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

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=1×10-8). 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.

Association of functional IL16 polymorphisms with cancer and cardiovascular disease: a meta-analysis

“…in Caucasians [47], diabetes mellitus [48], autoimmune diseases [49,50], endometriosis [45,51], and knee osteoarthritis [52,53]. A meta-analysis published in 2019 focusing only on renal cancer association studies also found no association between rs4778889 and rs11556218 and this disease [54].…”

Clinical Utilization of Pharmacogenetics in Psychiatry – Perspectives of Pharmacists, Genetic Counselors, Implementation Science, Clinicians, and Industry

“…Case studies of unanticipated drug response or drug-induced morbidity have included PGx analysis and large-cohort studies have analyzed the prevalence of PGx alleles to estimate risk of adverse outcomes or nonresponse [93][94][95][96][97][98]. More recently, whole exome or genome sequencing studies have reported on PGx findings, though PGx results are not (yet) included in the list of recommended secondary findings [99].…”

Increasing completion of asparaginase treatment in childhood acute lymphoblastic leukaemia (ALL): summary of an expert panel discussion

“…29 Also, a correlation between the SNPs in MYBBP1A, IL16 and SPEF2 with pancreatitis has been described. 35 Nevertheless, the impact of these variants is limited and predicting the risk of AAP and disease trajectories is not yet possible. 30 Since truncation of asparaginase therapy has been associated with reduced EFS, re-exposing AAP patients to asparaginase could be relevant to fully re-establish the probabilities of cure.…”