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

Abstract

Geneviève Nadeau,1 Erika Ouimet-Grennan,1 Michelle Aaron,1 Simon Drouin,2 Laurence Bertout,2 Albert Shalmiev,2 Patrick Beaulieu,2 Pascal St-Onge,2 Louis-Nicolas Veilleux,3 Frank Rauch,3 Kateryna Petrykey,1,2 Caroline Laverdière,1–2,4 Daniel Sinnett,1–2,4 Nathalie Alos,1–2,5* Maja Krajinovic1–2,4*1Department of Medicine, University of Montreal, Montreal, QC, Canada; 2Sainte-Justine University Hospital Research Centre, Montreal, QC, Canada; 3Division of paediatrics, Montreal Shriners Hospital for Children, Montreal, QC, Canada; 4Division of Hemato-Oncology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada; 5Division of Endocrinology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada *These authors contributed equally to this workBackground: 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) (rs2001616DUOX2, P=0.0002 (Pmax) and rs41270041ADAMTS4, 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.Keywords: acute lymphoblastic leukemia, late adverse effects, skeletal muscle deficit, genetic association study, whole exome sequencing

Keywords

• Acute lymphoblastic leukemia
• late adverse effects
• skeletal muscle deficits
• genetic association study
• whole exome sequencing