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Blood, 15 July 2005, Vol. 106, No. 2, pp. 717-720.
Prepublished online as a Blood First Edition Paper on March 29, 2005; DOI 10.1182/blood-2004-12-4941.
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NEOPLASIA
Brief report
Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia
Robert de Jonge,
Jan Hendrik Hooijberg,
Bertrand D. van Zelst,
Gerritz Jansen,
Christine H. van Zantwijk,
Gert Jan L. Kaspers,
Frits G. J. Peters,
Yaddanapudi Ravindranath,
Rob Pieters, and
Jan Lindemans
From the Departments of Clinical Chemistry and Pediatric Oncology/Hematology, Erasmus MC, Rotterdam, The Netherlands; the Departments of Pediatric Oncology/Hematology, Rheumatology, and Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; and Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit.
We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)
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