title: Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis.
abstract: Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a gene-specific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk.
authors.affiliation: Human Nutrition Unit, Faculty of Medicine, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Flatley
authors.forename: Kristelle
authors.initials: K
authors.lastname: McNeir
authors.forename: Latha
authors.initials: L
authors.lastname: Balasubramani
authors.forename: John
authors.initials: J
authors.lastname: Tidy
authors.forename: Emma L
authors.initials: EL
authors.lastname: Stuart
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Young
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Powers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D064550:Death-Associated Protein Kinases; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000821:virology
chemical_list: D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; D005492:Folic Acid; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045643:DNA Repair Enzymes