March 13, 2003Potential Blood Test For Colon Cancer Risk
MEDIA CONTACT: Vanessa Wasta
Johns Hopkins scientists have found a way to predict with a simple blood test which people may be at higher than normal risk for the most common form of colon cancer. The research, described in the March 14, 2003, issue of Science, focuses on genetic "red flags" housed not in the sequence of the DNA building blocks themselves, but in other subtle modifications made to the genetic code.
"We hope these findings will have the ability to identify people at increased risk for colon cancer, follow them closely and prevent disease or at least catch it early, similar to the approach doctors use in identifying patients at risk of heart disease," says Andrew P. Feinberg, M.D., King Fahd Professor of Medicine in the Kimmel Cancer Center at Johns Hopkins.
At present, the genetic marker blood tests are for research purposes only, Feinberg emphasized. "More efficient tests will take several more years at least to develop," said Feinberg, who with Hengmi Cui, Ph.D., and Marcia
Cruz-Correa, M.D., Ph.D., led the study. "We also need to follow patients over time to see if they develop cancer after the test is positive," he added.
Prior research at Hopkins and elsewhere has identified genetic mutations linked specifically to hereditary forms of colon cancer. The genetic information uncovered in this study applies to the much more common forms of colon cancer that occur sporadically among the general population. An estimated 155,000 cases are diagnosed annually in the United States.
Earlier work also by the Feinberg team has shown that a form of gene silencing called loss of imprinting (LOI) in a growth-promoting gene called IGF2 (for insulin like growth factor) is one of the first genetic defects that happen in up to 40 percent of colon cancers. In the new study, the researchers found IGF2-related LOI present in blood samples as well as in colon tissue.
In an analysis of blood samples from 172 individuals who had a colonoscopy, a total of 25 with various family and personal histories of colon cancer and polyps showed LOI in their blood. Results found that those with a family history of colon cancer were more than five times more likely to have LOI markers than those with no such family history. In individuals found to have polyps, odds were nearly three and a half times more likely to have LOI markers present in the blood. Individuals with a personal history of colon cancer were nearly 22 times more likely to have LOI markers. Additional data in the current study shows that in all 25 individuals whose blood was positive for LOI markers, the markers also were found in tissue on the left and right sides of the colon.
Loss of imprinting is a phenomenon linked to several types of childhood and adult cancers, as well as other diseases and syndromes. It occurs when the "wrong" gene copy gains or loses its "voice."
Normally two copies of each gene are inherited, one copy from the mother and one from the father. One of these copies is turned off, leaving the other "on." For imprinted genes, the copy that is turned off is always inherited from the same parent, either the mom or the dad, depending on the gene. But if a gene copy loses its imprinting marks and is incorrectly activated or silenced, cancer and other diseases may result.
"It's a battle of the sexes inside the genome, and each gene copy encodes different instructions to the cell," Feinberg says. "When you have LOI of the IGF2 gene in colon cancer, the mother's gene copy gets turned on by mistake and the cell gets a double dose of abnormal cell growth," says Feinberg.
Feinberg's team found that the maternal copy of the IGF2 gene gets incorrectly activated by removing small methyl groups attached to certain areas of the gene, a process called hypomethylation. Investigators are hopeful, he says, that they can find drugs to reverse this process and potentially prevent cancer. Imprinting and methylation are two elements of a larger field of research called epigenetics, which refers to changes to genes other than in the DNA sequence itself.
Since epigenetic influences tend to change over time, Feinberg plans to study a larger group of patients and follow them to confirm that LOI occurs before someone gets the disease. "It is possible that different people may
be susceptible at different rates to acquiring an epigenetic change. This might help to explain why we see chronic diseases more commonly in adults and longer-lived species."
Funding for this study was provided by the National Cancer Institute and Maryland Cigarette Restitution Fund Program.
Other members of the Hopkins research team are Francis Giardiello, David Hutcheon, David Kafonek, Sheri Brandenburg, Yiqian Wu, Xiaobing He, and Neil Powe.
Under a licensing agreement between Epigenomics AG and the Johns Hopkins University, Hengmi Cui, Marcia Cruz-Correa and Andrew P. Feinberg are entitled to a share of royalty received by the University on sales of
licensed technology described in this article. Feinberg also is a paid consultant to Epigenomics AG. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
Related Web Sites:
Kimmel Cancer Center at Johns Hopkins: http://www.hopkinskimmelcancercenter.org