title: Folate deficiency and FHIT hypermethylation and HPV 16 infection promote cervical cancerization.
abstract: Fragile histidine triad (FHIT) is a suppressor gene related to cervical cancer through CpG island hypermethylation. Folate is a water-soluble B-vitamin and an important cofactor in one-carbon metabolism. It may play an essential role in cervical lesions through effects on DNA methylation. The purpose of this study was to observe effects of folate and FHIT methylation and HPV 16 on cervical cancer progression. In this study, DNA methylation of FHIT, serum folate level and HPV16 status were measured using methylation-specific polymerase chain reaction (MSP), radioimmunoassay (RIA) and polymerase chain reaction (PCR), respectively, in 310 women with a diagnosis of normal cervix (NC, n=109), cervical intraepithelial neoplasia (CIN, n=101) and squamous cell carcinoma of the cervix (SCC, n=101). There were significant differences in HPV16 status (χ2=36.64, P<0.001), CpG island methylation of FHIT (χ2=71.31, P<0.001) and serum folate level (F=4.57, P=0.011) across the cervical histologic groups. Interaction analysis showed that the ORs only with FHIT methylation (OR=11.47) or only with HPV 16 positive (OR=4.63) or with serum folate level lower than 3.19ng/ml (OR=1.68) in SCC group were all higher than the control status of HPV 16 negative and FHIT unmethylation and serum folate level more than 3.19ng/ml (OR=1). The ORs only with HPV 16 positive (OR=2.58) or with serum folate level lower than 3.19ng/ ml (OR=1.28) in CIN group were all higher than the control status, but the OR only with FHIT methylation (OR=0.53) in CIN group was lower than the control status. HPV 16 positivity was associated with a 7.60-fold increased risk of SCC with folate deficiency and with a 1.84-fold increased risk of CIN. The patients with FHIT methylation and folate deficiency or with FHIT methylation and HPV 16 positive were SCC or CIN, and the patients with HPV 16 positive and FHIT methylation and folate deficiency were all SCC. In conclusion, HPV 16 infection, FHIT methylation and folate deficiency might promote cervical cancer progression. This suggests that FHIT may be an effective target for prevention and treatment of cervical cancer.
authors.affiliation: Maternal and Children Health care of Shanxi Province affiliated to Shanxi Medical University, Taiyuan China E-mail : wangjt59@163.com.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Bai
authors.forename: Jin-Tao
authors.initials: JT
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Jiang
authors.forename: Hui-Jie
authors.initials: HJ
authors.lastname: Kang
authors.forename: Chen-Fei
authors.initials: CF
authors.lastname: Gao
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000235:genetics* / Q000821:virology; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D005492:Folic Acid / Q000097:blood*; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000097:blood / Q000235:genetics* / Q000821:virology; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D005492:Folic Acid; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase