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

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

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

Author(s) -

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 Malthe Overgaard,

Petter QuistPaulsen,

Kaie Pruunsild,

Goda Vaitkevičienė,

Benjamin Ole Wolthers,

Hui Zhang,

Ramneek Gupta,

Jun J. Yang,

Kjeld Schmiegelow

Publication year - 2020

Publication title -

blood

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.515

H-Index - 465

eISSN - 1528-0020

pISSN - 0006-4971

DOI - 10.1182/blood.2020005064

Subject(s) - pharmacogenetics , methotrexate , genome wide association study , dosing , single nucleotide polymorphism , antimetabolite , hematology , biology , oncology , pharmacology , medicine , leukemia , cancer research , genetics , genotype , gene

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.

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