Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology

• Type of Material: Article
• Authors: Xuexia Wang, University of Wisconsin; Wei Liu, University of Alberta; Can-Lan Sun, City Hope National Medical Center; Saro H. Armenian, City Hope National Medical Center; Hakon Hakonarson, Childrens Hospital of Philadelphia; Lindsey Hageman, City Hope National Medical Center; Yan Ding, City Hope National Medical Center; Wendy Landier, City Hope National Medical Center; Javier G. Blanco, SUNY Buffalo; Lu Chen, University of Southern California; Adolfo Quinones, SUNY Buffalo; Daniel Ferguson, SUNY Buffalo; Naomi Winick, University of Texas Southwestern; Jill P. Ginsberg, Childrens Hospital of Philadelphia; Frank Keller, Emory University; Joseph P. Neglia, University of Minnesota; Sunil Desai, Stollery Childrens Hospital; Charles A. Sklar, Memorial Sloan Kettering Cancer Center; Sharon Castellino, Emory University; Irene Cherrick, Upstate Medical University; ZoAnn E. Dreyer, Baylor College of Medicine; Melissa M. Hudson, St Jude Childrens Research Hospital; Leslie L. Robison, St Jude Childrens Research Hospital; Yutaka Yasui, University of Alberta; Mary V. Relling, St Jude Childrens Research Hospital; Smita Bhatia, City Hope National Medical Center
• Language: English
• Date: 2014-03-01
• Publisher: AMER SOC CLINICAL ONCOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2014 by American Society of Clinical Oncology.
• Final Published Version (URL): http://dx.doi.org/10.1200/JCO.2013.50.3557
• Title of Journal or Parent Work: JOURNAL OF CLINICAL ONCOLOGY
• Volume: 32
• Issue: 7
• Start Page: 647
• End Page: +
• Grant/Funding Information: Supported by Grants No. U10 CA98543 from the National Cancer Institute (NCI), National Institutes of Health (NIH); No. 6093-08 from the Leukemia and Lymphoma Society; No. U01 GM92666 and GM73646 from the National Institute of General Medical Sciences Pharmacogenomics Research Network, NIH; and No. P30CA033572 from NCI, NIH, and American Lebanese Syrian Associated Charities.
• Keywords: CHILDHOOD-CANCER; BINDING-PROTEINS; CARDIOVASCULAR-DISEASE; Oncology; ASSOCIATION; POLYMORPHISMS; HEART-FAILURE; INDUCED CARDIOTOXICITY; Life Sciences & Biomedicine; HEMATOPOIETIC-CELL TRANSPLANTATION; RISK-FACTORS; SURVIVORS; Science & Technology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Toxicology; Health Sciences, Oncology

Abstract

Purpose: The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. Patients and Methods: By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. Results: By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10-7). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m2) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). Conclusion: Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS)-induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.