NEWS

Studies Move Closer to Genetic Test to Detect Colon Cancer

Geri Clark

The search for an effective, noninvasive test for colorectal cancer has taken another step forward. In this issue of the Journal, Seung Myung Dong, Ph.D., and colleagues present results that further validate the concept of a genetic test for this disease (see article, p. 858). They screened for three genetic targets—TP53, BAT26, and K-Ras—to detect tumor-associated mutations in the stool of 51 colorectal cancer patients.

DNA is potentially a better screening target than the current tests for colorectal cancer because mutant DNA is shed continuously from tumors and may be detectable early in disease development, possibly even before a polyp is visible.

In a paper published last November in Gastroenterology, David A. Ahlquist, M.D., and colleagues at the Mayo Clinic, Rochester, Minn., and Exact Laboratories of Maynard, Mass., described a similar genetic test to detect DNA from colorectal tumors in stool samples taken from patients with the disease.

The study was considered the first major step toward a new kind of early detection of colorectal cancer. "The Ahlquist paper was really state-of-the-art and a major milestone," said Wendy Atkin, Ph.D., of the Imperial Cancer Research Fund in the United Kingdom, who wrote an editorial that accompanies the new paper (see p. 798).

The current paper builds on that study. The three genetic markers were able to detect 71% of cancers. (Colorectal tumors are genetically heterogeneous, and no single mutation has been found that is expressed in all tumors, so it is necessary to screen for multiple genetic targets when looking for a malignancy.)

More importantly, however, Dong’s team was able to purify stool DNA from all of the patients in the study. "Although there have been other reports of successful amplifications of DNA from the stool, the reproducibility and efficiency of such amplifications have not been optimal," they write.

In addition, "this is the first study to identify exactly the same mutations in the stool as are present in the tumor," said Atkin.

While there is no doubt these results are promising, much more needs to be done to move this technique forward as a screening tool. Of primary concern is the fact that nearly 30% of the patients in this study did not have a detectable mutation in any of the three evaluated genes in their stool DNA. "All of the cancers in this study were advanced, and yet only 70% were detected," said Atkin. "That can’t exactly be extrapolated to a screening situation."

Also unanswered is the question of how well this kind of screening will work in asymptomatic patients. It is one thing to look for mutations in patients with advanced cancers. The real test of sensitivity and specificity will come in trying to identify cancers in people who have no obvious signs of disease.

"Our work needs to be further tested in a large cohort of asymptomatic patients to more precisely determine the prevalence of the mutations as well as the sensitivity and specificity of the assay," said Jin Jen, Ph.D., of the NCI’s Laboratory of Population Genetics and another of the study’s authors.

Refining the sensitivity and specificity of this kind of screening may involve finding more efficient genetic markers. "[The genes screened for in this study] were the best common changes that we currently have that are specific point mutations," said David Sidransky, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and one of the paper’s authors. "But there are many different kinds of molecular markers that are emerging—promoter methylation, chromosomal deletions, mitochondrial mutations—so I think this is the beginning of many similar studies looking at different molecular markers."

The good news is that the concept of testing for DNA mutations in the stool of patients with colorectal cancer has been undeniably proven at this point. And now that the concept has been proven, it’s likely that this technology can also be applied to other cancers.

"We could argue that colorectal cancer is the worst case scenario for this kind of screening," said Anthony Shuber, Ph.D., senior vice president and chief technology officer of Exact Sciences and a co-author of both the current paper and the earlier Ahlquist paper. "You have 11 feet of colon and are looking for rare genetic events. It’s a tremendous needle-in-a-haystack situation."

Other bodily fluids—such as sputum or blood—may prove easier to work with and provide additional cancer targets for this kind of testing. "We know it works," said Shuber. "Now we just have to fine tune it."



             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement