The progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors.We performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness.Our results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the "high risk" prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females.For the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects' trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.
Abstract Purpose: Cancer survivors’ exposure to chemotherapeutic agents leads to multiple long-term side effects with a decrease in their cardiorespiratory fitness. The first aim was to determine whether cardiorespiratory fitness and physical activity levels were lower among survivors than healthy Canadians, while the second aim was to report associations between genetic variants and cardiorespiratory fitness in survivors. Methods: Cardiorespiratory fitness (VO2peak) and moderate to vigorous physical activity (MVPA) were compared between childhood ALL survivors (N=221) and healthy Canadians (N=825). We performed whole-exome sequencing in survivors. Germline variants (both common and rare) in a selected set of trainability genes were analyzed for an association with cardiorespiratory fitness. Results: Survivors’ VO2 peak was found to be 22% lower than healthy Canadians. The cardiorespiratory fitness level was different between survivors and healthy Canadians despite a clinically equivalent level of MVPA. Positive associations between the cardiorespiratory fitness level and trainability genes (TTN, LEPR, IGFBPI, and ENO3 genes) were reported, especially in female survivors with a low cardiorespiratory fitness level. Conclusion: The cardiorespiratory fitness was significantly lower in survivors, which can be associated with variants in genes related to subjects’ trainability. At this time, it appears that more physical activity would be beneficial to survivors to achieve the same benefits as the healthy population. However, the optimal amount of physical activity needed to reach these benefits is not yet clear. The survivors’ responder or nonresponder status several years after the end of the treatments is unknown. This study has important implications for the field of exercise in oncology. Citation Format: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. The need to improve exercise prescriptions to support care in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B62.
Anthracycline-induced cardiotoxicity (AIC) is a serious and common side effect of anthracycline therapy. Identification of genes and genetic variants associated with AIC risk has clinical potential as a cardiotoxicity predictive tool and to allow the development of personalized therapies. In this review, we provide an overview of the function of known AIC genes identified by association studies and categorize them based on their mechanistic implication in AIC. We also discuss the importance of functional validation of AIC-associated variants in human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) to advance the implementation of genetic predictive biomarkers. Finally, we review how patient-specific hiPSC-CMs can be used to identify novel patient-relevant functional targets and for the discovery of cardioprotectant drugs to prevent AIC. Implementation of functional validation and use of hiPSC-CMs for drug discovery will identify the next generation of highly effective and personalized cardioprotectants and accelerate the inclusion of approved AIC biomarkers into clinical practice.
PURPOSE: About 65% of childhood survivors who were exposed to chemotherapeutic agents during treatment suffer from multiple late adverse effects. Even though both males and females were treated with chemotherapy during their cancer, the distinction between them is not always taken into consideration in an exercise oncology context. This study aims to assess cardiorespiratory fitness and moderate to vigorous physical activity (MVPA) of survivors in comparison to healthy participants. Genetic associations with cardiorespiratory fitness levels were reported to provide a better understanding of how physiological parameters differ in both males and females, and to find out whether gender and genetic parameters have an impact on their cardiorespiratory fitness. METHODS: Germline variants in a selected set of genes were analyzed for an association with cardiorespiratory fitness. Whole-exome sequencing in survivors (N=239) was performed. Cardiorespiratory fitness and MVPA data were compared between childhood ALL survivors (N=221) and healthy participants (N=825). Additional analyses were performed to study the physiological differences between males and females. RESULTS: We found that female survivors (27.7±6.7mL·kg-1·min-1) were more affected than males (36.8±7.1mL·kg-1·min-1) by low cardiorespiratory fitness. For a clinically equivalent level of MVPA, cardiorespiratory fitness was significantly lower in female survivors (27.7±6.7mL·kg-1·min-1), compared to healthy females (37.0±7.6mL·kg-1·min-1). Female survivors' physical deconditioning seems to increase with age. Female survivors have significant genetic associations between their cardiorespiratory fitness and their trainability genes (LEPR, IGFBPI and ENO3 genes) that play an important role in the functioning of their skeletal and cardiac muscles. CONCLUSIONS: Female survivors are at higher risk than males to have an impairment in their cardiorespiratory fitness and represent at-risk patients in regard to their genetic dispositions. The promotion of physical activity needs to be encouraged through the care system with the involvement of health care professionals in pediatric oncology. An evidence-based medicine approach is essential to help females to improve their cardiorespiratory fitness through physical activity.
A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. Herewe analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. This study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors that might lead to personalized prophylactic or therapeutic strategies.
