Q & A: Lynch Syndrome Prediction Model (web article)

Johns Hopkins University researchers and colleagues today published an article in JAMA introducing a prediction tool, called MMRpro, which identifies families with genetic defects that cause an increased risk of colorectal cancer and endometrial cancer in women. This assessment helps families make decisions about cancer prevention screenings.

Sining Chen, PhD, lead author of the study and an assistant professor in the Johns Hopkins Bloomberg School of Public Health’s departments of Environmental Health Sciences and Biostatistics, explains the key concepts of the new model.

Question: What is Lynch syndrome?

Sining Chen: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is characterized by the inheritance of genetic defects in the MLH1, MSH2 and MSH6 genes. Lynch syndrome predisposes families to developing colorectal cancer and endometrial cancer in women. Colorectal cancer due to Lynch syndrome also develops at younger ages than would be expected in people without the genetic defects. Lynch syndrome accounts for about 2 percent of all colorectal cancer diagnoses and a large fraction of early onset colorectal cancers. It is the most common familial colorectal cancer syndrome.

Q: What genetic defects are involved?

SC: The genes we are concerned with in Lynch syndrome are called “mismatch repair genes.” These genes repair mismatches that occur during the duplication of the genetic code when new cells are made. When there is a defect in these genes, mismatches may not be repaired properly and cancer cells may arise. Such defects can be passed from generation to generation. Families with genetic defects can develop Lynch syndrome, which is characterized by increased incidence of colorectal and endometrial cancers.

Q: How serious is colorectal cancer as compared to other cancers? Is it one of the leading causes of death?

SC: Colorectal cancer is the second largest cause of cancer deaths in the United States. A projected 150,000 people will be diagnosed with colorectal cancer in 2006 and 56,000 will die from it. However, the survival rate for people with colorectal cancers found early is more than 90 percent. People need to be aware of the high prevalence and the importance of early detection of colorectal cancer.

Q: How large of an issue is endometrial cancer?

SC: Endometrial cancer is the most common gynecologic cancer, with about 36,000 new diagnoses and 6,500 deaths every year. The risk of developing endometrial cancer by age 70 is approximately 2 percent in the female population, but 50 percent if the woman carries a genetic defect mentioned here.

Q: What should people do when they have concerns about inheriting Lynch syndrome?

SC: They should see a genetic counselor or familial cancer specialist, who is likely to use quantitative models, such as MMRpro, to help them make decisions about screening or genetic testing.

Q: How many cases of colon cancer in your family history should warrant concern?

SC: That depends on the specifics of the family history. But one close relative with early onset colorectal cancer or with endometrial cancer is sufficient to prompt a physician visit.

Q: If a family doctor isn't familiar with this model, what should a lay person do?

SC: Seek help from a trained genetic counselor, who should be able to understand the underlying mechanism of the model and to interpret the model predictions.

Q: What does MMRpro do?

SC: MMRpro provides the risk of carrying one of the genetic defects described above, and if an individual is still healthy, the risk of developing colorectal or endometrial cancer in the future. This helps identify individuals who are more likely to have a colorectal cancer-related genetic defect. The model is based on the person’s family history of colorectal and endometrial cancers.

Q: What information do you need to provide? What type of result do you get?

SC: Individuals provide the age of colorectal and endometrial diagnoses of affected relatives, and current age (or age of death) of unaffected relatives. If genetic testing was done, those results are also requested. MMRpro will provide a projected risk. Your doctor will give you recommendations on cancer screening or genetic testing based on the results.

Q: If information in one's family history of colorectal and endometrical cancer is missing, is the MMRpro model still able to accurately predict the probability of carrying an inherited defect?

SC: One of the advantages of MMRpro is its ability to handle gaps in family history information, such as a relative who has been out of contact for many years. However, the more information is provided, the more accurate the prediction.

Q: Is MMRpro only useful for families with the Lynch syndrome?

SC: The prediction tool is useful for all families and individuals who are interested in finding out whether their cancer is genetic and what their risks might be.

Q: What are the major advantages of your model compared to Amsterdam criteria and Bethesda guidelines?

SC: MMRpro is both more sensitive (that is, it identifies more mutation carriers) and more specific (it identifies fewer non-carriers) than these other approaches. MMRpro uses detailed cancer history information to make individualized evaluations, instead of classifying families into broad categories.

Q: Why is this study important?

SC: About 600,000 people in the United States carry Lynch syndrome genetic defects. Each of them has approximately a 50 percent chance of developing colorectal cancer by age 70, along with increased risks for other cancers. Colorectal cancer is one of the most preventable forms of cancer. Our model can identify people who carry the genetic defect early and help them make decisions about future screening.

Q: Is there somewhere where to can get more information?

SC: The model software and related information can be downloaded at http://astor.som.jhmi.edu/BayesMendel/mmrpro.html. To learn more about Lynch syndrome, a good starting point is www.mayoclinic.com/health/lynch-syndrome/DS00669.

Read the JHSPH news release on MMRpro.