Prediction models help identify increased risk of gene mutation linked with colorectal cancer

Prediction models that incorporate certain personal and family medical history characteristics can help identify high-risk patients who are likely to have a gene mutation associated with a type of colorectal cancer, according to two studies in the September 27 issue of JAMA.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer) is the most common hereditary colorectal cancer syndrome in Western countries, accounting for 2 percent to 5 percent of all colorectal cancers (CRCs). Lynch syndrome is primarily associated with mutations in the MLH1 and MSH2 genes. In hereditary breast-ovarian cancer syndrome, multiple models have been developed to predict mutations in the BRCA1 and BRCA2 genes, and these models are widely implemented by health care professionals as they assess their patients' genetic risk. For Lynch syndrome, the relative importance of specific aspects of personal and family medical history remains unclear.

Judith Balmana, M.D., formerly of the Dana-Farber Cancer Institute, Boston, and colleagues obtained data from 1,914 individuals undergoing genetic testing of MLH1 and MSH2 and developed a clinical model, the PREMM1,2 (Prediction of Mutations in MLH1 and MSH2) to predict the presence of mutations in the MLH1 and MSH2 genes based on personal and family medical history. A model was developed in an initial group of 898 individuals and subsequently validated in 1,016 patients.

Overall, 14.5 percent (130/898) of the study individuals were found to have mutations: 6.5 percent had mutations in MLH1 and 8.0 percent had mutations in MSH2. In the validation cohort, the overall prevalence of mutations was 15.3 percent. Mutations were particularly prevalent among probands (a patient who is the initial member of a family to come under study) with 2 or more separate CRCs, endometrial cancer, other Lynch syndrome–associated cancers, and multiple diagnoses. The prevalence of mutations in the probands increased with increasing numbers of first-degree relatives with CRC or endometrial cancer. Probands with mutations had a younger average age at CRC diagnosis than those who did not have mutations, and the age at diagnosis of CRC and endometrial cancer was also younger among the relatives of probands with mutations.

"How these risks are translated into clinical decision making depends on a variety of factors, including the availability of comprehensive genetic testing services (sequencing and large rearrangement analysis), the timelines of testing information for clinical management decisions, insurance coverage for testing, and the availability of tissue for analysis. Based on the risk estimate generated from the model and the above factors, a clinician may choose whether genetic evaluation should be pursued, as well as the approach to testing …" the authors write.

"Our prediction rule includes specific and discrete variables and does not rely on complex combinations of diagnoses across generations. The PREMM1,2 model has been externally validated and is available as a user-friendly Web-based model to provide clinicians with an objective tool to estimate the likelihood of finding mutations in the MLH1 and MSH2 genes and to help guide the strategy for molecular evaluation," the researchers conclude. (JAMA. 2006;296:1469-1478. Available pre-embargo to the media at

Editor's Note: Dr. Balmana is currently with the Universitat Autonoma Barcelona, Spain. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Model Helps Predict Risk of Developing Colorectal Cancer

In a related study, investigators used family medical history and tumor information to develop another model to predict genetic risk for colorectal or endometrial cancer, according to an article in the September 27 issue of JAMA.

Sining Chen, Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues conducted a study to develop a genetic counseling and risk prediction tool to estimate the probability of carrying a mutation in mismatch repair (MMR; a system within the cell for correcting errors in DNA) genes MLH1, MSH2, or MSH6, and the probability of developing colorectal or endometrial cancer. The researchers developed MMRpro, a model that estimates probability based on family history of colorectal and endometrial cancer. External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (between 1993-2005). All individuals were screened extensively for MLH1 and MSH2 mutations.

"MMRpro predicted the presence of approximately 129 mutations. This shows a close correspondence (calibration) with the observed 121 mutations (ratio of observed to expected results, 0.94)," the authors write. "This results in higher accuracy than existing alternatives and current clinical guidelines."

"This article introduces MMRpro, a model for prediction of genetic susceptibility in the Lynch syndrome, which makes efficient use of family history and tumor information and provides individualized evaluations. Because model-based prediction algorithms are increasingly used in genetic counseling and prevention activities, MMRpro is a timely tool for identifying and counseling families at risk for the Lynch syndrome and can improve current genetic counseling and early detection practice." (JAMA. 2006;296:1479-1487. Available pre-embargo to the media at

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Predicting and Preventing Hereditary Colorectal Cancer

In an accompanying editorial, James M. Ford, M.D., and Alice S. Whittemore, Ph.D., of the Stanford University School of Medicine, Stanford, Calif., comment on the studies in this week's JAMA concerning the development of predictive models for colorectal cancer.

"In summary, these prediction rules should form very useful tools for clinicians and their patients, as well as for epidemiologists who wish to assess both the magnitude of the hereditary nonpolyposis colorectal cancer problem and the potential usefulness of preventive efforts. What are the next steps? Evaluation of all [these] rules using a single data set would be helpful and allow for a direct comparison of the models. Studies using population-based data would be preferable, to assess the performance of the rule among individuals with little or no family history of the Lynch syndrome malignancies. Since the rules were developed and evaluated using samples primarily composed of white individuals with European ancestry, there also is great need to evaluate the performances of these rules when applied to ethnic minorities, as the prevalence and penetrance of Lynch syndrome is poorly understood in nonwhite populations," they write. (JAMA. 2006;296:1521-1523. Available pre-embargo to the media at

Editor's Note: Financial disclosures – none reported.


Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
    Published on All rights reserved.