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

Morten Tulstrup; Takaya Moriyama; Chuang Jiang; Marie Grosjean; Jacob Nersting; Jonas Abrahamsson; Kathrine Grell; Lisa Lyngsie Hjalgrim; Ólafur Gísli Jónsson; Jukka Kanerva; Bendik Lund; Stine Nygaard Nielsen; Rikke Linnemann Nielsen; Ulrik Overgaard; Petter Quist-Paulsen; Kaie Pruunsild; Goda Vaitkeviciene; Benjamin Ole Wolthers; Hui Zhang; Ramneek Gupta; Jun J Yang; Kjeld Schmiegelow

doi:10.1182/blood.2020005064

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

Morten Tulstrup, Takaya Moriyama, Chuang Jiang, Marie Grosjean, Jacob Nersting, Jonas Abrahamsson, Kathrine Grell, Lisa Lyngsie Hjalgrim, Ólafur Gísli Jónsson, Jukka Kanerva, Bendik Lund, Stine Nygaard Nielsen, Rikke Linnemann Nielsen, Ulrik Overgaard, Petter Quist-Paulsen, Kaie Pruunsild, Goda Vaitkeviciene, Benjamin Ole Wolthers, Hui Zhang, Ramneek GuptaJun J Yang, Kjeld Schmiegelow

Department of Paediatrics and Adolescent Medicine

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.

Original language	English
Journal	Blood
Volume	136
Issue number	10
Pages (from-to)	1161-1168
Number of pages	8
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood.2020005064
Publication status	Published - 3 Sept 2020

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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

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

@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,

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doi = "10.1182/blood.2020005064",

language = "English",

volume = "136",

pages = "1161--1168",

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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

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

SN - 0006-4971

VL - 136

SP - 1161

EP - 1168

JO - Blood

JF - Blood

IS - 10

ER -

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

Abstract

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