Work

Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients

Year: 2017

Type: article

Abstract: // Rachid Abaji 1,7 , Vincent Gagné 1 , Chang Jiang Xu 1 , Jean-François Spinella 1 , Francesco Ceppi 1 , Caroline Laverdière 1,2 , Jean-Marie Leclerc 1,2 , Stephen E. Sallan 3,4 , Donna Neuberg 5 , Jeffery L. Kutok 6 , Lewis B. Silverman 3,4 , Daniel Sinnett 1,2 and Maja Krajinovic 1,2,7 1 Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada 2 Department of Pediatrics, University of Montreal, Montreal, QC, Canada 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 4 Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA 5 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA 6 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 7 Department of Pharmacology, University of Montreal, Montreal, QC, Canada Correspondence to: Maja Krajinovic, email: // Keywords : acute lymphoblastic leukemia; asparaginase; exome-wide association; pharmacogenetics; whole-exome sequencing Received : April 21, 2017 Accepted : April 27, 2017 Published : May 17, 2017 Abstract Allergy, pancreatitis and thrombosis are common side-effects of childhood acute lymphoblastic leukemia (ALL) treatment that are associated with the use of asparaginase (ASNase), a key component in most ALL treatment protocols. Starting with predicted functional germline variants obtained through whole-exome sequencing (WES) data of the Quebec childhood ALL cohort we performed exome-wide association studies with ASNase-related toxicities. A subset of top-ranking variants was further confirmed by genotyping ( N =302) followed by validation in an independent replication group ( N =282); except for thrombosis which was not available for that dataset. SNPs in 12 genes were associated with ASNase complications in discovery cohort including 3 that were associated with allergy, 3 with pancreatitis and 6 with thrombosis. The risk was further increased through combined SNPs effect ( p ≤0.002), suggesting synergistic interactions between the SNPs identified in each of the studied toxicities. Interestingly, rs3809849 in the MYBBP1A gene was associated with allergy ( p = 0.0006), pancreatitis ( p =0.002), thrombosis ( p =0.02), event-free survival ( p =0.02) and overall survival ( p =0.003). Furthermore, rs11556218 in IL16 and rs34708521 in SPEF2 were both associated with thrombosis ( p =0.01 and p =0.03, respectively) and pancreatitis ( p =0.02). The association of SNPs in MYBBP1A, SPEF2 and IL16 geneswith pancreatitis was replicated in the validation cohort ( p ≤0.05) as well as in combined cohort ( p =0.0003, p =0.008 and p =0.02, respectively). The synergistic effect of combining risk loci had the highest power to predict the development of pancreatitis in both cohorts and was further potentiated in the combined cohort ( p =1x10 -8 ).The present work demonstrates that using WES data is a successful “hypothesis-free” strategy for identifying significant genetic markers modulating the effect of the treatment in childhood ALL.

Source: Oncotarget

DOI: 10.18632/oncotarget.17959