Kateryna Petrykey1,2, Aziz M Rezgui1, Mathilde Le Guern1, Patrick Beaulieu1, Pascal St-Onge1, Simon Drouin1, Laurence Bertout1, Fan Wang3, Jessica L Baedke3, Yutaka Yasui3, Melissa M Hudson3,4, Marie-Josée Raboisson5,6, Caroline Laverdière1,5, Daniel Sinnett1,5, Gregor U Andelfinger5,7, Maja Krajinovic1,2,5. 1. Immune Diseases and Cancer Research Axis, Sainte-Justine University Health Center (SJUHC), Montreal, QC H3T 1C5, Canada. 2. Department of Pharmacology & Physiology, Université de Montréal, QC, H3T 1J4, Canada. 3. Department of Epidemiology & Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 4. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. 5. Department of Pediatrics, Université de Montréal, QC, H3T 1C5, Canada. 6. Cardiology Unit, Sainte-Justine University Health Center (SJUHC), Montreal, QC, H3T 1C5, Canada. 7. Fetomaternal and Neonatal Pathologies Research Axis, Sainte-Justine University Health Center (SJUHC), Montreal, QC, H3T 1C5, Canada.
Abstract
Aim: Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. Patients & methods: To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Results: Significant associations were detected among common variants in the TTN gene, left ventricular ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the NOS1, ABCG2 and NOD2 was observed in relation to left ventricular ejection fraction, and in NOD2 and ZNF267 genes in relation to fractional shortening. Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the CBR1, ABCC5 and AKR1C3 genes. None of the associations was replicated in St-Jude Lifetime Cohort Study. Conclusion: Further studies are needed to confirm whether the described genetic markers may be useful in identifying patients at increased risk of these complications.
Aim: Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. Patients & methods: To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Results: Significant associations were detected among common variants in the TTN gene, left ventricular ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the NOS1, ABCG2 and NOD2 was observed in relation to left ventricular ejection fraction, and in NOD2 and ZNF267 genes in relation to fractional shortening. Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the CBR1, ABCC5 and AKR1C3 genes. None of the associations was replicated in St-Jude Lifetime Cohort Study. Conclusion: Further studies are needed to confirm whether the described genetic markers may be useful in identifying patients at increased risk of these complications.
Entities:
Keywords:
anthracycline-induced cardiotoxicity; cancer survivors; childhood acute lymphoblastic leukemia; doxorubicin; genetic association studies; late adverse effects; pharmacogenomic markers; whole-exome sequencing
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