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LYNCH SYNDROME, AN AUTOSOMAL DOMINANT MULTIcancer disorder, is the most common form of hereditary colorectal cancer, has a prevalence of 0.9% to 2.7%, and also accounts for approximately 2.3% of all endometrial cancers. However, patients with Lynch syndrome are frequently unrecognized because family history is often not fully assessed, and patients most commonly have few or no colorectal polyps, as opposed to the more easily identifiable polyposis syndromes. Patients with Lynch syndrome present with cancer at a relatively young age and they are at a higher risk of developing more than 1 type of cancer. The most common extracolonic tumors arise from the endometrium, stomach, ovary, small bowel, and urinary tract. Therefore, a key aspect in the care for these patients is the implementation of preventive and prophylactic measures aimed at decreasing cancer morbidity and mortality. Which measures and when to implement them strictly depend on the actual risk of developing these cancers, the age at which they start becoming prevalent, and how effective they are at preventing cancer development or detecting cancer at early stages. With appropriate knowledge of these factors, high-risk clinics can provide accurate counseling to patients with Lynch syndrome. The discovery of the mismatch repair genes as responsible for Lynch syndrome in the early 1990s has been instrumental in acquiring this knowledge because mutation carriers could start being identified and studies on cancer risk could be conducted. In this issue of JAMA, Bonadona et al report estimates of cancer risk for carriers of mutations in the most common Lynch-causing genes: MLH1, MSH2, and MSH6. The study includes the largest number of families reported so far with age-specific cumulative estimates of cancer risks. The majority of mutations were unique, which reduces the risk of a biasing founder mutation effect. Patients were enrolled in 40 cancer genetics clinics in France, and families were selected to be informative for this study if at least 1 relative of the proband had a known genotype status. One of the most significant findings was the relatively low cumulative risk of colorectal cancer for MLH1, MSH2, and MSH6 carriers (41%, 48%, and 12%, respectively, by age 70 years). A similar study by Stoffel et al reported risks as high as 97% for MLH1 male carriers vs 53% for female carriers, and 52% and 39% risk for MSH2 male and female carriers, respectively. Most other relatively large studies had reported cancer risks consistently higher than those reported by Bonadona et al. The risk for endometrial cancer also showed some differences with 54%, 21%, and 16% risk, respectively, for MLH1, MSH2, and MSH6 mutation carriers in the study by Bonadona et al vs 32% and 45% risk for MLH1 and MSH2 mutation carriers in the study by Stoffel et al. How can these differences be reconciled? Methodological approaches should be carefully evaluated because it is plausible that the source of patient recruitment can have an important effect on cancer risk evaluation. Most of these studies included patients enrolled in high-risk cancer genetics clinics, which selects for families with more enriched phenotypes. In 1 study, a small group of families recruited within a population-based study showed a more modest colorectal cancer risk. Although some of these studies have addressed selection bias, the approach to correct for that varies considerably and certainly could affect the results. Another confounding factor could be the effect of variants of unknown significance as this is still a substantial problem for mismatch repair genes. How these variants were classified in the different studies is not always clear. Rapidly evolving technologies also should result in a higher rate of mutation detection because a significant number of mutations still cannot be detected with current tools. Another aspect is the potential modifying role of cancer risk that some variants in other genes could exert. For instance, certain alleles in 8q23.3 and 11q23.1 result in a significantly higher risk of colorectal cancer for mismatch repair gene mutation carriers. Further studies will need to address the power of different alleles to modify cancer risk, which could affect risk assessment in Lynch syndrome mutation carriers. In addition, the

ContextThe selection of individuals for hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is challenging. Recently, the National Cancer Institute outlined a new set of recommendations, the revised Bethesda guidelines, for the identification of individuals with HNPCC who should be tested for microsatellite instability.ObjectiveTo establish the most effective and efficient strategy for the detection of MSH2/MLH1 gene carriers.Design, Setting, and PatientsA prospective, multicenter, nationwide study (the EPICOLON study) in 20 hospitals in the general community in Spain of 1222 patients with newly diagnosed colorectal cancer between November 1, 2000, and October 31, 2001.InterventionsMicrosatellite instability testing and MSH2/MLH1 immunostaining in all patients regardless of age, personal or family history, and tumor characteristics. Patients whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germline testing.Main Outcome MeasuresEffectiveness and efficiency of both microsatellite instability testing and immunostaining, either directly or previous selection of patients according to the revised Bethesda guidelines, were evaluated with respect to the presence of MSH2/MLH1 germline mutations.ResultsTwo hundred eighty-seven patients (23.5%) fulfilled the revised Bethesda guidelines. Ninety-one patients (7.4%) had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) or loss of protein expression (n = 81). Germline testing identified 11 mutations (0.9%) in either MSH2 (7 cases) or MLH1 (4 cases) genes. Strategies based on either microsatellite instability testing or immunostaining previous selection of patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8% and 81.8%; specificity, 98.0% and 98.2%; positive predictive value, 27.3% and 29.0%, respectively) to identify MSH2/MLH1 gene carriers. Logistic regression analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters (odds ratio, 33.3; 95% confidence interval, 4.3-250; P = .001).ConclusionThe revised Bethesda guidelines constitute a useful approach to identify patients at risk for HNPCC. In patients fulfilling these criteria, both microsatellite instability testing and immunostaining are equivalent and highly effective strategies to further select those patients who should be tested for MSH2/MLH1 germline mutations.