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Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients
- Source :
- Breast Cancer Research and Treatment. 167:249-256
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
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.
- Subjects :
- Adult
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Electron-Transferring Flavoproteins
ETFB
Low-frequency variants
Breast Neoplasms
Long-term cancer survivors
03 medical and health sciences
Breast cancer
Cancer Survivors
Internal medicine
medicine
Humans
Missense mutation
Anthracyclines
Exome
Genetic Predisposition to Disease
Gene
Genetic Association Studies
Aged
Heart Failure
Genetics
Cardiotoxicity
business.industry
Cancer
Chronic cardiotoxicity
Middle Aged
medicine.disease
Pediatric cancer
Mitochondria
Gene Expression Regulation, Neoplastic
030104 developmental biology
Cohort
Female
business
Subjects
Details
- ISSN :
- 15737217 and 01676806
- Volume :
- 167
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research and Treatment
- Accession number :
- edsair.doi.dedup.....329d57635268986e0dd5c56a580fddb7