Diagnostics & Imaging Week Correspondent

LONDON — The discovery of more genetic variants that are linked to bowel cancer has provided additional confirmation that common variants conferring relatively small risks play an important role in determining a person’s chances of developing this disease.

Although the variants, single nucleotide polymorphisms (SNPs) in a gene called SMAD7, are clearly linked to an increased risk of bowel cancer, researchers say the question of which variants cause the disease remains open.

Ian Tomlinson, of the Molecular and Population Genetics Laboratory at Cancer Research (London), told Diagnostics & Imaging Week: “Because the SNPs we have identified in this study are located well inside the boundaries of the SMAD7 gene, we are fairly sure that this gene plays a role in causing bowel cancer. It is particularly interesting because we know that SMAD7 is involved in two of the major pathways known to control the growth of cells in the large bowel, the Wnt pathway and the TGFbeta pathway.”

Further work will be needed, he added, to establish what effects the high-risk and low-risk alleles identified have on levels of SMAD7 RNA or protein production, or on other functions of the gene.

Richard Houlston, of the Institute of Cancer Research in Sutton, UK, told Diagnostics & Imaging Week: “This study potentially provides molecular targets which might be very useful in preventing colorectal cancer.”

A report on the study appears in Oct. 14 issue of Nature Genetics, in a paper titled: “A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.”

Houlston, Tomlinson and their colleagues have carried out a genome-wide association study with the aim of identifying SNPs that are inherited more commonly by people with colorectal cancer than by healthy controls.

There are an estimated 7 million common SNPs in the human genome, but because recombination generally takes place at particular “hotspots,” many of the SNPs are inherited together. Researchers can therefore use a panel of SNPs (known as tags) to infer which groups of SNPs have been inherited by people with colorectal cancer and which by healthy controls.

Further investigation of stretches of the genome that are inherited most commonly by people with disease and not by healthy controls can then help to pinpoint variations such as mutations and other SNPs.

This approach allowed members of the same team to report in July that they had found an SNP on a region of chromosome 8, which causes a 20% increase in the risk of developing colorectal cancer.

The current paper in Nature Genetics reports the team’s latest finding.

“The alleles concerned are probably present in 40% or 50% of the population, so most people have at least one allele that confers increased risk, and the increased level of risk is probably 1.2 to 1.3 fold,” Tomlinson said.

It will soon be possible, he added, to put together panels of the common variants in order to test people and provide them with estimates of their individual risks of developing bowel cancer.

Tomlinson said it is not necessary to pin down a variant that can be shown to cause bowel cancer before such testing could begin. “There is no real need to wait for this information because we now have these markers, and they are reliable for the UK population,” he said. “Each of the variants so far seems to act independently of the others, and all we need to do is to add the risks from the different SNPs, to build up a profile of risk for each individual.”

Tomlinson suggested that using a panel of, say, five or six SNPs could make it possible to detect people who are about three times more likely to develop bowel cancer than the general population. “This is on a par with the type of increased risk that you can often predict based on someone’s family history of bowel cancer,” he added, “and you could consider offering people at relatively high risk at least a one-off colonoscopy or more regular colonoscopy to try to prevent that cancer.”

The study is continuing. Houlston said: “Our aim now is to try to find the causal variant. Furthermore, it is essential to continue to conduct additional scans of this nature, to establish the contribution of common variation to the inherited risk of colorectal cancer.”