. 2020; 10(1):10363. PMC: 7316788. DOI: 10.1038/s41598-020-65979-x. View

15.

DeLuca D, Levin J, Sivachenko A, Fennell T, Nazaire M, Williams C . RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics. 2012; 28(11):1530-2. PMC: 3356847. DOI: 10.1093/bioinformatics/bts196. View

16.

Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R . Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013; 9(8):e1003118. PMC: 3738458. DOI: 10.1371/journal.pcbi.1003118. View

17.

Elliott P . Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol. 2006; 33(3 Suppl 8):S2-7. DOI: 10.1053/j.seminoncol.2006.04.020. View

18.

Veal G, Hartford C, Stewart C . Clinical pharmacology in the adolescent oncology patient. J Clin Oncol. 2010; 28(32):4790-9. PMC: 3018345. DOI: 10.1200/JCO.2010.28.3473. View

19.

Chao C, Xu L, Bhatia S, Cooper R, Brar S, Wong F . Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study. J Clin Oncol. 2016; 34(14):1626-33. DOI: 10.1200/JCO.2015.65.5845. View

20.

Bleyer A . Young adult oncology: the patients and their survival challenges. CA Cancer J Clin. 2007; 57(4):242-55. DOI: 10.3322/canjclin.57.4.242. View