Scientists at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins have developed a safe and reliable stool test that can detect the earliest, curable stages of colon cancer. Early studies of the test, which uses a newly developed technology to detect and highlight a key genetic marker of the disease, are reported in the Jan. 31 issue of the New England Journal of Medicine and are the culmination of more than a decade of effort to uncover disease mutations and apply them to screening and early detection.
In the current research, the investigators analyzed stool samples collected from 74 individuals, including 28 with early colon cancers, 18 with premalignant colon tumors called adenomas and 28 with no disease. The test detected a telltale genetic mutation in 61 percent of those with early colon cancer, half of those with premalignant adenomas and in none of those who were disease-free. The findings demonstrate that the test reliably detects cancers at an early and curable stage, and that it yielded no false positives.
"We still have a way to go before we can confidently use such a screening test in the general population, but we are encouraged by the fact that we've detected mutations in a significant fraction of the patients with early stage tumors and never in people free of disease," says Kenneth Kinzler, a professor of oncology at the Kimmel Cancer Center. The investigators expect it will take an additional three to five years before the test will be available clinically.
The new test is believed to be the first to reproducibly and reliably pinpoint colon cancer-linked APC gene mutations in DNA shed into feces. First identified in 1991 by research teams led by Bert Vogelstein, Kinzler and other scientists, APC mutations initiate the cascade of molecular and cellular errors that eventually result in tumor formation. Though the Hopkins team has always expected this early colon cancer marker was present in cells shed into stool, it required several years of additional research to develop the technology to identify reliably the mutated DNA in the stool of patients with early forms of colon cancer.
APC gene mutations are present in nearly every cancer, but just as mutated gene copies are shed into the stool, so are normal copies. "Mutated APC genes represent as few as one out of every 250 APC copies. Add to this the fact that there are thousands of possible mutations that can occur in the gene, and finding just one is like searching for the proverbial needle in the haystack when you don't even know the size or shape of the needle," says Giovanni Traverso, a research student in Vogelstein's and Kinzler's molecular genetics laboratory and lead author of the study.
To overcome this problem, the researchers developed a technology they called Digital Protein Truncation that lets them divide extracted DNA into separate, smaller portions so that mutated copies stand out. "Essentially, Dig-PT makes it possible to find the needle by dividing the haystack into very small, more manageable piles," Traverso explains. Dig-PT was used to analyze all the stool samples in the current study.
"Noninvasive colorectal screening methods like this offer great potential for the detection of early cancers," says Vogelstein, Clayton Professor of Oncology at the Kimmel Cancer Center and investigator, Howard Hughes Medical Institute. "The advantage of using the APC gene as a biomarker is that, unlike tests for hidden blood or some previously used markers, it is exquisitely specific and found in the earliest and curable stages of tumor formation. If this test identifies mutations of the APC gene, it means there is extremely likely to be a cancer or premalignant growth," he says. In addition, this test is painless and risk-free.
Vogelstein and Kinzler are recognized leaders in the genetics of colon cancer. In recent years, they have developed gene tests for inherited forms of colon cancer. In contrast, this new test is applicable to the much more common, nonhereditary type of colon cancer.
The third most common form of cancer, colon cancer is diagnosed each year in more than 130,000 U.S. citizens. Current tests used in the screening and detection of the disease include colonoscopy, which allows physicians to visibly examine the inside of the colon, and fecal occult blood tests, which identify hidden blood in the stool. When colon cancer is detected in an early stage, before it has spread to other tissues and organs, it can be cured up to 90 percent of the time.
The research was funded by the National Colorectal Cancer Research Alliance, the Caroline Law Fund, University of Texas M.D. Anderson Cancer Center, the Clayton Fund and the National Institutes of Health.