Journal of the National Cancer Institute Advance Access published online on February 24, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn499
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© The Author 2009. Published by Oxford University Press.
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Prediction of Lynch Syndrome in Consecutive Patients With Colorectal Cancer
Affiliations of authors: Department of Genetics (RCG, MOW, HBY) and Discipline of Medicine (PSP), Faculty of Medicine, Memorial University, St John’s, Newfoundland, Canada
Correspondence to: Roger C. Green, BSc, PhD, Discipline of Genetics, Faculty of Medicine, Memorial University, St John’s, Newfoundland, Canada A1B 3V6 (e-mail: rcgreen{at}mun.ca).
Background: Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models—Leiden, MMRpredict, PREMM1,2, and MMRpro—to distinguish between those who did and did not carry DNA mismatch repair gene mutations.
Methods: We studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. All statistical tests were two-sided.
Results: Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to 0.96. Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P < .015) for MSH6–PMS2 and MSH2–MLH1 mutation carriers, respectively. For the Leiden, MMRpredict, and PREMM1,2 models, correcting the risk scores for bias introduced by family size improved their power to discriminate between carriers and noncarriers. After correcting for family size, the best model was MMRpredict, which achieved a sensitivity of 94% (95% confidence interval [CI] = 73% to 99%) and a specificity of 91% (95% CI = 88% to 93%) and identified a smaller proportion of patients than the revised Bethesda criteria as those who should undergo additional molecular or immunohistochemical testing (11% vs 50%).
Conclusion: MMRpredict was the best-performing model for identifying colorectal cancer patients who are at high risk of carrying a DNA mismatch repair gene mutation and thus should be screened for Lynch syndrome.
| Context and Caveats Prior knowledge Inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) cause Lynch syndrome, which is one of the most prevalent inherited cancer syndromes. Several models have been developed that predict the occurrence of Lynch syndrome in high-risk patients and families. Study design Data from 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available (18 of whom carried such a mutation) were used to test the ability of four models—Leiden, MMRpredict, PREMM1,2, and MMRpro—to distinguish between those who did and did not carry DNA mismatch repair gene mutations. Contribution All four models overestimated the probability of a mutation, especially in low-risk patients, but could discriminate between carriers and noncarriers of mismatch repair mutations. The best model was MMRpredict when corrected for family size. This model identified fewer patients who should be screened for Lynch syndrome than previous models or criteria. Implications MMRpredict should be tested further as a prediction model for Lynch syndrome in the general population of patients with colorectal cancer. Limitations The cohort contained only 18 carriers of a DNA mismatch repair gene mutation. Patients who were older than 74 years when diagnosed with colorectal cancer were not included in this study. From the Editors
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Manuscript received June 23, 2008; revised December 2, 2008; accepted December 12, 2008.
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J Natl Cancer Inst 2009 101: 281.
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