Mutation Screening and Association Study of the Folylpolyglutamate Synthetase (FPGS) Gene with Susceptibility to Childhood Acute Lymphoblastic Leukemia

Abstract

<b>Background:</b> Folylpolyglutamate synthetase (FPGS), an important enzyme in the folate metabolic pathway,plays a central role in intracellular accumulation of folate and antifolate in several mammalian cell types. Loss ofFPGS activity results in decreased cellular levels of antifolates and consequently to polyglutamatable antifolatesin acute lymphoblastic leukemia (ALL). Materials and <br/><b>Methods</b>: During May 1997 and December 2003, 134children diagnosed with ALL were recruited from one hospital in Thailand. We performed a mutation analysis inthe coding regions of the FPGS gene and the association between single nucleotide polymorphisms (SNPs) withinFPGS in a case-control sample of childhood ALL patients. Mutation screening was conducted by polymerasechain reaction-single strand conformation polymorphism (PCR-SSCP) and subsequently with direct sequencing(n=72). Association analysis between common FPGS variants and ALL risk was done in 98 childhood ALL casesand 95 healthy volunteers recruited as controls. <br/><b>Results</b>: Seven SNPs in the FPGS coding region were identifiedby mutation analysis, 3 of which (IVS13+55C>T, g.1297T>G, and g.1508C>T) were recognized as novel SNPs.Association analysis revealed 3 of 6 SNPs to confer significant increase in ALL risk these being rs7039798 (p=0.014, OR=2.14), rs1544105 (p=0.010, OR= 2.24), and rs10106 (p=0.026, OR= 1.99). <br/><b>Conclusions</b>: These findingssuggested that common genetic polymorphisms in the FPGS coding region including rs7039789, rs1544105, andrs10106 are significantly associated with increased ALL risk in Thai children.