<p>Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors</p>

Abstract

Background: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers. Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models. Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616 DUOX2, P =0.0002 (Pmax) and rs41270041 ADAMTS4 , P =0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P =0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy ( P ≤0.02). Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.

Comparison of the Efficacy of Vindesine and Leurocristine for Pediatric Acute Lymphoblastic Leukemia and their Effects on Quality of Life

“…As a frequently occurring pediatric cancer [21][22][23], acute lymphoblastic leukemia may be caused by genetic factors, virus infection, and immunologic deficiency . In most cases, combined chemotherapy is provided to destroy the leukemia cells in the patients [26] to achieve a higher 5-year event-free survival (EFS) [27]. However, the P r e p r i n t treatment also leads to increased toxic effects.…”

Predictors of low and very low bone mineral density in long‐term childhood acute lymphoblastic leukemia survivors: Toward personalized risk prediction

“…36 The genetic aspect of sex-modulated associations between covariables, such as CRT and BMD, should also be further examined. 37,38 Limitations for this study include the use of DXA for BMD measurements as opposed to quantitative computed tomography (QCT), which allows a more precise assessment of bone density through volumetric BMD, limiting the probability of underestimating BMD for participants of short stature. Moreover, this is not a longitudinal study, as we do not have data regarding survivors' BMD status prior to receiving cancer treatments, and thus could not evaluate variation from baseline BMD for all participants.…”

Sex and Gender Considerations After Surviving Acute Lymphoblastic Leukemia: An Exercise Oncology Context

“…20 In childhood ALL survivors, genetic associations have also been reported between skeletal muscle function deficits and genes involved in muscle and bone metabolism. 21 These findings have an important influence on the female survivors' trainability and their capacity to improve their cardiorespiratory fitness levels, especially in those who received high doxorubicin doses.…”

“…To the best of our knowledge, every study of genetic associations in ALL survivors who were interested in health conditions (i.e., cardiorespiratory fitness and skeletal muscle function) and health-related fitness genes 18,21 reported that survivors exposed to a highly aggressive treatment regimen were most affected than survivors exposed to low treatment doses. Moreover, this is reinforced by anticancer drugs that can modify gene expression 22 and induce an impairment of cardiac function.…”