AUTHOR=Park Yoomi , Kim Hyery , Choi Jung Yoon , Yun Sunmin , Min Byung-Joo , Seo Myung-Eui , Im Ho Joon , Kang Hyoung Jin , Kim Ju Han 

TITLE=Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00654

DOI=10.3389/fphar.2019.00654

ISSN=1663-9812

ABSTRACT=<p><italic>Nudix Hydrolase 15 (NUDT15)</italic> and <italic>Thiopurine S-Methyltransferase (TPMT)</italic> are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with <italic>NUDT15</italic> or <italic>TPMT</italic> 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 <italic>NUDT15</italic> and <italic>TPMT</italic> was computed by aggregating <italic>in silico</italic> deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP &lt; 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( <italic>p</italic> &lt; 0.05) among <italic>NUDT15</italic> poor (PM, <italic>n</italic> = 1), intermediate (IM, <italic>n</italic> = 48), and normal (NM, <italic>n</italic> = 195) metabolizers. <italic>TPMT</italic> exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both <italic>NUDT15</italic> and <italic>TPMT</italic> ( <italic>p</italic> &lt; 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of <italic>NUDT15</italic>. GVB<italic><sup>NUDT15</sup></italic> 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 <italic>NUDT15</italic>-and-<italic>TPMT</italic> combined interaction analyses, GVB<italic><sup>NUDT15</sup></italic><sup>,</sup><italic><sup>TPMT</sup></italic> 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 <italic>below</italic> and four into <italic>above 25% DIP</italic> 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.</p>