Under a microscope, colon cancer is characterized by irregularly shaped cells with large nuclei and evident cell division. Here, nuclei are blue, tubulin spindles are green, and muscle fiber (myosin) is red.

Colorectal tumors take the lives of more adult Americans than any other cancer except lung cancer, even though colon cancer is almost always curable by surgery if detected early enough.

Yet most people never undergo a colon cancer screening test, says HHMI investigator Sanford Markowitz of Case Western Reserve University. Colonoscopy can detect more than 90 percent of colon tumors. But the procedure is expensive and unpleasant, and carries some degree of risk. Meanwhile, the fecal occult blood test (FOBT), the standard noninvasive screen that detects blood in the stool, catches only 15 percent of colon cancers.

Markowitz and his colleagues have now developed a noninvasive test, 3 times more sensitive than the FOBT, that relies on a telltale chemical signature in a gene called vimentin. While the gene in cancerous colon cells displays chemical modifications called methylations, it is rarely, if ever, methylated in healthy cells. On this basis, Markowitz's lab devised a biochemical assay that can detect the aberrant gene modification in as few as 15 cancer cells—a sensitivity that allows the test to be performed on DNA shed in a stool sample. In a clinical trial, the test detected vimentin methylations in 46 percent of colon cancer patients, and it caught early-stage tumors as effectively as it did late-stage tumors.

New progress toward a comprehensive noninvasive screening test for colorectal cancer has also been made by HHMI investigator Bert Vogelstein and his colleagues at the Sidney Kimmel Cancer Center at the Johns Hopkins Medical Institutions. The researchers recently reported that they could detect DNA fragments of mutant forms of a key cancer gene, called APC, in blood plasma from patients with certain types of colon cancer. "The test we developed for plasma DNA mutations can also be used to study fecal DNA mutations," says Vogelstein. "We are working with Sandy Markowitz's group to develop the optimal combination of DNA markers to use for this purpose."

Image: Nancy Kedersha / Photo Researchers, Inc.