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The newspaper of The Johns Hopkins University October 2, 2006 | Vol. 36 No. 5
Model Predicts Colon Cancer's Inheritable Defects

By Kenna Lowe
School of Public Health

Researchers from Johns Hopkins and other institutions have developed a new prediction model for genetic defects known as Lynch syndrome, which predisposes families to develop colorectal cancer. The model, called MMRpro, is based on an individual's detailed family history of colorectal and endometrial cancer, as well as on knowledge of how genetic mutations manifest themselves, in the form of tumors. It can assess a person's probability of carrying a particular defect within so-called mismatch repair genes. The study is published in the Sept. 27 issue of the Journal of the American Medical Association.

Sining Chen, lead author of the study and an assistant professor in the Johns Hopkins Bloomberg School of Public Health's Department of Environmental Health Sciences, said, "Genetic defects can be passed from parents to their children. As a result, colon cancer runs in families. Our model will help identify individuals likely to have particular genetic defects. The results will give them useful information about their colon cancer risk before they decide whether to undergo invasive screenings or expensive genetic testing."

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is characterized by the inheritance of defects in the MLH1, MSH2 and MSH6 genes. These three genes--known as mismatch repair, or MMR, genes--help repair mismatches that can occur during the duplication of the genetic code when new cells are made. Of the projected 600,000 carriers of MMR mutations in the United States, each has approximately a 50 percent chance of being diagnosed with colorectal cancer by age 70; women also have a 50 percent chance of developing endometrial cancer, according to Giovanni Parmigiani, senior author of the study and a professor of oncology, biostatistics and pathology at Johns Hopkins.

The researchers applied MMRpro software to 279 individuals' family histories. The study participants were tested with sensitive laboratory mutation-detection techniques. MMRpro predictions were compared to the laboratory test results, as well as to predictions made with widely used assessment guidelines.

The researchers found that MMRpro predicted mutation carriers more accurately than two other assessment tools--the Bethesda guidelines and the Amsterdam criteria--that are currently available to families faced with the possibility that they have inherited the genetic defects related to colon cancer. MMRpro can identify more mutation carriers and fewer noncarriers than other assessment tools. MMRpro was able to assess individuals who do not have cancer as well as those who already do; existing assessment tools can be applied only to individuals with cancer. In addition, certain MMR genetic mutations are hard to detect in laboratory tests; MMRpro was able to provide a useful risk assessment when conventional laboratory tests did not find a genetic mutation.

"Colorectal cancer is the second-largest cause of cancer deaths in the U.S. It is also one of the most preventable forms of cancer. We expect that MMRpro will contribute significantly to controlling the disease by prioritizing high-risk individuals for intensive screening and early detection," Chen said. "We also expect that it will be a tool for investigators interested in understanding inherited colorectal cancer, allowing them to select families to more efficiently study these genetic defects."

The study authors warn that MMRpro results should be interpreted by physicians and cancer counselors. The model software is available at and at 65844.html.

The study was written by Chen, Wenyi Wang, Parmigiani, Kenneth W. Kinzler, Francis M. Giardiello and Kathy Romans at Johns Hopkins. Additional co-authors are Shing Lee, Khedoudja Nafa, Johanna Lee, Patrice Watson, Stephen B. Gruber, David Euhus, Jeremy Jass, Steven Gallinger, Noralane Lindor, Graham Casey, Nathan Ellis, the Colon Cancer Family Registry and Kenneth Offit.

Funding was provided by grants from the Specialized Program of Research Excellence in Gastrointestinal Cancer at the Johns Hopkins Medical Institutions, the National Cancer Institute, the Cancer Research and Prevention Foundation, the John G. Rangos Sr. Family Charitable Foundation, the Clayton Fund, the Niehaus-Southworth-Weissenbach Research Fund and the Evan Frankel Fellowship.


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