Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia
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Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia. / 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.
In: Clinical Pharmacology and Therapeutics, Vol. 109, No. 3, 2021, p. 1538-1545.Research output: Contribution to journal › Journal article › Research › peer-review
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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.
PY - 2021
Y1 - 2021
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.
U2 - 10.1002/cpt.2095
DO - 10.1002/cpt.2095
M3 - Journal article
C2 - 33124053
AN - SCOPUS:85096644891
VL - 109
SP - 1538
EP - 1545
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 3
ER -
ID: 253137253