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 genespecific 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.

APOBEC-mediated genomic alterations link immunity and viral infection during human papillomavirus-driven cervical carcinogenesis

“…Studies have investigated the possibility that genespecific hypermethylation profiles could serve as predictive biomarkers of cervical cancer risk, but their findings must be verified in prospective studies. In addition, folate is presumed to play a role in modulating the risk of cervical cancer by influencing promoter hypermethylation of tumor suppressor genes (17).…”

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

“…Whether genome-wide hypomethylation represents an early or causative tumorigenic event or a passive consequence of cancer remains unknown (reviewed elsewhere (21)). The detection of hypomethylation in cancer precursor lesions and normal adjacent tissue, and the induction of cancers in animal models with experimentally induced hypomethylation suggest a causative role (30,(41)(42)(43). However, the occurrence of many cancers without apparent hypomethylation, and the progression of hypomethylation with cancer stage suggest a passive role (20,21).…”

Folate Deficiency and FHIT Hypermethylation and HPV 16 Infection Promote Cervical Cancerization

“…However, this study also has limitation. We only showed the relationships between folate and FHIT and HPV in cervical cancer progression, but did not indicate mechanisms of action even though other studies have indicated that folate may play an essential role in cervical lesions through impacting on DNA methylation (Flatley et al, 2009;Piyathilake et al, 2011). Future studies should avoid these limitations.…”