Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis

Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2782-9. doi: 10.1158/1055-9965.EPI-09-0493. Epub 2009 Sep 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis Regulatory Proteins / genetics
  • Cadherins / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • DNA Methylation*
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Death-Associated Protein Kinases
  • Erythrocytes / metabolism
  • Female
  • Folic Acid / blood
  • Folic Acid / metabolism*
  • Glutathione S-Transferase pi / genetics
  • Humans
  • Middle Aged
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Receptors, Retinoic Acid / genetics
  • Tumor Suppressor Proteins / genetics
  • Uterine Cervical Dysplasia / genetics*
  • Uterine Cervical Dysplasia / metabolism*
  • Uterine Cervical Dysplasia / pathology
  • Uterine Cervical Dysplasia / virology
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology
  • Young Adult


  • Apoptosis Regulatory Proteins
  • Cadherins
  • Receptors, Retinoic Acid
  • Tumor Suppressor Proteins
  • Folic Acid
  • DNA Modification Methylases
  • MGMT protein, human
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • DNA Repair Enzymes