Gene silencing in colorectal cancer may prove useful

A gene that is frequently switched off in colorectal cancer cells seems to help the cancer but may also make it easy to detect, scientists say. Conveniently, the modification that silences the NDRG4 gene can often be spotted in stool samples, providing an inexpensive test, the researchers report in the July 1 Journal of the National Cancer Institute.

What’s more, the molecular change sometimes shows up in growths called polyps, which can be precancerous. If further research shows that the genetic aberration in polyps is also detectable in stool samples, doctors might one day be able to screen vast numbers of people for colorectal cancer risk before resorting to more expensive colonoscopies, says study coauthor Manon van Engeland, a molecular biologist at Maastricht University in the Netherlands.

“Colonoscopy remains the gold standard” for detecting precancerous polyps and colorectal cancer itself, she says. But in developing countries where few people receive any form of screening, she says, “you could use this biomarker to preselect those people needing to undergo a colonoscopy, and that could be very quick and cost-effective.”

While the role of NDRG4 is poorly understood, two other genes in the NDRG family are known tumor suppressors. In some cancers, these genes are bogged down or silenced altogether by a chemical process called promoter methylation. This process adds a methyl molecule to the gene’s promoter region, DNA that switches on the gene as needed. Methylating the promoter can silence the gene and thwart production of the protein it encodes.

When van Engeland and her team tested NDRG4’s promoter in colorectal cancer cells obtained from 267 cancer patients, the researchers found the region was methylated in three-fourths of the patients. In noncancerous colon cells removed from 48 people, the promoter was methylated in only four people.

Tests on not-yet-cancerous polyps from colorectal cancer patients showed that the NDRG4 promoter was methylated in 22 of 36 patients, whereas only five of 36 people without cancer had polyps with this aberration.

Next, the researchers revved up the activity of the NDRG4 gene in colorectal cancer cell lines. This inhibited the cells’ ability to form colonies, the first step toward tumor growth. That indicates NDRG4 is a cancer suppressor gene, van Engeland says.

The researchers then tested stool samples from 75 colorectal cancer patients and 75 healthy people to see whether this simple test could differentiate which people had NDRG4 modifications. They found that it could, revealing NDRG4 promoter methylation in 42 of the patients with cancer and in only three without it.

“This is a wonderful paper,” says Kounosuke Watabe, a cancer pathologist at Southern Illinois University School of Medicine in Springfield. “This is an innovative way to identify patients.” Because polyps shed tissue, he says, it’s likely that a stool sample test for polyps with aberrant genetics will prove accurate as well.

“Genetic diagnosis of colorectal cancers and meaningful [polyps] has now reached a new phase,” says physician Gad Rennert of the Carmel Medical Center in Haifa, Israel, writing in the same JNCI issue. With fine-tuning, these sorts of genetic tests may provide “a suitable and affordable means of prevention and early detection of colorectal cancer in the general population.”

However, the NDRG4 promoter screen isn’t foolproof. Various research teams are investigating other markers for colorectal cancer, van Engeland says. “One day we should combine our forces and see which marker panel works best.”