Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients.
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.
['Abaji|Rachid|R|', 'Gagné|Vincent|V|', 'Xu|Chang Jiang|CJ|', 'Spinella|Jean-François|JF|', 'Ceppi|Francesco|F|', 'Laverdière|Caroline|C|', 'Leclerc|Jean-Marie|JM|', 'Sallan|Stephen E|SE|', 'Neuberg|Donna|D|', 'Kutok|Jeffery L|JL|', 'Silverman|Lewis B|LB|', 'Sinnett|Daniel|D|', 'Krajinovic|Maja|M|']
D000293:Adolescent D000483:Alleles D000970:Antineoplastic Agents D001215:Asparaginase D002648:Child D002675:Child, Preschool D005260:Female D005787:Gene Frequency D055106:Genome-Wide Association Study D005838:Genotype D006801:Humans D008297:Male D016017:Odds Ratio D000071184:Pharmacogenomic Variants D020641:Polymorphism, Single Nucleotide D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma D011379:Prognosis D015203:Reproducibility of Results D012680:Sensitivity and Specificity D000073359:Whole Exome Sequencing
whole-exome sequencing acute lymphoblastic leukemia asparaginase exome-wide association pharmacogenetics