Association Between Polymorphisms Of Folate Metabolism-Related Genes And Susceptibility To Nasopharyngeal Carcinoma

Background:Nasopharyngeal carcinoma(NPC)is a rare tumor in most parts of the world,with annual age-standardized incidence rates typically below 1 per 100,000 people/year in both sexes.The tumor occurs most often in Southern Chinese who reside in Guangdong Province,at an incidence rate 30-50 per 100,000 people/year,in contrast with＜1 per 100,000 people/year in white Europeans.Numerous factors,both environmental and genetic,have been associated with the risk of developing NPC.The environmental factors include infection with the Epstein-Barr virus(EBV),as well as frequent consumption of high levels of nitrosamine from preserved food such as salted fish.In addition,host factors also play a major role in NPC development.Folate is a water-soluble B vitamin and important cofactor in one-carbon metabolism.Folic acid is the fully oxidized monoglutamyl form of this vitamin that is used commercially in supplements and in fortified foods.The role of folate in human health and disease has rapidly been expanding.Folate deficiency has also been linked to the risk of several malignancies in humans,including cancer of the colorectum,oropharynx,esophagus,stomach,pancreas, lungs,cervix and ovary,and neuroblastoma and leukemia.There are two principal mechanisms through which low folate status may increase the risk of cancers.Firstly,folate deficiency,by reduced intracellular S-adenosylmethionine,can alter cytosine methylation in DNA,leading to inappropriate activation of proto-oncogenes and induction of malignant transformation.Secondly,folate is essential for normal DNA synthesis and repair.However,to serve as the active mediator,folate require metabolism catalyzed by several enzymes including RFC1 et al.,which play a central role in biotransformation of folate.Their functional nucleotide polymorphisms(such as MTRR 66A＞G,SHMT1 1420C＞T,SLC19A1 80G＞A,and MTHFD1 1958G＞A)would alter their activity,then may contribute to risk of cancer.Objective:A low dietary intake of folate has been linked to risk of several cancers,but epidemiologic studies with reference to NPC are scanty.So,we aimed to identify the susceptibility of genes contributing to NPC,which would assist in predicting individual and population risks of NPC development and would help to clarify pathogenesis of this malignancy.At the same time,this would be in favor of diagnosis and treatment of NPC.Methods:A case-control study was designed,which included 593 NPC patients and 480 controls.Risk of NPC was estimated by unconditional Logistic model.Odds ratios(OR)and 95%confidence intervals(CI) were adjusted for age,sex,smoking status,smoking level (pack-years),and alcohol use.Results:After investigating 15 polymorphisms in 13 genes(SLC19A1, MTHFD1,MTHFR,BHMT,SHMT1,GNMT,CBS,MTR,MTRR,MAT1A,TYMS,DHFR and AHCY)in the pathway of the folate metabolism,we found that compared with the GG and AA genotype,the GA genotype of BHMT was associated with significant increased susceptibility to NPC(P= 0.0002,OR=1.604,95%CI=1.250-2.058);compared with the GA or AA genotypes,the GG genotype of MTRR A66G was associated with significant increased susceptibility to NPC(P=0.0001,OR=3.226, 95%CI=1.786-5.848).In NPC progression,results showed that MAT1A rs17677908 AG and TYMS 3'UTR -/6bp was associated with the severity of NPC(P_trend=0.003 and 0.0002,respectively).In addition,individuals possessing TYMS 3' UTR -/- had increased risks of local tumor invasion,with ORs of 1.912(P=0.001,95%CI=1.297-2.825)respectively.Individuals carrying MAT1A rs17677908 AA had increased risks of lymph node involvement,with ORs of 2.882(P=0.002,95%CI=1.466-5.682).Conclusion:Polymorphisms of folate metabolism-related genes were associated with risk of occurrence and advance of NPC.