Researchers discover genetic trigger that plays a key role in cancer of the oesophagus

Cancer Research UK scientists at the University of Oxford have identified a gene which plays a key role in the development of cancer of the oesophagus by triggering changes in the oesophagus lining. The discovery, reported today in the journal Proceedings of the National Academy of Sciences, sheds new light on the molecular mechanisms involved in the development of Barrett’s oesophagus, a condition which is a major predisposing factor causing cancer of the oesophagus.

Barrett’s oesophagus is a condition affecting up to two per cent of the population in Britain in which the cells lining the oesophagus begin to change to look more like the cells lining the intestine. The condition usually develops following injury to the lining of the oesophagus due to long-term gastric reflux, when stomach contents, including acid and bile, flow back into the oesophagus causing inflammation and heartburn. People with Barrett’s oesophagus are at least 50 times more likely to develop cancer of the oesophagus than those without. Cancer of the oesophagus is the ninth most common cancer in the UK with over 7,400 new cases each year, and is one of the most rapidly increasing cancers in the western world.

The Oxford team have now identified a gene, CDX1, which acts as a trigger for the changes to the cell lining that occur in Barrett’s oesophagus. CDX1 is known to play a key role in the development of the intestine and is normally switched on in the intestine and switched off in the oesophagus. The team discovered that exposure to bile salts and cytokines (chemicals released during inflammation) caused the gene to be inappropriately switched on, triggering a change in oesophageal lining cells to resemble intestinal cells.

Renowned geneticist Sir Walter Bodmer, Principal of Hertford College, Oxford, conducted the study with colleagues at the Cancer Research UK Cancer and Immunogenetics Laboratory at Oxford University. ‘The changes involved in Barrett’s oesophagus are of great clinical importance because patients with this condition have an increased risk of developing cancer of the oesophagus,’ he said. ‘However, little is known about the molecular changes that induce and maintain Barrett’s oesophagus. The discovery that CDX1 is switched on when exposed to bile salts and cytokines provides us with important insights into the basic molecular mechanisms of this condition.’

The team are now investigating in greater detail how gastric reflux causes the CDX1 gene to be switched on in the oesophagus. Understanding more about what triggers Barrett’s oesophagus should help in the search for preventative measures. A ten-year trial by Cancer Research UK is currently testing whether aspirin and an anti-ulcer drug can prevent the development of Barrett’s oesophagus, and therefore prevent thousands of cases of cancer of the oesophagus.

Cancer Research UK’s Medical Director, Professor John Toy, said: ‘The UK is at the centre of a small explosion of cases of oesophageal cancer. Only a minor proportion of those with Barrett’s oesophagus go on to develop the disease, however, the number of people with oesophageal cancer in the UK is approximately twice the level seen in the US. That’s why it’s vital we understand more about what triggers Barrett’s oesophagus and find ways to prevent it. Cancer Research UK’s aspirin and anti-ulcer drug trial may be the first step towards a promising and realistic method of preventing many cases of this form of cancer.’