Common DNA Variant Increases Colorectal Cancer Risk

TORONTO, July 9 -- Prostate cancer and colorectal cancer appear to have a common genetic risk factor.

Malcolm Dunlop, M.D., of the University of Edinburgh, a senior authors on a Canadian-led international case-control study, said the findings of a common genetic variant causing a predisposition to the two malignancies, are likely to lead to a "whole different understanding" of how colorectal cancer occurs.

The take-home message of the finding is that the development of a small percentage of these two malignancies may have a common mechanism, although how it all works is unknown.

The results of the study, led by Brent Zanke, M.D., Ph.D., of Cancer Care Ontario here, were reported online in Nature Genetics along with case-control studies from the United Kingdom and the U.S. There is no immediate clinical impact of the finding, researchers said, because it applies to the population at large rather than individuals.

The Canadian and British studies used a genome-wide association scanning to locate single nucleotide polymorphisms (SNPs) that are more common in people with colorectal cancer than in healthy controls.

While about a third of all colorectal cancer has a genetic component, Dr. Dunlop said, known genes tend to be rare but have a large effect.

On the other hand, the new variant - in a region of chromosome 8q24 - is seen in about half the population and contributes an excess risk, per copy, of about 20%, he said.

Once variants were found, they were tested against validation cohorts. After several passes - Dr. Dunlop referred to "sieving through multiple sets of cases and controls" - both groups found a single variant that is highly associated with colorectal cancer.

The variant, dubbed rs6983267, was the only marker that remained significantly associated with colorectal cancer. The Canadian study put the statistical significance at roughly P=10^-8, he said, while the British group put it at P=10^-14.

"The statistical support for this is incontrovertible," Dr. Dunlop said.

For people bearing one copy of the variant, the risk ratio for developing colorectal cancer was 1.27 (with a 95% confidence interval from 1.16 to 1.39), according to Ian Tomlinson, Ph.D., of Cancer Research UK, who led the British study.

For those carrying two copies, the risk ratio was 1.47 (with a 95% confidence interval from 1.34 to 1.62, he and colleagues reported.

While estimates vary slightly, an excess risk of "about 1.2 is about right," senior author Richard Houlston, M.D., Ph.D., of the Institute of Cancer Research in Sutton, England.

The American group took a different approach, according to Christopher Haiman, Ph.D., of the University of Southern California.

Starting with a collection of variants known to increase the risk of prostate cancer, they tested them in a case-control analysis of samples from the Multiethnic Cohort Study, an epidemiological study of more than 215,000 people from Los Angeles and Hawaii.

From the larger sample, the researchers looked at 1,807 people with colorectal cancer and 5,511 healthy controls.

Again, only the variant rs6983267 was significantly associated with colorectal cancer, with an increased risk per copy of 22%, which was significant at =4.4 X 10^-6, Dr. Haiman and colleagues reported.

The finding is important, Dr. Haiman said, because it is the first time a common genetic risk factor has been shown to be associated with multiple cancer types.

In fact, he said, there "may be a common biological mechanism" involved, although more study will be needed to discover what that might be.

The British group suggested that the pathway to colorectal cancer may be through the development of adenoma. In a study of 1,477 people with colorectal adenoma and 2,136 controls, the variant was significantly associated with an increased risk of adenoma.

In fact the risk increase was about the same as that seen for full-blown cancer, with an odds ratio 1.21 and a 95% confidence interval from 1.10 to 1.34, which was significant at P=6.89 X 10^-5.

The new variant is likely to "affect a large number of people, but to a small extent," Dr. Dunlop said.

The Canadian-led study was supported by Genome Canada, Gnome Qubec, the Quebec regional development and research ministry, the Ontario Institute for Cancer Research, the Colon Cancer Family Registry, the National Cancer Institute, the NIH, Cancer Research UK, the UK Medical Research Council, the Scottish Executive Chief Scientist's Office, the Digestive Disorders Foundation, the French Ministry of Research, Fondation de France, Projet Hospitalier de Researche Clinique, Ligue Nationale contre le Cancer, Groupement des Enterprises Francaises dans la Lutte contre le Cancer, and the European Commission. Dr. Zanke, reports being founder and equity holder of Arctic Dx, a new Canadian biotechnology company that has received a license in the field of diagnostics for intellectual property generated by several Canadian institutions involved in this research. The company has no financiers or employees. No other potential conflicts were reported.

The Keck study was supported by the NIH and the National Cancer Institute. The authors declared no competing interests.