Researchers find first evidence for a genetic cause for Barrett's oesophagus
Common variants at two chromosomes predispose to pre-cancerous condition
- Date : 12 Sep 2012
- Topic : Gastrointestinal cancers
Genetic variations that are linked with the onset of Barrett's oesophagus, a pre-cancerous condition of the lower end of the oesophagus, have been identified for the first time. The discovery of variations in regions on two chromosomes makes it possible to develop screening tests for people at high risk of developing the disease.
Although it's been thought for some time that there may be genetic causes for Barrett's oesophagus as well as environmental ones, such as drinking alcohol and eating fatty food, so far researchers have not found any genetic variations that are associated with the condition.
Now, a multi-national team of researchers led by Prof. Janusz Jankowski of the Blizard Institute of Cell and Molecular Science at Queen Mary, University of London, UK, has identified genetic variations on chromosome 6p21 and on chromosome 16q24. Their research is published online September 9 in Nature Genetics.
Barrett's oesophagus is usually caused by acid reflux and the incidence has been increasing over the past few years, with 10-20% of patients with acid reflux developing Barrett's oesophagus. It can progress to become Barrett's dysplasia, when the cells become pre-cancerous, and can then develop into esophageal adenocarcinoma. Five-year survival following a diagnosis of adenocarcinoma is less than 15%, and so it is important to detect and treat the conditions while they are still in their early stages.
A genetic cause for Barett’s oesophagus
Prof. Jankowski and colleagues from over 100 centres in the UK and 20 more around the world, conducted a genome-wide analysis in which they analysed 660,000 genetic variations in 1,800 patients with Barrett's oesophagus and tested the top 200,000 genetic variations in another set of 1,105 patients, comparing them with large groups of people (over 5,000 in total), acting as controls, who did not have Barrett's oesophagus. During this process they identified variations in the sequence of single nucleotides in two chromosomes. They then tested these two single nucleotide polymorphisms (SNPs) in a further 4,500 patients.
The two SNPs on chromosomes 6p21 and 16q24 showed compelling evidence that they were associated with the development of Barrett's oesophagus. This is the first time a genetic link has been shown. The findings provide a basis for genetically screening 30% of the Western population who get acid reflux to see which 10 to 20% of them (3% of the population overall) will go on to develop Barrett's oesophagus. These genetic variations could also form the basis for developing new targets for therapy.
The researchers found that one of the genetic variations was close to a gene, FOXF1, which is known to be involved in the development of the gastrointestinal tract, and the other to the major histocompatability complex (MHC) region where there are genes involved with the immune system, inflammation and the sense of smell.
Although it's not completely clear yet what roles are played by the underlying genes, the location of one of the SNPs near to the gene FOXF1 suggests there may be structural factors in the stomach and oesophagus that predispose a person to develop the condition. This is consistent with evidence that a structural deficit, namely hiatus hernia, is known to be strongly associated with Barrett's oesophagus. The researchers also found evidence to show that SNPs that are known to be associated with increased body weight were also showing a likely association with Barrett's oesophagus; this suggests that genetic effects may partly underpin the epidemiological observation that obesity is a risk factor for Barrett's oesophagus.
In human, the MHC region occurs on chromosome 6 and consists of 150 genes, of which at least 50% have functions in immunity, autoimmune responses or surveillance. Finding a gene here suggests that the immune system is not under control and is in overdrive in patients with Barrett's oesophagus. This suggests that it could be controlled by antiinflammatory agents.
The researchers plan to test another 10,000 patients in order to replicate these results and to see if they can find any other genes that can predict who will go on to develop Barrett's oesophagus.
Barrett's oesophagus can be inherited like Crohn's or celiac disease. It is likely that the body's control of inflammation and subtle changes to repair mechanisms dictate predisposition to the disease. New findings make it possible to screen people to predict who will progress to develop Barrett's oesophagus, and enable researchers to design new drugs to treat the condition. Given that reflux oesophagitis is the commonest medical condition in the Western adult population, affecting one in three people, these finding have a huge potential impact.
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