Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Breast cancer research and treatment, 2018, Vol.167 (1), p.249-256

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.