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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 who...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546438/ https://www.ncbi.nlm.nih.gov/pubmed/28574850 http://dx.doi.org/10.18632/oncotarget.17959 |
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author | Abaji, Rachid Gagné, Vincent Xu, Chang Jiang Spinella, Jean-François Ceppi, Francesco Laverdière, Caroline Leclerc, Jean-Marie Sallan, Stephen E. Neuberg, Donna Kutok, Jeffery L. Silverman, Lewis B. Sinnett, Daniel Krajinovic, Maja |
author_facet | Abaji, Rachid Gagné, Vincent Xu, Chang Jiang Spinella, Jean-François Ceppi, Francesco Laverdière, Caroline Leclerc, Jean-Marie Sallan, Stephen E. Neuberg, Donna Kutok, Jeffery L. Silverman, Lewis B. Sinnett, Daniel Krajinovic, Maja |
author_sort | Abaji, Rachid |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5546438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-55464382017-08-23 Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients Abaji, Rachid Gagné, Vincent Xu, Chang Jiang Spinella, Jean-François Ceppi, Francesco Laverdière, Caroline Leclerc, Jean-Marie Sallan, Stephen E. Neuberg, Donna Kutok, Jeffery L. Silverman, Lewis B. Sinnett, Daniel Krajinovic, Maja Oncotarget Research Paper 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. Impact Journals LLC 2017-05-17 /pmc/articles/PMC5546438/ /pubmed/28574850 http://dx.doi.org/10.18632/oncotarget.17959 Text en Copyright: © 2017 Abaji et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Abaji, Rachid Gagné, Vincent Xu, Chang Jiang Spinella, Jean-François Ceppi, Francesco Laverdière, Caroline Leclerc, Jean-Marie Sallan, Stephen E. Neuberg, Donna Kutok, Jeffery L. Silverman, Lewis B. Sinnett, Daniel Krajinovic, Maja Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title | Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title_full | Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title_fullStr | Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title_full_unstemmed | Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title_short | Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients |
title_sort | whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood all patients |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546438/ https://www.ncbi.nlm.nih.gov/pubmed/28574850 http://dx.doi.org/10.18632/oncotarget.17959 |
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