WFRF:(Lund Paulsen M.)
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- Tulstrup, M. (author)
Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
- Article/chapterEnglish2020
Publisher, publication year, extent ...
- American Society of Hematology,2020
Numbers
- LIBRIS-ID:oai:gup.ub.gu.se/298094
- https://gup.ub.gu.se/publication/298094URI
- https://doi.org/10.1182/blood.2020005064DOI
Supplementary language notes
- Language:English
Part of subdatabase
- SwePubSwePub
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Notes
- 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 and genre
- MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
- MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng
- acute lymphoblastic-leukemia
- high-dose methotrexate
- maintenance
- therapy
- nudt15 polymorphisms
- nopho all2008
- free survival
- chemotherapy
- children
- cell
- polyglutamates
- Hematology
Added entries (persons, corporate bodies, meetings, titles ...)
- Moriyama, T. (author)
- Jiang, C. (author)
- Grosjean, M. (author)
- Nersting, J. (author)
- Abrahamsson, Jonas,1954Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences(Swepub:gu)xabrjo (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)
- Göteborgs universitetInstitutionen för kliniska vetenskaper (creator_code:org_t)
Related titles
- In:Blood: American Society of Hematology136:10, s. 1161-11680006-49711528-0020
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- Grell, K.
- Hjalgrim, L. L.
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- Zhang, H.
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