The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia.
Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL.
University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, Vrazov trg 2, 1000 Ljubljana, Slovenia. Electronic address: katja.goricar@mf.uni-lj.si.
Katja
K
Goričar
University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, Vrazov trg 2, 1000 Ljubljana, Slovenia. Electronic address: nina.erculj@mf.uni-lj.si.
Nina
N
Erčulj
University Medical Center, University Children's Hospital, Oncology and Haematology Unit, Bohoričeva 20, Ljubljana, Slovenia. Electronic address: barbara.faganel@gmail.com.
Barbara
B
Faganel Kotnik
University Medical Center, University Children's Hospital, Center for Medical Genetics, Vrazov trg 1, Ljubljana, Slovenia. Electronic address: marusa.debeljak@kclj.si.
Maruša
M
Debeljak
University Medical Center, University Children's Hospital, Center for Medical Genetics, Vrazov trg 1, Ljubljana, Slovenia. Electronic address: tinka.hovnih@kclj.si.
Tinka
T
Hovnik
University Medical Center, University Children's Hospital, Oncology and Haematology Unit, Bohoričeva 20, Ljubljana, Slovenia. Electronic address: janez.jazbec@mf.uni-lj.si.
Janez
J
Jazbec
University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, Vrazov trg 2, 1000 Ljubljana, Slovenia. Electronic address: vita.dolzan@mf.uni-lj.si.
Vita
V
Dolžan
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D051135:Rad51 Recombinase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
D004268:DNA-Binding Proteins; C110901:X-ray repair cross complementing protein 3; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
Childhood leukemia; DNA repair; Folate pathway; Polymorphism; Susceptibility