Methyl donor status and oral HPV infection in young adults: importance to oropharyngeal cancer

  • Topic: Head-Neck Cancer
  • Institution: University of Sheffield
  • Country: United Kingdom
  • Status: Completed

Scientific abstract

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Background

Rates of HPV- linked oropharyngeal cancer (OPC) are reported to be increasing worldwide at a rate suggesting that the number of cases of HPV-linked OPC will soon exceed cases of HPV-linked cervical cancer. The factors governing HPV infection, latency, integration and persistence are poorly understood but there is evidence to suggest that dietary methyl donors may play an influential role, and there are supporting plausible mechanisms. 

Aims & Objectives

This study was conducted with two aims; to determine the prevalence of oral high risk HPV (HR-HPV) infection in adults in a city in the North of England, and to explore any association with methyl donor status; also to develop an in vitro model of methyl donor depletion of OPC cells and to determine how depletion affects the cancer cell phenotype.

Methods & results

Of 700 adults recruited to the study and providing buccal cell and blood samples only 15 had an oral infection with a high risk strain of HPV. People with oral HR-HPV infection were more likely to be male, be a past or current smoker, and have a greater number of oral sexual partners. There were no differences in the buccal cell concentration of methionine, choline, betaine or folate, or whole blood folate concentration, between oral HR-HPV positive and oral HR-HPV negative people. Buccal cell homocysteine concentration was lower in HR-HPV positive people but this finding needs to be interpreted cautiously given the small number of cases.

An in vitro model of methyl donor depletion was developed in HPV-positive OPC cells (UD-SCC2). Depletion of methionine, choline and folate resulted in reduced cell proliferation, increased apoptosis, and reduced cell migration. Furthermore, the expression of the DNA methyltransferase 3a (DNMT3a) gene was increased and this effect was reversed on methyl donor repletion. Expression of the apoptosis-regulating gene DAPK was increased at gene and protein level, possibly explaining effects on apoptosis. The data show that depleting OPC cells of methyl donors produces a favourable cancer cell phenotype.

Plain language abstract

Background

Rates of cancers of the mouth are increasing worldwide. This is due to an increase in those mouth cancers that are linked with infection with a virus called the human papillomavirus (HPV). HPV infection is very well known to cause cervical cancer, but this virus can also increase the risk of other cancers including mouth cancers. The global prevalence of HPV infection in the mouth is not known with any certainty, and there is current interest in generating reliable data.

There is some evidence that diet, including the intake of the vitamin folate, may influence how readily a person becomes infected with HPV and gets rid of the virus. This will in turn influence risk of developing HPV-linked cancers.

Aims & objectives

We have conducted an investigation into the prevalence of HPV infection in the mouth of adults in Sheffield, UK, and explored whether infection is associated with markers of dietary intake of folate and other nutrients that behave in a similar way (‘methyl donors’). We have also developed a system to allow us to examine whether a lack of dietary ‘methyl donors’ in mouth cancer cells affects the way the cancer cells behave. 

How the study was carried out

700 men and women were recruited to the study. Each person provided a small blood sample and samples of mouth cells. The concentration of methyl donors was measured in the mouth cells, and folate was also measured in the blood. Cells were test for infection with HPV. Only 2.1% had an oral infection with HPV, which is similar to recent findings from other countries. People with HPV infection of the mouth were more likely to be male, be a past or current smoker, and had a greater number of oral sexual partners. HPV infection in the mouth was not associated with the amount of the dietary ‘methyl donors’ in mouth cells, or with the amount of folate in the blood. This does not mean that diet does not influence HPV infection in the mouth; we need to find different ways of answering this question.

Key findings & conclusions

However, when we grew mouth cancer cells in lower amounts than usual of dietary ‘methyl donors’ we found that the cells behaved very differently. Overall the cells became less like aggressive cancer cells - they grew more slowly and were less able to move from one place to another (migrate). They were also more likely to die by a special, regulated, process of death, called apoptosis. We were able to explain this observation by demonstrating a change in the amount of a gene that influences cell death. These findings are important because they suggest that factors in our diet can influence the aggressiveness of cancers and perhaps influence whether cancer cells spread from one part of the body to another.