Epigenetic 'switches' could cause cancer

Scientists at the Children's Nutrition Research Center, USA, have shown that epigenetic changes alone could cause cancer.

The study used a mouse model to show that epigenetic changes — which does not alter DNA sequence, but affects how DNA is methylated — can stably switch off genes with the potential to cause cancer.

Dr Lanlan Shen, senior author of the study and associate professor of pediatrics at Baylor College of Medicine, said: 'We knew that epigenetic changes are associated with cancer, but didn't know whether these were a cause or consequence of cancer. Developing this new approach for "epigenetic engineering" allowed us to test whether DNA methylation changes alone can drive cancer'.

The team introduced a gene segment designed to attract methyl groups into the mouse genome, upstream to the p16 gene, which normally functions to regulate cell division. It was observed that as the mice approached adulthood, increased incidence of p16 methylation led to the spontaneous occurrence of cancers, and reduced survival rates.

Dr Peter Jones, research director and head of the cancer epigenomics lab at Michigan's Van Andel Research Institute who was not involved in the work, told The Scientist: 'For many years we've been very convinced that DNA methylation changes and epigenetic silencing contribute to human cancer, and there have been a lot of observations that support that concept'.

'What [this] paper does, which I think is very clever, is to selectively silence a tumour-suppressor gene - that's the p16 gene - in a mouse model system and then show that those mice do develop cancers. This shows that epigenetic silencing can lead directly to the formation of cancer'.

However, some authors cast doubt on the results and have argued whether or not some other means of gene silencing was associated with the transgene. Dr Jones responded: 'The idea of using a sequence which attracts methylation and shows that this gives rise to an increase in tumorigenesis, I think, is pretty solid evidence'.

'It's a very clever paper. I think the results are very clean and clear. It's a gene that is known to be methylated', Dr Jones said, referring to p16. 'It's known to be methylated very early in the cancer process... In the test tube, my lab has shown directly that the methylation of this particular region silences the gene, so I think all the dots have been connected and this was just a final cherry on the top of the cake, so to speak, to show this causality'.

Dr Robert Waterland, associate professor of pediatrics at Baylor, who was also involved in the study, added: 'This opens up the door for a whole new paradigm of how to understand tumorigenesis'.

'If we can identify epigenetic changes that predispose people to cancer, these may actually be treatable or preventable, so this opens up a lot of optimism in new ways to deal with cancer'.

The study was published in the Journal of Clinical Investigation.