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Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome
Sining Chen, PhD;
Wenyi Wang, MA;
Shing Lee, ScM;
Khedoudja Nafa, PharmD, PhD;
Johanna Lee, MPH;
Kathy Romans, MS;
Patrice Watson, PhD;
Stephen B. Gruber, MD, PhD, MPH;
David Euhus, MD;
Kenneth W. Kinzler, PhD;
Jeremy Jass, MD(Lond), DSc(Lond);
Steven Gallinger, MD, MSc;
Noralane M. Lindor, MD;
Graham Casey, PhD;
Nathan Ellis, PhD;
Francis M. Giardiello, MD;
Kenneth Offit, MD, MPH;
Giovanni Parmigiani, PhD; for the Colon Cancer Family Registry
JAMA. 2006;296:1479-1487.
Context Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.
Objective To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.
Design, Setting, and Patients External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.
Main Outcome Measure Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.
Results In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.
Conclusions MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.
Author Affiliations: Johns Hopkins Bloomberg School of Public Health (Drs Chen and Parmigiani and Ms Wang) and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Drs Kinzler, Giardiello, and Parmigiani and Ms Romans), Baltimore, Md; Columbia University Mailman School of Public Health, New York, NY (Ms S. Lee); Memorial Sloan-Kettering Cancer Center, New York, NY (Drs Nafa and Offit and Ms J. Lee); Creighton University School of Medicine, Omaha, Neb (Dr Watson); University of Michigan Medical School, Ann Arbor (Dr Gruber); University of Texas Southwestern Medical Center, Dallas (Dr Euhus); Department of Pathology, McGill University, Montreal, Quebec (Dr Jass); University of Toronto, Toronto, Ontario (Dr Gallinger); Mayo Clinic College of Medicine, Rochester, Minn (Dr Lindor); Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (Dr Casey); and Department of Medicine, University of Chicago, Chicago, Ill (Dr Ellis).
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