WFRF:(Lund Paulsen M.)
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Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
- Tulstrup, M. (author)
- Moriyama, T. (author)
- Jiang, C. (author)
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- Grosjean, M. (author)
- Nersting, J. (author)
- Grell, K. (author)
- Hjalgrim, L. L. (author)
- Jonsson, O. G. (author)
- Kanerva, J. (author)
- Lund, B. (author)
- Nielsen, S. N. (author)
- Nielsen, R. L. (author)
- Quist-Paulsen, P. (author)
- Pruunsild, K. (author)
- Wolthers, B. O. (author)
- Zhang, H. (author)
- Gupta, R. (author)
- Yang, J. J. (author)
- Schmiegelow, K. (author)
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- (creator_code:org_t)
- American Society of Hematology, 2020
- 2020
- English.
- In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:10, s. 1161-1168
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Keyword
- acute lymphoblastic-leukemia
- high-dose methotrexate
- maintenance
- therapy
- nudt15 polymorphisms
- nopho all2008
- free survival
- chemotherapy
- children
- cell
- polyglutamates
- Hematology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Tulstrup, M.
- Moriyama, T.
- Jiang, C.
- Grosjean, M.
- Nersting, J.
- Abrahamsson, Jon ...
- show more...
- Grell, K.
- Hjalgrim, L. L.
- Jonsson, O. G.
- Kanerva, J.
- Lund, B.
- Nielsen, S. N.
- Nielsen, R. L.
- Quist-Paulsen, P ...
- Pruunsild, K.
- Wolthers, B. O.
- Zhang, H.
- Gupta, R.
- Yang, J. J.
- Schmiegelow, K.
- show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
- MEDICAL AND HEAL ...
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- Blood
- By the university
- University of Gothenburg
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