Scientists at Jefferson Medical College and Fox Chase Cancer Center, armed with a $2.4 million National Cancer Institute grant, are using state-of-the-art microarray technology to watch patterns of gene expression, hoping to uncover the molecular signatures of how cancer begins. The project is aimed at evaluating potential cancer prevention agents.
Alfred G. Knudson Jr., M.D., Ph.D., Distinguished Scientist and a senior member in the Division of Basic Science at Fox Chase Cancer Center in Philadelphia is principal investigator of the project. Bruce Boman, M.D., Ph.D., director of the division of medical oncology and medical genetics at Jefferson Medical College of Thomas Jefferson University in Philadelphia, Steven McKenzie, M.D., Ph.D., associate professor of pediatrics at Jefferson Medical College, lead the Jefferson research team. Dr. McKenzie is based at A.I. duPont Hospital for Children in Wilmington.
"We would like to determine expression profiles of genes in normal tissues and hereditary cancer tissues," explains Dr. Boman, who is also a member of Jefferson's Kimmel Cancer Center. "For germline mutations in hereditary cancer patients, every cell has the mutation. The question is, what gene expression is being altered in these tissues in the first steps toward cancer? We're using a microarray chip containing over 40,000 genes so we can tell which genes are altered in their level of expression."
The researchers will compare genes in tissues in hereditary colon, breast and kidney cancers to tissues in normal healthy subjects. "We'll get the expression profile for which genes are altered in their expression, and we'll take that information and treat the cells in vitro with chemopreventive drugs," he says.
"Then we'll see which genes revert back to precancerous states. We'll get an idea which might be our target genes." The colon cancer samples are being done at Jefferson, while the breast and kidney samples will be done at Fox Chase.
Microarray technology is a powerful tool for looking at the complexity of cancer. Rather than focus on specific genes, microarrays allow scientists to concentrate on thousands of genes at the same time and determine how those genes are expressed -- whether they are active, overactive, or quiet in both normal and cancerous tissue. Some researchers, for example, are using microarrays to analyze genetic changes retrospectively in large clinical trials, enabling them to find genetic differences between cancer patients who respond well to treatment and those who do not.
"It's tough to know how each gene fits into the large picture of cancer initiation," Dr. Boman says. "There are more than 100,000 genes in each cell type, and maybe 10-20,000 are expressed. Multiple genetic changes may be involved in each type of cancer cancer -- it's all very complex." The germline mutations in hereditary cancer patients the researchers will focus on include the BRCA1 gene in breast cancer, which malfunctions to cause disease, and the adenomatous polyposis coli gene is one of the culprits in hereditary colorectal cancer.
"We're trying to do a broad analysis of as many genes as we can," he says. "We're interested in the cancer initiation step, the moment the cell becomes cancerous, because we think it could be reversible with chemopreventive agents."
"The next step is to figure out what those genes tell us, what pathways they are involved in, what families they belong to, and what proteins they encode," he says. "That involves other fields and specialties in molecular biology. We have to be able to draw correlations in how interactions occur through the cellular pathways, in which various genes are involved."