title: Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.
  
  
  METHODS
  The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
  
  
  RESULTS
  MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
  
  
  CONCLUSIONS
  We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA. jun.yang@stjude.org.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Landier
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Hageman
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kornegay
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: F Lennie
authors.initials: FL
authors.lastname: Wong
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Smita
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D054796:Drug Dosage Calculations; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D040941:Heredity; D006579:Heterozygote; D006630:Hispanic or Latino / Q000235:genetics; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects*; D010597:Pharmacogenetics; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D000096964:Nudix Hydrolases
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D011755:Pyrophosphatases; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases