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

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.

• 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
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 167 Issue 1 Pg. 249-256 (01 2018) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 28913729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracyclines
• ETFB protein, human
• Electron-Transferring Flavoproteins

Topics

• Adult
• Aged
• Anthracyclines (adverse effects)
• Breast Neoplasms (complications, drug therapy, genetics, pathology)
• Cancer Survivors
• Cardiotoxicity (genetics, physiopathology)
• Electron-Transferring Flavoproteins (genetics)
• Exome (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Association Studies
• Genetic Predisposition to Disease
• Heart Failure (chemically induced, genetics, pathology)
• Humans
• Middle Aged
• Mitochondria (drug effects, pathology)