Dr Claire Palles studies whole genome sequencing data and targeted analyses with the aim of discovering genetic variants that affect susceptibility to colorectal cancer and Barrett’s oesophagus. Samples from over 1000 patients could be used to predict adverse drug responses to standard chemotherapeutics.
The gastrointestinal track is responsible for more cancers than any other system. A condition called Barrett's oesophagus, characterised by a change in the cells lining the oesophagus, can lead to oesophageal adenocarcinoma. Only few people with Barrett's oesophagus will go on to develop cancer, and genome sequencing studies aim to identify genetic risk factors and therefore better target high-risk patients.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: Why is it important to study gastrointestinal cancers?
Claire Palles: Gastrointestinal cancers are malignant tumours that occur in the digestive system. These organs are responsible for more cancers, therefore more cancer deaths, than any other system in our bodies. We are interested in all types of gastrointestinal cancer but our lab is particularly focused on tumours that occur in the pipe that joins the throat to the stomach - the oesophagus.
Q: What is Barrett’s oesophagus and why can it cause oesophageal cancer?
CP: Barrett’s oesophagus is a common non-cancerous condition. It is characterised by a change in the cells that line the oesophagus. Rectangular cells that we normally see in the intestines replace the flat cells that normally line the oesophagus. This change happens in response to damage to the oesophagus lining by stomach acid, which the oesophagus is exposed to during periods of reflux. Cancer can occur in Barret’s oesophagus when the cells become abnormal and start to grow out of control. 95-99% of people with Barret’s oesophagus will never go on to develop a type of oesophageal cancer called adenocarcinoma, however it is a risk factor.
Q: How can genome sequencing help identify the risks?
CP: By examining the genetic sequence of large numbers of people, we can compare those sequences, compare those codes, and identify positions in the genome that vary. We can then go on to see whether the variants are at a higher frequency in people with the disease, such as oesophageal cancer, and people without the disease. At the moment, we understand very few of the genetic causes of most diseases. By doing whole genome sequencing in large numbers of people (hundreds of thousands of people), we hope that we will be able to identify the majority if not all of the genetics causes of diseases such as cancer.
Q: What are the most important lines of research that have developed over the last 5-10 years?
CP: In my field of research, the fall in the cost of reading genetic sequences, be that whole genomes or individual positions that we are interested in, has completely changed the type of studies we are able to perform. Ten years ago in 2006, it cost over £10million to read a whole genome sequence. Today is costs less £2,000. It is now economically and practically possible to read the genetic sequences of large numbers of people, hundreds of thousands of people, as is being done in projects such as UK Biobank and the hundred thousand genomes project. We know that most genetic variants confer only small risks by themselves, and we predict that in a single person there will be tens to hundreds of these variants that explain that individual person’s cancer risk. The only way we will be able to detect genetic variants with such small effects is by examining whole genome sequences in large numbers of people, and following up what the functions of those variants are in the lab, seeing what those variants do to our cells.
Q: Why does your research matter and why should we fund it?
CP: At the moment we don't know much about the genetic causes of gastrointestinal cancer. We know a lot more than we used to but we still can't accurately predict which patients will go on to develop cancer. Similarly, in Barret’s oesophagus we can't predict the small minority of patients with this condition that will progress to oesophageal adenocarcinoma. In my lab we are studying large numbers of people with gastrointestinal cancers so that we can uncover many more of the genetic variants that cause these cancers and thereby improve risk prediction. My lab is also working on the function of the genetic variants that we have already shown to be associated with risk of Barret’s oesophagus and oesophageal adenocarcinoma so we can understand more about the biology of these conditions.
Q: How does your research fit into translational medicine within the department?CP: The genetic variants that we find to be associated with gastrointestinal cancer can be tested for in blood samples from patients that come into clinic. Once we can identify enough of the genetic variants that cause gastrointestinal cancers, we will be able to set up inexpensive tests to predict a patient’s risk. In a clinic this information can be used to make sure that high-risk patients are screened regularly. Any abnormal cells that are there get detected, they can be removed and we can thereby reduce the number of people that go on to develop cancer.