New genetic variant increasing risk of bowel cancer identified

23 Sept 2010

A single variant in a person’s DNA can promote bowel cancer development, according to an international study led by scientists at The Institute of Cancer Research (ICR).

A slight change in a genetic variant called rs16888589 — an ‘A’ in the DNA code rather than a ‘G’ — produces 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.

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.”