Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients
Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes...
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Frontiers Media S.A.
2019-06-01
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Series: | Frontiers in Pharmacology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00654/full |
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doaj-3681c2031c204a16b44c6fce7ff43874 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yoomi Park Hyery Kim Jung Yoon Choi Jung Yoon Choi Sunmin Yun Byung-Joo Min Myung-Eui Seo Ho Joon Im Hyoung Jin Kang Hyoung Jin Kang Ju Han Kim Ju Han Kim |
spellingShingle |
Yoomi Park Hyery Kim Jung Yoon Choi Jung Yoon Choi Sunmin Yun Byung-Joo Min Myung-Eui Seo Ho Joon Im Hyoung Jin Kang Hyoung Jin Kang Ju Han Kim Ju Han Kim Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients Frontiers in Pharmacology 6-mercaptopurine drug toxicity variant burden pharmacogenetics pharmacogenomics next-generation sequencing |
author_facet |
Yoomi Park Hyery Kim Jung Yoon Choi Jung Yoon Choi Sunmin Yun Byung-Joo Min Myung-Eui Seo Ho Joon Im Hyoung Jin Kang Hyoung Jin Kang Ju Han Kim Ju Han Kim |
author_sort |
Yoomi Park |
title |
Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients |
title_short |
Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients |
title_full |
Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients |
title_fullStr |
Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients |
title_full_unstemmed |
Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients |
title_sort |
star allele-based haplotyping versus gene-wise variant burden scoring for predicting 6-mercaptopurine intolerance in pediatric acute lymphoblastic leukemia patients |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-06-01 |
description |
Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15. GVBNUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15-and-TPMT combined interaction analyses, GVBNUDT15,TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis. |
topic |
6-mercaptopurine drug toxicity variant burden pharmacogenetics pharmacogenomics next-generation sequencing |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00654/full |
work_keys_str_mv |
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doaj-3681c2031c204a16b44c6fce7ff438742020-11-25T01:17:09ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-06-011010.3389/fphar.2019.00654448146Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia PatientsYoomi Park0Hyery Kim1Jung Yoon Choi2Jung Yoon Choi3Sunmin Yun4Byung-Joo Min5Myung-Eui Seo6Ho Joon Im7Hyoung Jin Kang8Hyoung Jin Kang9Ju Han Kim10Ju Han Kim11Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South KoreaDepartment of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South KoreaDepartment of Pediatrics, Seoul National University College of Medicine, Seoul, South KoreaSeoul National University Cancer Research Institute, Seoul, South KoreaSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South KoreaSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South KoreaSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South KoreaDepartment of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South KoreaDepartment of Pediatrics, Seoul National University College of Medicine, Seoul, South KoreaSeoul National University Cancer Research Institute, Seoul, South KoreaSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South KoreaCenter for Precision Medicine, Seoul National University Hospital, Seoul, South KoreaNudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15. GVBNUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15-and-TPMT combined interaction analyses, GVBNUDT15,TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.https://www.frontiersin.org/article/10.3389/fphar.2019.00654/full6-mercaptopurinedrug toxicityvariant burdenpharmacogeneticspharmacogenomicsnext-generation sequencing |