Research Article For reprint orders, please contact: reprints@futuremedicine.com Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients Vincent Gagn ´ e 1 , Anne Aubry-Morin 1 , Maria Plesa 1,3 , Rachid Abaji 1,3 , Kateryna Petrykey 1,3 , Pascal St-Onge 1 , Patrick Beaulieu 1 , Caroline Laverdi ` ere 1,2 , Nathalie Alos 1,2 , Jean-Marie Leclerc 1,2 , Stephen E Sallan 4,5 , Donna Neuberg 6 , Jeffery L Kutok ‡,7 , Lewis B Silverman 4,5 , Daniel Sinnett 1,2 & Maja Krajinovic* ,1,2,3 1 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada 2 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada 3 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada 4 Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02115, USA 5 Division of Hematology/Oncology, Children’s Hospital, Boston, MA 02115, USA 6 Department of Biostatistics & Computational Biology, Dana–Farber Cancer Institute, Boston, MA 02215, USA 7 Department of Pathology, Brigham & Women’s Hospital, Boston, MA 02215, USA *Author for correspondence: maja.krajinovic@umontreal.ca ‡ Current position: Senior VP & Chief Scientific Officer, Infinity Pharmaceuticals, Inc. Aim: To evaluate top-ranking genes identified through genome-wide association studies for an associa- tion with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana–Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were an- alyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1- SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication. First draft submitted: 26 June 2019; Accepted for publication: 17 September 2019; Published online: 5 November 2019 Keywords: acute lymphoblastic leukemia • cosrticosteroids • Dana–Farber Cancer Institute cohort • dexametha- sone • osteonecrosis • prednisone • Quebec childhood acute lymploblastic leukemia cohort • single nucleotide polymorphism Osteonecrosis (ON) is one of the major complications of childhood acute lymphoblastic leukemia (ALL) treat- ment [1–3]. It can be symptomatic and cause severe pain, joint damage and articular collapse or can remain asymptomatic and cause no disabilities. Although corticosteroids (CS) like prednisone (PDN) and dexamethasone (DXM) are widely used in ALL protocols [1,4–6] for their capacity to induce apoptosis of leukemia cells, they can also lead to symptomatic ON in a subset of patients [7–11]. It is a dose-limiting toxicity that can precipitate early withdrawal of CS from therapy for ALL [12]. Other factors may potentiate the effect of CS like concomitant drugs used in ALL therapy [13] or clinical prognostic factors, such as age at diagnosis higher than 10 years [1], female gender [2] and higher body mass index [14]. In order to detect the genetic component underlying the risk of ON, which may lead to personalized treatment or prophylactic options, several genome-wide association studies (GWAS) have been conducted recently, linking a number of polymorphisms to ON development [12,15,16]. For example, variants were identified near the glutamate receptor GRIN3A locus [12], near BMP7 [15] and in ACP1 gene [16]. Pharmacogenomics (Epub ahead of print) ISSN 1462-2416 10.2217/pgs-2019-0087 C  2019 Future Medicine Ltd