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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=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.

SUBMITTER: Abaji R

PROVIDER: S-EPMC5546438 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

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

Oncotarget 20170701 27

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 ...[more]

PMID: 28574850

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Project description:Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS.As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development.Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent.Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.

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

Publications

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

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