An international study led by scientists at The Institute of Cancer Research (ICR) has shown how a single variant in a person’s DNA can promote bowel cancer development. The study is published today in the journal PLoS Genetics.
The scientists found that if people inherit an ‘A’ in their DNA code rather than a ‘G’ at a genetic variant called rs16888589 they produce more protein from a gene called EIFH3. Importantly, the team showed that high levels of the eifh3 protein lead to the development of bowel cancer.
Lead researcher Professor Richard Houlston, from the ICR, says: “We know from other cancers that too much of the protein eifh3 leads to an increase in cell proliferation, growth and survival, but this is the first confirmation it is involved in bowel cancer development.
“It’s interesting that even a single change to the DNA sequence can alter how much protein is produced and increase the risk of this disease. Finding proteins involved in cancer development is crucial, as they are potential targets for new drugs.”
Genome-wide association studies have previously identified fourteen DNA variants that each increase a person’s risk of bowel cancer by between 1.5- and 2-fold. Inheriting more than one variant increases the risk even further. These variants, called single nucleotide polymorphisms (SNPs), are a single letter change in the DNA code - the sequence of letters that acts as our blueprint.
These genetic screens identify variants that are linked to the disease, but are not necessarily responsible for causing the disease. For example, the variants may just be inherited at the same time as the key DNA. So to fully understand the biological process that leads to the development of cancer, scientists need to find the causative – and not the associated – genetic change.
The starting point for the study was a variant on chromosome 8q23 that Professor Houlston’s team has previously shown increased bowel cancer risk by up to a 1.5-fold.
In a study partly funded by Cancer Research UK, scientists at the ICR re-sequenced 22,000 bases (letters) of DNA around the variant and identified all of the single letters in this region that differed between individuals.
More than 100 variants were found and these were examined in 2,000 people with bowel cancer and 2,000 people without the disease. Four SNPs stood out. All were located near a gene called EIFH3, in a region of DNA believed to be involved in switching the gene on or off. Further studies showed how one of these four variants called rs16888589 caused a change in the amount of protein produced by EIFH3.
Dr Lesley Walker, Cancer Research UK’s director of science information, said: “This study is another important step towards understanding the gene faults that put some people at greater risk of bowel cancer, and it also gives us clues to how the disease develops. Research like this opens up new possibilities for identifying people with a higher risk of bowel cancer, and for developing new treatments that target cancers with particular genetic faults.”
‘Allelic Variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H’ is published in open access journal PLoSgenetics today.
Bowel cancer is the third most common cancer in the UK and over the last three years 38,000 people were diagnosed with the disease with 16,000 dying from their cancer.
Cancer predisposition genes account for about 30 to 35 percent of all bowel cancers. Bowel cancer genetics is complex, we know now there are several variants that increase the risk of disease and that they can interact with each other to further increase risk.
The Institute of Cancer Research (ICR)
www.icr.ac.uk
