(View plain language abstract)
The incidence of oropharyngeal cancer in younger adults is increasing, especially cancer positive for human papillomavirus (HPV) infection. Oral HPV infection is a risk factor, independent of tobacco use and alcohol consumption. Research into the influence of dietary factors for risk of oropharyngeal cancer is limited although studies have shown a significant reduction in risk for people habitually consuming a diet high in fruit and vegetables. Some vegetables and fruits are good dietary sources of the methyl donors folate, choline and betaine and there is evidence that high dietary folate reduces risk of HPV-associated oropharyngeal cancer and that this protective effect is enhanced when associated with a low intake of methionine, another methyl donor. Folate status has also been linked with the pathogenesis of high risk-HPV infection in the cervix, but the direction of influence is not clear. The factors governing HPV infection, latency, integration, and persistence are complex and incompletely understood but there are several plausible routes whereby methyl donor status could influence the pathogenesis of HPV and thereby promote a cancer-enabling phenotype.
Phase one will comprise a screening study among men and women (20-40 years) for the presence of high-risk human papilloma virus (HR-HPV) infection in oral epithelial cells. A case-control study will then be carried out in 50 people who carry HR-HPV infection and 150 HR-HPV negative controls, matched to cases by age, sex and smoking status. Oral epithelial cells will be used for the determination of methyl donor profile, through the measurement of methionine, folate, choline, betaine and homocysteine and blood collected for the measurement of folate status. Logistic regression analysis will be used to examine whether systemic folate status or oral epithelial cell methyl donor profile are associated with HPV infection. To support the case control study, an oral epithelial cell system will be established to test hypotheses linking methyl donor depletion with a cancer-enabling phenotype.
Strategies to prevent and manage oropharyngeal cancer must include a consideration of modifiable factors which influence oral HPV persistence and clearance. This study will provide the first clear indication as to whether methyl donor status associates with oral HPV infection, supported by mechanistic data. Taken together, the results of the human study and the supporting mechanistic study will inform the case for and design of dietary trials for the prevention of oropharyngeal cancer through effects on the natural history of HPV infection.
The number of people worldwide diagnosed with cancer in the mouth and pharynx has increased very greatly over the last decade and this increase is likely to continue. This is especially true for cancers linked with an infection with the virus human papillomavirus (HPV). Importantly, the age at which mouth cancer is diagnosed is decreasing and is now most likely in men and women aged 40 years or younger. It has been known for some time that alcohol and smoking are risk factors for mouth cancer but infection with HPV is now known to be important too. Studies have shown that some dietary factors may influence whether a person acquires an infection with HPV and whether that infection stays for a long time. This is important because it suggests that diet could influence the likelihood of developing mouth cancer. At present the evidence is quite limited but a group of dietary compounds called methyl donors, which include the vitamin folate, may be important. Methyl donors are found in a range of foods including some vegetables, cereals and nuts.
The overall aim of the study is to explore whether there is an association between the amount of methyl donor compounds in cells from the mouth and infection with HPV in those cells. We also wish to carry out experiments with cells from the mouth to help try to understand how methyl donors might work in protecting a person against HPV infection and its persistence.
We will carry out the study in two parts. The first part of the study will be to examine links between HPV infection in cells collected from the mouth and the amount of methyl donor compounds in these cells. We will recruit about 700 men and women between 20 and 40 years of age, from Sheffield. We will collect cells from the mouth and then test for infection with HPV. We will also measure the amount of the vitamin folate in a blood sample from each person and look for a link between this and whether the person has an infection with HPV. We will then select people with HPV infection and those without and compare the amount of methyl donor compounds in mouth cells from these two groups. We will be able to work out whether methyl donor compounds in the diet are linked with the likelihood of a person having an infection with HPV. We will then investigate possible mechanisms for the ways in which methyl donor compounds could alter the way a cell behaves to make it more likely to become infected with HPV and become a cancer cell. We will do this by using special cells collected from the mouth and growing them either with plenty of methyl donor compounds or with only a very small amount. We will examine important aspects of the cell behaviour under these two conditions.
Because HPV infection is a risk factor for cancer in the mouth we need to find ways of reducing the chances of getting an infection and increase the chances of getting rid of it quickly. Our study will help us understand whether methyl donor compounds in the diet might be important and how they might work. This will help us to decide whether particular dietary patterns might protect against cancer in the mouth.