Aim: To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). Patients & methods: To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. Results: The minor allele of rs1944294 in CDH2 gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). Conclusion: The variant in CDH2 gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.
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.
On November 10, 1942, after winning the battle of Alamein, Winston Churchill delivered these famous words: "Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning."Adults living with CHD are a growing population, as they are now surviving into adulthood and even reaching geriatric ages thanks to the emergence of surgical and medical innovations. 1 In all adults with CHD, the fastest-growing population is the one with complex congenital lesions. 1 Fontan patients are among the most resource-intensive populations from a health service perspective. They experience multiple extracardiac complications that are mainly related to sustained decreased cardiac output and increased systemic venous pressure. 2 This means that Fontan patients are living with a lifespan state of compensated or decompensated heart failure. 2 The functional consequences of their singular cardiovascular physiology have been expressed as both a reduced life expectancy when compared to other CHD population 3 and a decreased exercise capacity. 4 Moreover, skeletal muscle strength has been shown to be similar to that of patients with advanced heart failure, 5 since they have increased adiposity and, as shown by Cordina et al., Fontan-associated myopenia. 6 The advent of the Fontan operation has certainly improved outcomes for patients with univentricular heart, but given the ensuing complications, treating physicians feel this is "the end of the beginning," to use Churchill's words.Psoas muscle area, an indicator of sarcopenia, has proven to be an important marker of worse cardiovascular outcomes and of increased risk of mortality in patients with long-standing heart failure and increased cardiovascular burden. [7][8][9][10][11] It has also been shown to be correlated with indicators of physical frailty such as low handgrip strength and short physical performance battery. 12 Frailty is a broad multidimensional syndrome that reflects a patient's vulnerability. It encompasses multiple clinical elements such as muscle mass, strength, malnutrition, and functional performance. 13 Sarcopenia is therefore a crucial element in the assessment of frailty. We hypothesised that Fontan patients, despite their young age, exhibit sarcopenia resembling that more often seen in elderly patients with cardiovascular comorbidities rather than in healthy agematched controls.At the McGill Adult Unit for Congenital Heart Disease (MAUDE clinic, Montreal, Canada), a total of 67 patients with Fontan are actively followed. Multiple imaging modalities are used as part of the routine screening for Fontan-associated liver disease, including abdominal ultrasound, CT, and magnetic resonance. In this setting, 17 out of 67 Fontan patients had a CT of the abdomen performed and thus were included in the study. The psoas muscle areas were measured on the CT scan using the validated web-based software Coreslicer.com. 14 Measurements were done in the axial plane, at the highest level of the L4 vertebrae. There is no gold standard numb...
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