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Markowitz, Vogelstein Lead Development of Novel Detection Technique

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In work appearing in August in Nature Biotechnology, a group of researchers developed a novel, highly sensitive technique to detect methylated DNA. Because methylation signatures change in cancer, they hope it will be useful for early detection of colon and other tumors. A simple, inexpensive, noninvasive test that could be used instead of a colonoscopy — this test isn't fail-proof — is key to saving lives.

"Having an alternative to colonoscopy could make an important contribution to public health, so we've been interested in whether you could develop a molecularly-based, noninvasive screening test for colon cancer for a long time," says Sanford Markowitz at the Case Western Reserve University School of Medicine, who led the study alongside Johns Hopkins University's Bert Vogelstein.

The technique combines bisulfite conversion with BEAMing, a technology developed previously in Vogelstein's lab, to come up with methyl-BEAMing. In BEAMing — BEAM stands for beads, emulsion, amplification, and magnetics — individual DNA fragments are attached to coated magnetic beads and can be amplified by submerging DNA and the beads in a water-oil mixture and then performing PCR. This "supersensitive" technique, says Markowitz, allows researchers to study individual molecules of DNA, which is important when detecting the handful of methylated molecules in a sample that might signal early cancer.

"BEAMing is a way to do PCR on a bead starting with a single molecule of DNA," he says. Building off previous work that showed that a region of the vimentin gene is hypermethlyated in a majority of colorectal cancer patients, the researchers wanted to see whether they could use the technique to detect one molecule in thousands that might be methylated. After performing bisulfite conversion, they used BEAMing to amplify the vimentin gene so that there were thousands of copies of the gene attached to each magnetic bead. They then hybridized fluorescent probes for methylated and unmethylated states to the beads, and followed that up with fluorescence-activated cell sorting to count the number of molecules that were methylated.

"It turns out you really do need a method this sensitive," Markowitz says. When they applied the method to blood samples from carriers of early stage disease, Markowitz and his team found only one or two molecules of methylated DNA in two milliliters of blood, which is one molecule in about 5,000 unmethylated molecules. "We applied this method as a colon cancer blood test and we were able to pick up about 50 percent of the folks who have these early stage colon cancers," he says. That's four times better than the current standard, a blood serum marker used to detect recurrence. Also, the new method could detect 41 percent of colon cancers in the stool, as well as half of pre-cancerous polyps. The researchers say their method improves standard methylation-specific PCR by 62-fold.

Next up is looking for genes beyond vimentin, as this was just the first-generation test. "We're already hard at work looking for additional markers that you could add to the test" to improve it, Markowitz says.

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