Genome wide association studies for treatment-related adverse effects of pediatric acute lymphoblastic leukemia

2020 ◽  
pp. e1509
Author(s):  
Raffaella Franca ◽  
Giulia Zudeh ◽  
Marianna Lucafò ◽  
Marco Rabusin ◽  
Giuliana Decorti ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Effects ◽  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Genome Wide

scholarly journals Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients

2019 ◽  
Vol 20 (17) ◽  
pp. 1189-1197 ◽  
Author(s):  
Vincent Gagné ◽  
Anne Aubry-Morin ◽  
Maria Plesa ◽  
Rachid Abaji ◽  
Kateryna Petrykey ◽  
...  
Keyword(s):  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Childhood All ◽  
Exome Sequencing Data ◽  
Genome Wide ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana–Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.

scholarly journals Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies

2019 ◽  
Vol 103 (6) ◽  
pp. 1131-1139 ◽  
Author(s):  
William S. Oetting ◽  
Baolin Wu ◽  
David P. Schladt ◽  
Weihua Guan ◽  
Jessica van Setten ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Inherited genetic variation in childhood acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (26) ◽  
pp. 3988-3995 ◽  
Author(s):  
Takaya Moriyama ◽  
Mary V. Relling ◽  
Jun J. Yang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Host Susceptibility ◽  
Genome Wide Association Studies ◽  
Childhood All ◽  
Germline Variants ◽  
Complex Interactions ◽  
Genome Wide

Abstract Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

scholarly journals Genome-wide transethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia

2021 ◽  
Author(s):  
Soyoung Jeon ◽  
Adam J. de Smith ◽  
Shaobo Li ◽  
Minhui Chen ◽  
Ivo S. Muskens ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Ethnic Groups ◽  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Increased Risk

The incidence patterns of childhood acute lymphoblastic leukemia (ALL) differ across ethnic groups but have been studied mostly in populations of predominantly European ancestries. Risk variants identified from previous genome-wide association studies (GWAS) do not fully explain heritable risk. In an effort to address these limitations, we performed a meta-analysis of ALL in 76,317 participants across four ethnic groups, including 17,814 non-European individuals and 3,482 total cases. We generally replicated previously identified loci associated with ALL (15 out of 16 loci replicated after Bonferroni corrections). We further identified five novel associations at genome-wide significance, including three novel loci and two secondary associations at previously known loci (17q12 and near CEBPE). The three putatively novel loci (rs9376090 near MYB/HBS1L on chr6q23.3, rs10998283 near TET1 on chr10q21.3, and rs9415680 near JMJD1C/NRBF2 on chr10q21.3) were previously shown to be associated with multiple blood cell traits and other hematopoietic cancers. When trans-ethnic information is used, polygenic risk scores constructed from GWAS loci in our trans-ethnic meta-analysis showed similar efficacy in independent Latino (LAT) and non-Latino white (NLW) ALL cohorts (AUC ~ 0.67-0.68) and could partly explain the increased risk of ALL in LAT compared to NLW. Cross-population analysis also showed high but significantly less than 100% genetic correlation between LAT and NLW, suggesting potential differences in the underlying genetic architecture between ethnic groups. In summary, our findings enhance the understanding of genetic contribution to ALL risk across diverse populations and highlight the importance to include multiple ethnic groups in GWAS.  

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