June 14, 2002

DNA-based test sought for colorectal cancer screening

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Dr. William Grady is working to identify a genetic test for the early detection of colorectal cancer. (photo by Dana Johnson)

DNA-based test sought for colorectal cancer screening

Dr. William M. Grady, assistant professor of Medicine and Cancer Biology, has received a clinical investigator award that will provide $1 million over five years to support his work to develop a DNA-based test to screen for colorectal cancer.

Grady and his colleagues are studying potential molecular markers for colorectal cancer that can be detected in stool. Specifically, they are looking for chemical changes in DNA, called DNA methylation, that affect a variety of tumor suppressor genes.

Colorectal cancer is the second leading cancer killer in the United States, affecting an estimated 148,000 Americans this year and claiming more than 56,000 lives. Most colon cancer starts as a precancerous growth (polyp) in the colon that can be detected and removed during colonoscopy.

It is well accepted that colorectal cancer is largely preventable if caught at the polyp stage. Colonoscopy, believed to be the most accurate test to detect polyps and early colon cancer, is recommended for everyone over age 50. However, it is inconvenient and expensive.

“Roughly one-third of people will develop polyps during their lifetimes, and 1/20th of people will develop colon cancer,” Grady said. “This means that although many people will develop polyps, most people will not and thus do not need colon cancer screening. Our goal is to develop a simpler test than colonoscopy that would identify markers in a stool sample. That test would then be used to select those people who should have colonoscopy to remove the polyps that have been detected through this test.”

The Damon Runyon Cancer Research Foundation/Lilly Clinical Investigator Award is designed to “help rescue an endangered species,” the physician willing to devote his or her career to the development and application of new diagnostic, therapeutic and prevention strategies for cancer through clinical and translational research.

“Earmarked for young physicians wishing to commit themselves to substantive and innovative clinical research, the award bridges the gap between the research laboratory and patient care,” according to the foundation’s Web site. “Though there’s never been a more pressing need or more promising time for clinical cancer research, fewer young physicians enter this area of investigation every year.”

The foundation was created in 1946 by popular radio journalist Walter Winchell after the cancer death of his friend, storywriter and journalist Damon Runyon. Winchell himself died of cancer in 1972.

The foundation supports young investigators working in all areas of cancer research, including all types of tumors as well as areas relevant to multiple cancers, such as tumor metastases. The foundation has invested more than $135 million and supported more than 3,000 scientists. The Clinical Investigator Award was established in 2000 in partnership with Eli Lilly & Company.

DNA methylation stops the transcription of genes, a necessary step in gene regulation that results in a gene’s instructions being carried out, Grady explained. “The methylation process is taken over by the cancer cells, which then use it to silence the tumor suppressor genes, which ordinarily would allow abnormal cells to die or prevent them from growing.”

Grady’s laboratory team is tracking DNA methylation during the process of colorectal cancer formation to identify markers that will pinpoint early-to-advanced disease. They also are searching for markers in stool samples from patients with hereditary nonpolyposis colon cancer, who have a 70 percent lifetime chance of developing colon cancer and who therefore undergo frequent screening.

Among the candidate genes that the laboratory is working with are CDKN2A/p16, a regulator of cell growth; MLH1 and MGMT, which normally repair errors in DNA; TIMP3, whose silencing permits the epidermal growth factor to be activated; COX2 and THBS1, which turns on the cancer-related gene TGF beta.

The researchers have developed an assay to detect methylation and are working with a company called Exact Sciences on technology to allow the DNA to be extracted from stool.

Grady, who joined the Vanderbilt faculty in 2000, completed additional training in molecular and cell biology as an extension of his gastroenterology fellowship at Case Western University. While working with his mentor, Dr. Sandy Markowitz, Grady developed an assay for detecting tumor-specific methylated MLH1 in people with colon cancer. “It identified 30 percent of colon cancers that carried methylated MLH1, but was found to be more effective in finding advanced cancers, not early ones,” Grady said.

These findings led to Grady’s current area of research, which focuses on determining whether these assays will also be useful in detecting early colon cancer.

Grady said he was particularly pleased that the award has resulted from preliminary data generated by an undergraduate student in his lab, Mahan Ghiassi, a junior at Vanderbilt who has been accepted to Vanderbilt School of Medicine through the Early Acceptance Program. The initial work was supported by fellowship grants from the Foundation of Health and Nutrition.

Grady’s lab has also become an associate member in the Early Detection Research Network of the National Cancer Institute, which will provide support to carry out additional studies on the molecular marker assays he has developed.