BioWorld International Correspondent

LONDON - The discovery of an additional common genetic variant that increases a person's risk of developing bowel cancer is bringing closer the day when physicians will be able to offer people genetic screening to identify those at high risk of the disease.

The variant reported in the December issue of Nature Genetics brings to three the number of genetic regions that strongly influence the risk of bowel cancer, which have been pinpointed during the past 12 months by a team funded by Cancer Research UK.

Ian Tomlinson, joint lead researcher based at Cancer Research UK's London Research Institute, told BioWorld International: "We have found a genetic variant on chromosome 15 that causes up to 50 percent increased risk of bowel cancer in the general population."

The variant is common enough for about 40 percent of the population to have one or two copies of the high-risk variant, he added.

"We can start to add this gene to the ones we have found already, and to the others that we hope to find in the future, to increase the possibility of genetic testing, and therefore the means to prevent bowel cancer in people at high genetic risk in the future," Tomlinson said.

Tomlinson jointly led the research with Richard Houlston from the Institute of Cancer Research. Their latest study appears in Nature Genetics in a paper titled: "Common genetic variants at the CRAC1 (HMPLS) locus on chromosome 15q13.3 influence colorectal cancer risk".

Work already is under way to identify further variation in the region pinpointed, with the hope of working out the mechanism by which the genetic changes cause disease.

"If we can do this, it could open up the possibility of some sort of targeted prophylaxis, which could potentially stop cancers happening in the first place," Tomlinson said.

Targeted screening could begin much sooner, he predicted. "It should be possible to pick up people who are at higher risk on the basis of their genotypes, and they could be offered colonoscopy if they are found to be greatly at risk," he added.

In a previous investigation, the researchers located a genetic region responsible for hereditary mixed polyposis syndrome (HMPS), a condition that increases bowel cancer risk in Ashkenazi Jews. In the latest study, they narrowed down the region of the HMPS gene. They then found, to their surprise, single nucleotide polymorphisms in that area, which were associated with increased risk of bowel cancer in the general population. That required the analysis of nearly 15,000 people, including about 8,000 with bowel cancer.

Said Tomlinson, "If we add this gene, which is close to a gene called GREMLIN1 on chromosome 15, to the ones that we have already published - one on chromosome 8, and the variant of the SMAD7 gene on chromosome 18 - then we think that people who are homozygous for the risk alleles at all these sites are up to threefold increased risk of developing bowel cancer, compared with those who have the low-risk alleles at all three sites."

It still is unclear whether the GREMLIN1 variants found in this study are the same as those that cause HMPS in people of Ashkenazi Jewish descent. "It is conceivable that because of other genetic factors in the Ashkenazi gene pool, the same variation may translate into more severe disease in Ashkenazi Jews," Tomlinson said. "However, I think it is more likely that the disease is caused by the same gene but with different forms of variation in Ashkenazi Jews to the general population."

The protein encoded by GREMLIN1 is involved in the TGF-beta/bone morphogenetic protein pathway, which already is known to have an important role in the development of bowel cancer; the protein encoded by SMAD7 also plays a part in the pathway.

Lesley Walker, Cancer Research UK's director of cancer information, said "Cancer Research UK is launching a series of genomewide studies, including searches for genes that influence lung and ovarian cancer risk. Discoveries like this will improve our understanding of cancer and help us to develop targeted screening and treatment for people at increased risk of the disease."

No Comments