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Published in: Breast Cancer Research and Treatment 1/2018

01-01-2018 | Epidemiology

Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients

Authors: Sara Ruiz-Pinto, Guillermo Pita, Miguel Martín, Teresa Alonso-Gordoa, Daniel R. Barnes, María R. Alonso, Belén Herraez, Purificación García-Miguel, Javier Alonso, Antonio Pérez-Martínez, Antonio J. Cartón, Federico Gutiérrez-Larraya, José A. García-Sáenz, Javier Benítez, Douglas. F. Easton, Ana Patiño-García, Anna González-Neira

Published in: Breast Cancer Research and Treatment | Issue 1/2018

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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.
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Metadata
Title
Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients
Authors
Sara Ruiz-Pinto
Guillermo Pita
Miguel Martín
Teresa Alonso-Gordoa
Daniel R. Barnes
María R. Alonso
Belén Herraez
Purificación García-Miguel
Javier Alonso
Antonio Pérez-Martínez
Antonio J. Cartón
Federico Gutiérrez-Larraya
José A. García-Sáenz
Javier Benítez
Douglas. F. Easton
Ana Patiño-García
Anna González-Neira
Publication date
01-01-2018
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4497-9

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