Prediction of germline mutations and cancer risk in the lynch syndrome Journal Article
| Authors: | Chen, S.; Wang, W.; Lee, S.; Nafa, K.; Lee, J.; Romans, K.; Watson, P.; Gruber, S. B.; Euhus, D.; Kinzler, K. W.; Jass, J.; Gallinger, S.; Lindor, N. M.; Casey, G.; Ellis, N.; Giardiello, F. M.; Offit, K.; Parmigiani, G. |
| Article Title: | Prediction of germline mutations and cancer risk in the lynch syndrome |
| Abstract: | Context: Identifying families at high risk for the Lynch syndrome (ie, hereditary non-polyposis 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. ©2006 American Medical Association. All rights reserved. |
| Keywords: | adult; middle aged; carrier protein; dna binding protein; gene mutation; genetics; mutation; dna-binding proteins; cancer risk; united states; outcome assessment; endometrial neoplasms; endometrium cancer; demography; nuclear protein; prevalence; practice guideline; validation study; algorithms; risk; nuclear proteins; colorectal neoplasms; confidence interval; germ line; medical information; algorithm; probability; models, statistical; colorectal tumor; mismatch repair; carrier proteins; australia; familial cancer; genetic screening; statistical model; canada; mlh1 protein, human; protein msh2; endometrium tumor; colorectal neoplasms, hereditary nonpolyposis; g t mismatch binding protein; g-t mismatch-binding protein; msh2 protein, human; muts homolog 2 protein; germ-line mutation; patient referral; genetic counseling; family; autosomal dominant inheritance |
| Journal Title: | JAMA - Journal of the American Medical Association |
| Volume: | 296 |
| Issue: | 12 |
| ISSN: | 0098-7484 |
| Publisher: | American Medical Association |
| Date Published: | 2006-09-27 |
| Start Page: | 1479 |
| End Page: | 1487 |
| Language: | English |
| DOI: | 10.1001/jama.296.12.1479 |
| PUBMED: | 17003396 |
| PROVIDER: | scopus |
| PMCID: | PMC2538673 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 104" - "Export Date: 4 June 2012" - "CODEN: JAMAA" - "Source: Scopus" |
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