New Test for Colon Cancer Risk?

Researchers find gene irregularity may translate into higher odds of disease

THURSDAY, March 13, 2003 (HealthDayNews) -- Researchers may have devised a simple blood test to identify people who are at risk for developing colorectal cancer.

The test hunts down a specific genetic change that causes cells to reproduce at an unnaturally rapid rate, says a study from Johns Hopkins University that appears in the March 14 issue of Science.

From a public health standpoint, this could be extremely good, and timely, news.

The U.S. Centers for Disease Control and Prevention (CDC) reported on March 13 that only 53.1 percent of American adults who are 50 and older had any type of screening for colorectal cancer within the recommended time frame. This is despite evidence indicating that one-third of colorectal cancer deaths could be avoided through the screenings, which detect the precancerous growths called polyps that can lead to the disease.

Part of the reason for these low screening rates may be that people simply do not like the tests available to them. According to just-released research in the March issue of the American Journal of Gastroenterology, most people dislike the preparation that is required for both the computed tomography (CT) colonoscopy and the traditional colonoscopy, although they generally prefer the CT version of the test.

Both tests require patients to drink copious amounts of liquid laxative to completely clean out their colon before the test.

If ever there were an argument for screening, the statistics have it. Colorectal cancer is the second leading cancer killer in the United States, with about 155,000 new cases diagnosed each year. This year alone, according to the new CDC estimates, 57,100 people will die from it.

And although some genetic mutations that put people at risk for the disease have been identified, the majority of colorectal cancer cases are "sporadic," meaning there's no known hereditary cause.

That's why the Science findings are so promising.

"Of the people who wind up developing cancer, about 5 percent have a known genetic factor. However, it's thought that many more patients actually have a genetic risk, but we have no way of detecting that or recognizing it," says senior study author Dr. Andrew P. Feinberg, the King Fahd Professor of Medicine at Johns Hopkins' Kimmel Cancer Center in Baltimore. "Our hope is to develop something that might be useful in people who don't have a family history. There are no molecular tests for cancer risk in the general population, so that's the kind of thing that we're hoping this will develop into."

Although various screening methods, including colonoscopies, are available for colorectal cancer, it's not possible to screen all of the people all of the time.

"It's hugely expensive and a tremendous drain on resources. We couldn't do it even if everybody agreed to it," says Dr. Robert C. Kurtz, chief of the gastroenterology and nutrition service at Memorial Sloan-Kettering Cancer Center in New York City. "We're looking for any type of help to say this person has a greater risk so we can hone in and use our valuable resources for a select group."

The genetic change that Feinberg and his team are concerned with involves a process called loss of imprinting (LOI). Normally, humans acquire one copy of each gene from each parent. For certain so-called "imprinted genes," only one of these genes is actually turned on. The other is "silenced" and does not function, which is normal. When both imprinted genes are mistakenly turned on, however, problems can and do occur.

Feinberg's team had already demonstrated that up to 40 percent of colon cancers exhibited a loss of imprinting in the IGF2 gene, which is involved in cell growth. In other words, both IGF2 genes were turned on and were directing cells to multiply.

In their study, the researchers looked at blood samples from 172 patients who had had a colonoscopy and found an interesting pattern. LOI was present in 28 percent of people who had a family history of colorectal cancer and in 56 percent of those with a personal history of the cancer. In contrast, only about 10 percent of those with no family or personal history had the abnormality.

What this means is that people with a family history of colon cancer were more than five times more likely to have the LOI change than those with no family history. Those who had had polyps (considered precursors to colon cancer) were almost three and a half times more likely to have the marker. Those with a prior personal history of colon cancer were almost 22 times more likely to have the marker.

Imprinting is part of a field called epigenetics, which is interested in changes in genes other than changes in the basic DNA sequence.

"It's not a conventional genetic type of mutation, not a change in the DNA sequence," Feinberg explains.

Feinberg is not sure why certain cells undergo the change in the IGF2 genes, but he says it may have to do with a process called hypomethylation, which involves removals of parts of the maternal gene.

"We're guessing that you're not born with this, but that the stability of certain kinds of epigenetic markers may vary in the population," Feinberg says. "It may be that some people have a stronger way of preserving epigenetic markers than other people do. That may be itself genetically determined."

If more studies validate these initial findings, physicians could target certain patients for closer surveillance and for risk-reduction strategies such as diet modification. There may also be a way to change the genetic abnormality.

"Because it's epigenetic and doesn't involve an irreversible change, we would try to develop new therapies that might be able to restore the pattern to normal, maybe a chemoprevention agent," Feinberg says.

Such a fix is a long way off, but Johns Hopkins University is entering into a licensing agreement with Epigenomics, a company based in Berlin and Seattle, to develop a prognostic test to identify those at risk.

"This has to be validated quite a bit with lots of bigger studies and who knows what's going to happen," Kurtz says. "But the bottom line is that this type of study is very, very exciting. The ideal test would ... be able to say ... that you have a very low risk for colon cancer or you should be screened. In a nutshell, that's what all this is about."

More information

For more on colorectal cancer, visit the U.S. Centers for Disease Control and Prevention, the National Cancer Institute or the American Cancer Society.

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