Genetic factors in treatment-related cardiovascular complications in survivors of childhood acute lymphoblastic leukemia

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.

Keywords: anthracycline-induced cardiotoxicity; cancer survivors; childhood acute lymphoblastic leukemia; doxorubicin; genetic association studies; late adverse effects; pharmacogenomic markers; whole-exome sequencing.

Figure 1.. P-value distribution of all common variants tested in the entire PETALE cohort for left ventricular ejection fraction (LVEF) M-mode (%) represented as a Manhattan plot.

Manhattan plot was created to display the statistical significance between all common genetic variants used in the candidate gene association study (data combined from three candidate genes datasets) and LVEF M-mode (%) outcome and ranked according to their associated p-value. TTN: Titin.