Folate and Vitamin B12 May Play a Critical Role in Lowering the HPV 16 Methylation–Associated Risk of Developing Higher Grades of CIN

Abstract

We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52 and 58) and enhancer site 7862 of HPV 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of the current study was to replicate our previous findings and in addition to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16 positive women diagnosed with either CIN 2+ or ≤ CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and higher HPV 16m or those with higher plasma vitamin B12 and higher HPV 16m were 75% (P<0.01) and 60% (P=0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P=0.03) and 40% (P=0.07) increase in the odds of having a higher degree of HPV 16m, respectively. The present study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.

Risk factors for cervical intraepithelial neoplasia and cervical cancer in Chinese women: large study in Jiexiu, Shanxi Province, China

“…Flatley' study showed that a low folate level increased the risk of cervical cancer 30. Moreover, Piyathilake recently reported that folate and vitamin B12 may play critical roles in lowering the HPV16 methylation-associated risk of developing higher grades of CIN 31. Consistent with these findings, our data indicate that a low dietary folate intake may be a regional risk factor for increased CIN incidence in this area.…”

Human papillomavirus in cervical cancer and oropharyngeal cancer: One cause, two diseases

“…Higher folate levels protected against HPV infections and were associated with eradicating infection in HPV‐positive women in a 2‐year prospective study . Folate and vitamin B12 at high concentrations independently protect against the development of CIN‐2 and CIN‐3, possibly through methylation of the HPV E6 promoter and enhancer, which is involved in cervical carcinogenesis …”

“…51 Folate and vitamin B12 at high concentrations independently protect against the development of CIN-2 and CIN-3, possibly through methylation of the HPV E6 promoter and enhancer, which is involved in cervical carcinogenesis. 52 In addition, specific cervical microbial profiles are associated with the risk of CIN 2 or greater, suggesting the usefulness of combined approaches, including probiotics and vitamin supplementation along with vaccination (reviewed below), to reduce the overall risk of cervical cancer. 53…”

Cervical Intraepithelial Neoplasia and Cervical Cancer. Is Human Papillomavirus the Only Risk Factor?

“…Piyathilake и соавт. (2014) пришли к выводу, что персистенция ВПЧ и развитие CIN и РШМ зави-сят от метилирования ДНК самого вируса [12]. Пол ноце н но е ме т и л и р ов ание ДНК ВПЧ после внедрения в клетку способствует подавлению синтеза его онкобелков.…”

“…Метилирование генома ВПЧ-16 зависит от уровня фолатов как донаторов метильной группы и ведет к значительному подавлению синтеза онкобелков (в частности, Е6). Достижение оптимального уровня фолатов может приводить к снижению экспрессии генов онкобелков в клетках, инфицированных ВПЧ [12]. Позже в экспериментальной работе (2018), где изучалось влияние уровня фолатов на геномную интеграцию ДНК ВПЧ-16 in vivo на новой мышиной модели для быстрой онкогенной трансформации кератиноцитов человека, S. Xiao и соавт.…”