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Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia

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Harvard

Jiang, C, Yang, W, Moriyama, T, Liu, C, Smith, C, Yang, W, Qian, M, Li, Z, Tulstrup, M, Schmiegelow, K, Crews, KR, Zhang, H, Pui, C-H, Evans, W, Relling, M, Bhatia, S & Yang, JJ 2021, 'Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia', Clinical Pharmacology and Therapeutics, bind 109, nr. 6, s. 1538-1545. https://doi.org/10.1002/cpt.2095

APA

Jiang, C., Yang, W., Moriyama, T., Liu, C., Smith, C., Yang, W., Qian, M., Li, Z., Tulstrup, M., Schmiegelow, K., Crews, K. R., Zhang, H., Pui, C-H., Evans, W., Relling, M., Bhatia, S., & Yang, J. J. (2021). Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia. Clinical Pharmacology and Therapeutics, 109(6), 1538-1545. https://doi.org/10.1002/cpt.2095

CBE

Jiang C, Yang W, Moriyama T, Liu C, Smith C, Yang W, Qian M, Li Z, Tulstrup M, Schmiegelow K, Crews KR, Zhang H, Pui C-H, Evans W, Relling M, Bhatia S, Yang JJ. 2021. Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia. Clinical Pharmacology and Therapeutics. 109(6):1538-1545. https://doi.org/10.1002/cpt.2095

MLA

Vancouver

Author

Jiang, Chuang ; Yang, Wenjian ; Moriyama, Takaya ; Liu, Chengcheng ; Smith, Colton ; Yang, Wentao ; Qian, Maoxiang ; Li, Ziping ; Tulstrup, Morten ; Schmiegelow, Kjeld ; Crews, Kristine R ; Zhang, Hui ; Pui, Ching-Hon ; Evans, William ; Relling, Mary ; Bhatia, Smita ; Yang, Jun J. / Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia. I: Clinical Pharmacology and Therapeutics. 2021 ; Bind 109, Nr. 6. s. 1538-1545.

Bibtex

@article{373442df936e419eb8c967c7d7f2073e,
title = "Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia",
abstract = "6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition.",
keywords = "5'-Nucleotidase/genetics, Adolescent, Alleles, Antimetabolites, Antineoplastic/pharmacokinetics, Child, Child, Preschool, Cohort Studies, Erythrocytes/metabolism, Female, Gene Expression Regulation, Neoplastic/genetics, Genome-Wide Association Study, Germ-Line Mutation, Humans, Linkage Disequilibrium, Male, Mercaptopurine/pharmacokinetics, Multigene Family, Multivariate Analysis, Mutation, Missense, Polymorphism, Single Nucleotide, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics, Thioguanine/blood, Young Adult",
author = "Chuang Jiang and Wenjian Yang and Takaya Moriyama and Chengcheng Liu and Colton Smith and Wentao Yang and Maoxiang Qian and Ziping Li and Morten Tulstrup and Kjeld Schmiegelow and Crews, {Kristine R} and Hui Zhang and Ching-Hon Pui and William Evans and Mary Relling and Smita Bhatia and Yang, {Jun J}",
note = "{\textcopyright} 2020 The Authors. Clinical Pharmacology & Therapeutics {\textcopyright} 2020 American Society for Clinical Pharmacology and Therapeutics.",
year = "2021",
month = jun,
doi = "10.1002/cpt.2095",
language = "English",
volume = "109",
pages = "1538--1545",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia

AU - Jiang, Chuang

AU - Yang, Wenjian

AU - Moriyama, Takaya

AU - Liu, Chengcheng

AU - Smith, Colton

AU - Yang, Wentao

AU - Qian, Maoxiang

AU - Li, Ziping

AU - Tulstrup, Morten

AU - Schmiegelow, Kjeld

AU - Crews, Kristine R

AU - Zhang, Hui

AU - Pui, Ching-Hon

AU - Evans, William

AU - Relling, Mary

AU - Bhatia, Smita

AU - Yang, Jun J

N1 - © 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.

PY - 2021/6

Y1 - 2021/6

N2 - 6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition.

AB - 6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition.

KW - 5'-Nucleotidase/genetics

KW - Adolescent

KW - Alleles

KW - Antimetabolites, Antineoplastic/pharmacokinetics

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Erythrocytes/metabolism

KW - Female

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Genome-Wide Association Study

KW - Germ-Line Mutation

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Mercaptopurine/pharmacokinetics

KW - Multigene Family

KW - Multivariate Analysis

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Thioguanine/blood

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85096644891&partnerID=8YFLogxK

U2 - 10.1002/cpt.2095

DO - 10.1002/cpt.2095

M3 - Journal article

C2 - 33124053

VL - 109

SP - 1538

EP - 1545

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 6

ER -

ID: 72405977