CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study

• Authors: Xuexia Wang, University of Wisconsin-Milwaukee; Can-Lan Sun, City of Hope National Medical Center; Adolfo Quinones-Lombrana, State University of New York at Buffalo; Purnima Singh, University of Alabama Birmingham; Wendy Landier, University of Alabama Birmingham; Lindsey Hageman, University of Alabama Birmingham; Molly Mather, City of Hope National Medical Center; Jerome I. Rotter, University of California Los Angeles; Kent D. Taylor, University of California Los Angeles; Yii-Der Ida Chen, University of California Los Angeles; Saro H. Armenian, City of Hope National Medical Center; Naomi Winick, University of Texas Southwestern Medical Center; Jill P. Ginsberg, Childrens Hospital of Philadelphia; Joseph P. Neglia, University of Minnesota; Kevin C. Oeffinger, Memorial Sloan Kettering Cancer Center; Sharon Castellino, Emory University; Zoann E. Dreyer, Texas Childrens Cancer Center; Melissa M. Hudson, St Jude Children's Research Hospital; Leslie L. Robison, St Jude Children's Research Hospital; Javier G. Blanco, State University of New York at Buffalo; Smita Bhatia, University of Alabama Birmingham
• Journal Title: Journal of Clinical Oncology
• Volume: Volume 34, Number 8
• Publisher: American Society of Clinical Oncology | 2016-03-10, Pages 863-870
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1200/JCO.2015.63.4550
• Subjects: Health Sciences, Oncology; Health Sciences, Public Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; GENE-ENVIRONMENT INTERACTION; ADVANCED HEART-FAILURE; TROPONIN-T ISOFORMS; CHILDHOOD-CANCER; INDUCED CARDIOTOXICITY; TASK-FORCE; SURVIVORS; DOXORUBICIN; ADULT; PREDICTION

Abstract

Purpose: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk. Methods: A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples. Results: No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10-5). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m2 of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P <.001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m2 or less. This gene-environment interactionwas successfully replicated in an independent set of anthracyclinerelated cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence ofmore than one cTnT variant results in a temporally splitmyofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence ofmore than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P =.005). Conclusion: We report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.