ANN ARBOR—
Researchers at the University of Michigan and the KHC National Center of Cancer Control in Haifa, Israel, have been awarded a $4.8 million grant to study genetic aspects of colon cancer. The five-year study, funded by the National Cancer Institute, will examine how genetic susceptibility to cancer may be modified by diet, medications, and lifestyle.
The Molecular Epidemiology of Colorectal Cancer study will identify and interview more than 2,000 individuals in Israel who have colon cancer and compare them to a cancer-free group of equal size. Investigators hope to learn why some people who carry genes that increase their risk of colon cancer develop tumors while others with the same gene do not.
“Colon cancer is a complex disease, and genetic susceptibility is only part of the story,” says Stephen Gruber, M.D., Ph.D., principal investigator of the study, and assistant professor of internal medicine and epidemiology in the U-M Health System. “Many people with a genetic susceptibility to colon cancer never develop the disease, and we need to figure out why. If we can recognize what protects those people who are most susceptible, it should help us learn how to do a better job preventing colon cancer in all populations.”
Researchers elected to conduct the study in Israel because three different ethnic populations there have very different risks of colon cancer. Individuals of Ashkenazi Jewish descent have relatively high rates of colon cancer, whereas colon cancer is rare in people of Arabic descent. Sephardic Jews have an intermediate risk of colon cancer.
“It is not clear why different populations within Israel have such different risks of colon cancer, nor do we understand the influences of immigration,” says Gadi Rennert, M.D., Ph.D., co-principal investigator of the study and director of the KHC National Center for Cancer Control at Carmel Medical Center and Technion in Haifa, Israel. “This study should provide insight into how cancer develops, not just within one specific ethnic group, but how common themes can be unraveled for many populations.”
Previous studies have shown that more than one-half million Ashkenazi Jews worldwide carry a specific genetic alteration that doubles a person’s risk of developing colon cancer. The frequency of this genetic change, called I1307K, is uncommon in Sephardic Jews and nearly non-existent in the Arabic population of Israel.
I1307K does not directly cause colon cancer, but increases susceptibility to cancer by destabilizing an important part of a colon cancer gene. “I1307K seems to work like an oil slick in the middle of this colon cancer gene,” says Gruber. “The machinery that copies the cell’s hereditary material (DNA) has a tough time negotiating this part of the gene and frequently crashes.”
Scientists can go back to this “crash site” and investigate the scene of the accident to reconstruct exactly how a cancer developed by looking at the DNA in the region where the damage occurred. Study investigators hope to use this information to help determine why some people manage this unstable region more successfully than others.
Gruber and his colleagues believe there are probably other similar genetic alterations that have yet to be discovered. While most of the genetic alterations that have been discovered appear to increase the risk of cancer, some genes may offer some protection against cancer.
The study population will be drawn entirely from Israel while the analyses will be conducted jointly in the United States and Israel. In addition to studying how diet, lifestyle, and medications may differ in the cancer patients and the comparison group, investigators also will perform a battery of tests on the tumor samples using standard microscopes and high tech molecular tools that magnify genetic material.
Gruber summarized the goals of the project: “We would like to find better tools to lower the risk of colorectal cancer with this study. Clarifying how genes, lifestyle, and environmental factors work together should give us these tools, and hopefully we will have made another small step towards preventing cancer.”
EDITORS: If you would like to set up an interview with Dr. Gruber or Dr. Rennert, call Pete Barkey, UMHS Public Relations at (734) 764-2220.

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