Researchers Continue to Improve Identification of Lynch Syndrome

Researchers Continue to Improve Identification of Lynch Syndrome

Two new tools have been developed to predict an individuals risk of carrying a gene mutation linked with hereditary colorectal cancer. Use of these tools may guide decisions about genetic testing. Descriptions of these tools were published in the Journal of the American Medical Association.

Lynch Syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), results from inherited mutations in genes involved in DNA mismatch repair.[1] These mutations greatly increase the risk of developing colorectal cancer and also increase the risk of several other cancers.

Average age at diagnosis of colorectal cancer is 44 years in individuals with an HNPCC mutation, compared to 64 years in the general population. Other cancers that are more common in HNPCC families include cancers of the endometrium (the lining of the uterus), ovary, small intestine, ureter, and renal pelvis.

Overall, roughly 3% to 5% of all colorectal cancers are thought to result from HNPCC mutations. Although tools have been developed to identify individuals who are most likely to carry HNPCC mutations, limitations in these approaches have prompted researchers to search for more accurate methods. Accurate prediction of the likelihood of carrying an HNPCC mutation will allow for focused use of genetic testing.

One of the new approaches to predicting an individuals risk of carrying an HNPCC mutation involves use of a statistical model known PREMM1,2.[2] This model uses information about personal and family history to generate an estimate of the probability of a mutation in the MLH1 or MSH2 genes. This information includes diagnoses-and ages at diagnosis-of colorectal cancer, endometrial cancer, and other HNPCC-related cancers.

The other new approach involves use of a statistical model known as MMRpro.[3] The model estimates the likelihood of carrying a mutation in any of three genes-MLH1, MSH2, or MSH6. The model also estimates an individuals probability of developing colorectal or endometrial cancer. The model considers personal and family history of colorectal and endometrial cancers, and also considers the results of previous HNPCC-related tests (if any) that have been conducted within the family.

Although these models were developed in different populations and were not directly compared to each other, the overall accuracy of each appeared to be similar. Furthermore, they appeared to be more accurate than other commonly used approaches to estimating HNPCC risk.

Use of these and other similar approaches may improve the identification of individuals who could benefit from genetic testing for an HNPCC mutation. It is important to note, however, that many factors contribute to decisions about genetic testing. Genetic counselors and other health professionals can help patients understand the risks and benefits of genetic testing.


[1] National Cancer Institute. Genetics of Colorectal Cancer (PDQ®). Health Professional Version. (Accessed January 19, 2006).

[2] Balmana J, Stockwell DH, Steyerberg EW et al. Prediction of MLH1 and MSH2 Mutations in Lynch Syndrome. JAMA. 2006;296:1469-1478.

[3] Chen S, Wang W, Lee L et al. Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome. JAMA. 2006;296:1479-1487.

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HNPCC Families Show Abnormal Reflection of Light from Tissues in Mouth (9/22/2006)

Researchers Develop Tool to Improve Prediction of Lynch Syndrome (7/5/2006)

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