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Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia

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Harvard

Tulstrup, M, Moriyama, T, Jiang, C, Grosjean, M, Nersting, J, Abrahamsson, J, Grell, K, Hjalgrim, LL, Jónsson, ÓG, Kanerva, J, Lund, B, Nielsen, SN, Nielsen, RL, Overgaard, U, Quist-Paulsen, P, Pruunsild, K, Vaitkeviciene, G, Wolthers, BO, Zhang, H, Gupta, R, Yang, JJ & Schmiegelow, K 2020, 'Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia', Blood, vol. 136, no. 10, pp. 1161-1168. https://doi.org/10.1182/blood.2020005064

APA

Tulstrup, M., Moriyama, T., Jiang, C., Grosjean, M., Nersting, J., Abrahamsson, J., Grell, K., Hjalgrim, L. L., Jónsson, Ó. G., Kanerva, J., Lund, B., Nielsen, S. N., Nielsen, R. L., Overgaard, U., Quist-Paulsen, P., Pruunsild, K., Vaitkeviciene, G., Wolthers, B. O., Zhang, H., ... Schmiegelow, K. (2020). Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. Blood, 136(10), 1161-1168. https://doi.org/10.1182/blood.2020005064

CBE

Tulstrup M, Moriyama T, Jiang C, Grosjean M, Nersting J, Abrahamsson J, Grell K, Hjalgrim LL, Jónsson ÓG, Kanerva J, Lund B, Nielsen SN, Nielsen RL, Overgaard U, Quist-Paulsen P, Pruunsild K, Vaitkeviciene G, Wolthers BO, Zhang H, Gupta R, Yang JJ, Schmiegelow K. 2020. Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. Blood. 136(10):1161-1168. https://doi.org/10.1182/blood.2020005064

MLA

Vancouver

Author

Tulstrup, Morten ; Moriyama, Takaya ; Jiang, Chuang ; Grosjean, Marie ; Nersting, Jacob ; Abrahamsson, Jonas ; Grell, Kathrine ; Hjalgrim, Lisa Lyngsie ; Jónsson, Ólafur Gísli ; Kanerva, Jukka ; Lund, Bendik ; Nielsen, Stine Nygaard ; Nielsen, Rikke Linnemann ; Overgaard, Ulrik ; Quist-Paulsen, Petter ; Pruunsild, Kaie ; Vaitkeviciene, Goda ; Wolthers, Benjamin Ole ; Zhang, Hui ; Gupta, Ramneek ; Yang, Jun J ; Schmiegelow, Kjeld. / Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. In: Blood. 2020 ; Vol. 136, No. 10. pp. 1161-1168.

Bibtex

@article{de849640da544b029e73c42d4eb21e93,
title = "Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia",
abstract = "Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.",
author = "Morten Tulstrup and Takaya Moriyama and Chuang Jiang and Marie Grosjean and Jacob Nersting and Jonas Abrahamsson and Kathrine Grell and Hjalgrim, {Lisa Lyngsie} and J{\'o}nsson, {{\'O}lafur G{\'i}sli} and Jukka Kanerva and Bendik Lund and Nielsen, {Stine Nygaard} and Nielsen, {Rikke Linnemann} and Ulrik Overgaard and Petter Quist-Paulsen and Kaie Pruunsild and Goda Vaitkeviciene and Wolthers, {Benjamin Ole} and Hui Zhang and Ramneek Gupta and Yang, {Jun J} and Kjeld Schmiegelow",
note = "{\textcopyright} 2020 by The American Society of Hematology.",
year = "2020",
month = sep,
day = "3",
doi = "10.1182/blood.2020005064",
language = "English",
volume = "136",
pages = "1161--1168",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "10",

}

RIS

TY - JOUR

T1 - Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia

AU - Tulstrup, Morten

AU - Moriyama, Takaya

AU - Jiang, Chuang

AU - Grosjean, Marie

AU - Nersting, Jacob

AU - Abrahamsson, Jonas

AU - Grell, Kathrine

AU - Hjalgrim, Lisa Lyngsie

AU - Jónsson, Ólafur Gísli

AU - Kanerva, Jukka

AU - Lund, Bendik

AU - Nielsen, Stine Nygaard

AU - Nielsen, Rikke Linnemann

AU - Overgaard, Ulrik

AU - Quist-Paulsen, Petter

AU - Pruunsild, Kaie

AU - Vaitkeviciene, Goda

AU - Wolthers, Benjamin Ole

AU - Zhang, Hui

AU - Gupta, Ramneek

AU - Yang, Jun J

AU - Schmiegelow, Kjeld

N1 - © 2020 by The American Society of Hematology.

PY - 2020/9/3

Y1 - 2020/9/3

N2 - Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

AB - Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

U2 - 10.1182/blood.2020005064

DO - 10.1182/blood.2020005064

M3 - Journal article

C2 - 32391884

VL - 136

SP - 1161

EP - 1168

JO - Blood

JF - Blood

SN - 0006-4971

IS - 10

ER -

ID: 62071975