Search for Colon Cancer Markers Yields Unlikely Target
Researchers have identified a novel biological marker for colon cancer that can be detected in DNA from the stool of some patients with the disease. They used the marker to detect colon cancer in nearly half the DNA samples they analyzed, a result that compares favorably with two noninvasive colon cancer screening tests.
Dr. Sanford Markowitz and his colleagues at Case Western Reserve University and University Hospitals in Cleveland identified the marker, part of a gene called vimentin. They tested it in collaboration with Exact Sciences of Marlborough, Mass., which sells a stool-based DNA test that analyzes about 20 mutations associated with colon cancer.
Unlike those mutations, vimentin has no known role in colon cancer. In fact, the gene is not even active in the normal colon. But it makes a good marker because, in some patients, the gene undergoes a chemical change known as methylation, and this can be detected in DNA from stool.
The researchers tested vimentin in DNA from 94 colon cancer patients. They detected the cancer in 46 percent of the cases, including in 43 percent of cases with stage I or stage II disease, according to findings in the August 3 Journal of the National Cancer Institute.
"This is a first step," says Dr. Markowitz, who is a Howard Hughes Medical Institute investigator. "We are excited that we hit nearly half of the cases with a single marker, and we hope that by combining the gene with other markers, we can reach the sensitivity required for a clinical test."
The additional markers might be mutations or methylated genes, or perhaps some combination. Vimentin will now be evaluated in a larger population, and Exact Sciences has acquired the rights to commercialize the technology.
Dr. Markowitz began searching for methylated markers several years ago. It had become clear that developing a screening test using genetic mutations would be difficult due to the diversity of mutations in colon cancer.
Meanwhile, interest was growing in "epigenetic" changes, such as DNA methylation, that are common in cancer and can alter the activity of genes. "We have now shown that you can go after these markers in stool and that they do pretty well if you select them carefully," Dr. Markowitz says.
A detection rate of 46 percent leaves room for improvement, but the result should be put in perspective, notes Dr. Dean Brenner of the University of Michigan Cancer Center in Ann Arbor, who co-authored a commentary accompanying the study.
The most widely used noninvasive colon cancer test, fecal occult blood testing (FOBT), detects between 15 and 30 percent of cases. The DNA mutation test by Exact Sciences detects the cancer in 56 percent of cases, according to published results.
"What's really interesting here is that a single methylated target is clearly better than the test for blood in the stool, and it approaches the level of sensitivity you get from testing many genetic mutations," says Dr. Brenner.
"The fact that a gene with no known role in colon cancer becomes methylated in some patients is also interesting," he continues. "And it's not clear why this happens."
Colonoscopy is considered the gold standard of screening tests, but the procedure requires a preparatory cleansing of the large intestine, is invasive, and typically costs more than $1,000. By contrast, FOBT costs a dollar or less, while the Exact Sciences DNA-based test runs between $300 and $400.
The big challenge now will be to increase the sensitivity of screening tests while lowering the costs, notes Dr. Brenner.
By Edward R. Winstead