Prediction of germline mutations and cancer risk in the lynch syndrome

Sining Chen, Wenyi Wang, Shing Lee, Khedoudja Nafa, Johanna Lee, Kathy Romans, Patrice Watson, Stephen B. Gruber, David Euhus, Kenneth W. Kinzler, Jeremy Jass, Steven Gallinger, Noralane Morey Lindor, Graham Casey, Nathan Ellis, Francis M. Giardiello, Kenneth Offit, Giovanni Parmigiani

Research output: Contribution to journalArticle

260 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1479-1487
Number of pages9
JournalJournal of the American Medical Association
Volume296
Issue number12
DOIs
StatePublished - Sep 27 2006

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Hereditary Nonpolyposis Colorectal Neoplasms
Germ-Line Mutation
Genetic Counseling
Mutation
Colorectal Neoplasms
DNA Mismatch Repair
Guidelines
Neoplasms
Endometrial Neoplasms
Confidence Intervals
Microsatellite Instability
Aptitude
Penetrance
Calibration
Canada
Meta-Analysis
Outcome Assessment (Health Care)
Costs and Cost Analysis
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Chen, S., Wang, W., Lee, S., Nafa, K., Lee, J., Romans, K., ... Parmigiani, G. (2006). Prediction of germline mutations and cancer risk in the lynch syndrome. Journal of the American Medical Association, 296(12), 1479-1487. https://doi.org/10.1001/jama.296.12.1479

Prediction of germline mutations and cancer risk in the lynch syndrome. / Chen, Sining; Wang, Wenyi; Lee, Shing; Nafa, Khedoudja; Lee, Johanna; Romans, Kathy; Watson, Patrice; Gruber, Stephen B.; Euhus, David; Kinzler, Kenneth W.; Jass, Jeremy; Gallinger, Steven; Lindor, Noralane Morey; Casey, Graham; Ellis, Nathan; Giardiello, Francis M.; Offit, Kenneth; Parmigiani, Giovanni.

In: Journal of the American Medical Association, Vol. 296, No. 12, 27.09.2006, p. 1479-1487.

Research output: Contribution to journalArticle

Chen, S, Wang, W, Lee, S, Nafa, K, Lee, J, Romans, K, Watson, P, Gruber, SB, Euhus, D, Kinzler, KW, Jass, J, Gallinger, S, Lindor, NM, Casey, G, Ellis, N, Giardiello, FM, Offit, K & Parmigiani, G 2006, 'Prediction of germline mutations and cancer risk in the lynch syndrome', Journal of the American Medical Association, vol. 296, no. 12, pp. 1479-1487. https://doi.org/10.1001/jama.296.12.1479
Chen, Sining ; Wang, Wenyi ; Lee, Shing ; Nafa, Khedoudja ; Lee, Johanna ; Romans, Kathy ; Watson, Patrice ; Gruber, Stephen B. ; Euhus, David ; Kinzler, Kenneth W. ; Jass, Jeremy ; Gallinger, Steven ; Lindor, Noralane Morey ; Casey, Graham ; Ellis, Nathan ; Giardiello, Francis M. ; Offit, Kenneth ; Parmigiani, Giovanni. / Prediction of germline mutations and cancer risk in the lynch syndrome. In: Journal of the American Medical Association. 2006 ; Vol. 296, No. 12. pp. 1479-1487.
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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.",
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AU - Romans, Kathy

AU - Watson, Patrice

AU - Gruber, Stephen B.

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AU - Kinzler, Kenneth W.

AU - Jass, Jeremy

AU - Gallinger, Steven

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