Sara Ruiz-Pinto1, Guillermo Pita1, Miguel Martín2, Teresa Alonso-Gordoa3, Daniel R Barnes4, María R Alonso1, Belén Herraez1, Purificación García-Miguel5, Javier Alonso6, Antonio Pérez-Martínez5, Antonio J Cartón7, Federico Gutiérrez-Larraya7, José A García-Sáenz8, Javier Benítez1,9, Douglas F Easton4,10, Ana Patiño-García11, Anna González-Neira12. 1. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. 2. Gregorio Marañón Health Research Institute (IISGM), Universidad Complutense, 28007, Madrid, Spain. 3. Department of Medical Oncology, Hospital Universitario Ramón y Cajal, 28034, Madrid, Spain. 4. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK. 5. Department of Pediatric Hemato-Oncology, Hospital Universitario La Paz, 28046, Madrid, Spain. 6. Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, 28220, Majadahonda, Spain. 7. Department of Pediatric Cardiology, Hospital Universitario La Paz, 28046, Madrid, Spain. 8. Medical Oncology Service, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, 28040, Madrid, Spain. 9. Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain. 10. Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK. 11. Department of Pediatrics, Universidad de Navarra, University Clinic of Navarra, 31008, Pamplona, Spain. 12. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. agonzalez@cnio.es.
Abstract
PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.
PURPOSE:Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancerpatients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancerpatients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancerpatients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.
Entities:
Keywords:
Anthracyclines; Chronic cardiotoxicity; ETFB; Long-term cancer survivors; Low-frequency variants
Authors: Timothy N McOwan; Lauren A Craig; Anne Tripdayonis; Kathy Karavendzas; Michael M Cheung; Enzo R Porrello; Rachel Conyers; David A Elliott Journal: Cardiooncology Date: 2020-05-21