Effects of germline variants in DHFR and FPGS on methotrexate metabolism and relapse of leukemia
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Effects of germline variants in DHFR and FPGS on methotrexate metabolism and relapse of leukemia. / Tulstrup, Morten; Moriyama, Takaya; Jiang, Chuang; Grosjean, Marie; Nersting, Jacob; Abrahamsson, Jonas; Grell, Kathrine; Lyngsie Hjalgrim, Lisa; Jonsson, Olafur G; 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.
I: Blood, Bind 136, Nr. 10, 2020, s. 1161–1168.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Effects of germline variants in DHFR and FPGS 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 - Lyngsie Hjalgrim, Lisa
AU - Jonsson, Olafur G
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 - Copyright © 2020 American Society of Hematology.
PY - 2020
Y1 - 2020
N2 - Methotrexate (MTX) during maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL), but dosing strategies to achieve adequate treatment intensity are challenged by inter-individual 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 Paediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic SNP rs1382539 located in a regulatory element of DHFR was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) due to suppression of enhancer activity, while 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 = 0.044). These findings show a genetic basis for inter-patient variability in MTX response and could be used to improve future dosing algorithms.
AB - Methotrexate (MTX) during maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL), but dosing strategies to achieve adequate treatment intensity are challenged by inter-individual 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 Paediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic SNP rs1382539 located in a regulatory element of DHFR was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) due to suppression of enhancer activity, while 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 = 0.044). These findings show a genetic basis for inter-patient 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: 241096189