Area Editoriale
CONTEXT: Identifying families athigh risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectalcancer) is critical for both genetic counseling and cancer prevention. Currentclinical guidelines are effective but limited by applicability and cost.OBJECTIVE: To develop and validate a genetic counseling and risk predictiontool that estimates the probability of carrying a deleterious mutation in mismatchrepair genes MLH1, MSH2, or MSH6 and the probability of developing colorectalor endometrial cancer. DESIGN, SETTING, AND PATIENTS: External validation ofthe MMRpro model was conducted on 279 individuals from 226 clinic-basedfamilies in the United States,Canada, and Australia(referred between 1993-2005) by comparing model predictions with results ofhighly sensitive germline mutation detection techniques. MMRpro models theautosomal dominant inheritance of mismatch repair mutations, with parameters basedon meta-analyses of the penetrance and prevalence of mutations and of thepredictive values of tumor characteristics. The model's prediction is tailoredto each individual's detailed family history information on colorectal andendometrial cancer and to tumor characteristics including microsatelliteinstability. MAIN OUTCOME MEASURE: Ability of MMRpro to correctly predictmutation carrier status, as measured by operating characteristics, calibration,and overall accuracy. RESULTS: In the independent validation, MMRpro provided aconcordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio ofobserved to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). Thisresults in higher accuracy than existing alternatives and current clinicalguidelines. CONCLUSIONS: MMRpro is a broadly applicable, accurate predictionmodel that can contribute to current screening and genetic counseling practicesin a high-risk population. It is more sensitive and more specific than existingclinical guidelines for identifying individuals who may benefit from MMRgermline testing. It is applicable to individuals for whom tumor samples arenot available and to individuals in whom germline testing finds no mutation.Leggil'articolo