Identifying families at high risk for the Lynch syndrome is critical for both genetic counseling and cancer prevention.
Current clinical guidelines are effective but limited by applicability and cost.
Professor Sining Chen and colleagues from Baltimore estimated the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and developing colorectal or endometrial cancer.
The team aimed to develope and validate a genetic counseling and risk prediction tool.
External validation was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia between 1993 and 2005.
MMRpro was used for external validation, which models the autosomal dominant inheritance of mismatch repair mutations.
The researchers compared model predictions with results of highly sensitive germline mutation detection techniques.
|MMRpro had an observed to predicted case ratio of 0.9|
|Journal of the American Medical Association|
The parameters were based on meta-analyses of the penetrance and prevalence of mutations.
The researchers also based the parameters on the predictive values of tumor characteristics.
The model's prediction was tailored to each individual's family history on colorectal cancer, and to tumor characteristics including microsatellite instability.
The team's main outcome was the ability of MMRpro to correctly predict mutation carrier status.
Mutation carrier status was measured by operating characteristics, calibration, and overall accuracy.
The team found that in the independent validation, MMRpro provided a concordance index of 0.8 and a ratio of observed to predicted cases of 0.9.
The researchers found that this resulted in higher accuracy than existing alternatives and current clinical guidelines.
Professor Chen's team concludes, “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 MMRpro germline testing.”
“It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.”