Submitted July 8, 2008
Accepted October 31, 2008
Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia
Robert de Jonge*, Wim J.E. Tissing, Jan Hendrik Hooijberg, Gerrit Jansen, Gertjan J. L. Kaspers, Jan Lindemans, Godefridus J Peters, and Rob Pieters
Clinical Chemistry, Erasmus MC, Rotterdam, Netherlands
Pediatric Oncology/Hematology, Beatrix Children's Hospital, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands
Rheumatology, VU University Medical Center, Amsterdam, Netherlands
Medical Oncology, VU University Medical Center, Amsterdam, Netherlands
Pediatric Oncology/Hematology, Erasmus MC-Sophia, Rotterdam, Netherlands
* Corresponding author; email: r.dejonge{at}erasmusmc.nl.
Polymorphisms in folate pathway genes may influence the susceptibility to ALL. DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS -151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR]=2.1; 95% confidence interval [CI]=1.3-3.2; P=0.002) and the RFC1 80A-allele (OR=1.5; 95%CI=1.1-2.1; P=0.02). Likewise, the NNMT IVS -151TT genotype showed a 2.2-fold increased ALL risk (OR=2.2; 95%CI, 1.1-4.6; P=0.04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R-allele and the MTHFR 677T-allele (OR=0.7; 95%CI=0.5-1.0; P<0.05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS -151CC / MTHFR 677CT+TT patients exhibited a 2-fold reduction in ALL risk while RFC1 80AA / NNMT IVS -151CT+TT subjects had a 4.2-fold increase in ALL risk (P=0.001). For the first time, we associate the RFC1 80G>A and NNMT IVS -151C>T variants to an increased ALL susceptibility.
