Professor Laurence Lovat (Oesophageal cancer)
2016 - Core Development Grant
Institution: University College London
Title: Salivary EpigeNetics to Stratify Oesophageal Cancer Risk (SENSOR)
Project Start Date: 01.11.17
Completion Date: 30.04.19
What is the background to this project?
Oesophageal cancer, or cancer of the gullet, kills almost 8,000 people each year in the UK each year. Survival is poor, with 85% of those who develop the disease dying from it, and the mortality rate has worsened in the last 40 years, increasing by 46%. Additionally, people from more deprived socioeconomic backgrounds are both more likely to develop the disease and to die from it. Men are more at risk than women, and there are regional variations within the UK, with the North West of England, and the North and West of Scotland as the most affected areas.
One of the reasons why oesophageal cancer has such poor survival is that it is often diagnosed too late. Understanding who is more at risk, and having the means to identify those people and monitor them regularly is essential to be able to stem the mortality rate. There are two main types of oesophageal cancer: squamous cell carcinoma and adenocarcinoma. Smoking increases the risk of both types, while drinking increases the risk of squamous cell carcinoma and excess body weight and long-term acid reflux (heartburn) increases the risk of adenocarcinoma.
Long-term acid reflux increases risk because regular exposure to stomach acid can cause changes to the lining of the oesophagus (the gullet), specifically to the cells that line the inside of the lower oesophagus. The affected cells are more at risk of becoming cancerous. These changes are known as Barrett’s Oesophagus and it is estimated that 1 in 10 people with long-term acid reflux will go on to develop this condition. In turn, 1 in 10 to 20 people with Barrett’s Oesophagus will develop oesophageal cancer. Because of this small but significant risk, people who have Barrett’s Oesophagus are usually monitored every few years with endoscopy (using a flexible tube with a camera on the tip, which is passed down the throat, along the oesophagus and into the stomach).
However, monitoring Barrett’s Oesophagus with endoscopy is expensive, time consuming and uncomfortable for patients, so there is a strong need to develop a simple, acceptable test to identify who is at risk of oesophageal cancer before it develops.
How will the project be carried out?
To support this need Core has funded Professor Laurence Lovat, at University College London Hospital, to explore whether a small sample of saliva can be used to create such a test. Why saliva? Saliva has been shown to contain genetic information in the form of DNA that is shed from cells around the body. This genetic information has the potential to tell us whether some cells in the body might be becoming cancerous.
Professor Lovat will look at DNA that has passed from the blood stream into the saliva. Rather than looking at the genes present in the DNA, he will explore certain genetic markers, specifically a type of ‘gene-switches’ that are involved in how genes are switched on and off. Interestingly, these ‘gene-switches’ can change to reflect the stages of a disease, so they could be used to indicate when a disease might be present but also, importantly, could flag up when a disease is in its early stages. The study of these ‘gene-switches’ is known as epigenetic, and is a promising and exciting area of research.
To explore whether epigenetics can be used to determine a person’s risk of developing oesophageal cancer risk, Professor Lovat and his team will collect saliva samples from: people with a normal oesophagus; people with low-risk Barrett’s oesophagus; people with high-risk Barrett’s oesophagus (determined by cells that have started to transform into cancer cells); and people with established oesophageal adenocarcinoma. They will collect 40 samples from each group, giving them a total of 160 samples.
The researchers will then investigate whether the genetic markers, or ‘gene-switches’, are different between the 4 groups of people tested. They will apply computational tools to identify a group of ‘gene-switches’ that can be used to differentiate the 4 groups.
What will be the benefit for patients?
This exciting project could pave the way for a new screening test for oesophageal cancer risk. The researchers hope to identify a series of promising ‘gene-switches’, which they will go on to test in larger trials. They plan to request further funding from the National Institute for Health Research to demonstrate that their screening test can work in a large population.
The ultimate aim is to replace the current invasive and expensive endoscopy screening with a simple test based on a spit of saliva, which would be more acceptable for patients but equally effective in identifying those at risk of developing oesophageal cancer.
Additionally, the researchers have estimated that, if successful, this approach could save the NHS around £24 million per year by avoiding regular endoscopies. Importantly, this approach has the potential to revolutionise screening for many other cancers, not just oesophageal cancer.
How is the breath test (ECCO paper available here) different to the spit test?
A breath test measures chemicals that are found in the breath. These chemicals are found in very tiny quantities and may be coming directly from the abnormal areas of the stomach. The new spit test does something different. It is looking at changes in the way genes are expressed when cells start to turn from normal towards cancer. Cells release small amounts of their DNA and RNA into the blood which is then transferred into the saliva. DNA contains not only the genes which determine the blueprint of the body. It also has switches which can turn these genes on. This is called epigenetics. RNA is the molecule that is produced when particular genes are activated. It is then translated into proteins which do the work in the cells. The new spit test aims to assess how DNA and RNA levels change from normal people to those in cancer and to use these changes to detect cancer risk.
"We urgently need a cheap, accurate screening test to identify people at risk of oesophageal cancer. The funding from CORE will allow us to create this test using salivary epigenetics. This is a brand new field and we are so grateful for the opportunity CORE is giving us to do this exciting work."Professor Laurence Lovat