Background & Aims: Early recognition of patients at risk for Lynch syndrome is critical but often difficult. Recently, a predictive algorithm-the PREMM1,2model-has been developed to quantify the risk of carrying a germline mutation in the mismatch repair (MMR) genes MLH1 and MSH2. However, the model's performance in an unselected, population-based colorectal cancer population as well as its performance in combination with tumor MMR testing are unknown. Methods: We included all colorectal cancer cases from the EPICOLON study, a prospective, multicenter, population-based cohort (n = 1222). All patients underwent tumor microsatellite instability analysis and immunostaining for MLH1 and MSH2, and those with MMR deficiency (n = 91) underwent tumor BRAF V600E mutation analysis and MLH1/MSH2 germline testing. Results: The PREMM1,2model with a ≥5% cut-off had a sensitivity, specificity, and positive predictive value (PPV) of 100%, 68%, and 2%, respectively. The use of a higher PREMM1,2cut-off provided a higher specificity and PPV, at expense of a lower sensitivity. The combination of a ≥5% cut-off with tumor MMR testing maintained 100% sensitivity with an increased specificity (97%) and PPV (21%). The PPV of a PREMM1,2score ≥20% alone (16%) approached the PPV obtained with PREMM1,2score ≥5% combined with tumor MMR testing. In addition, a PREMM1,2score of <5% was associated with a high likelihood of a BRAF V600E mutation. Conclusions: The PREMM1,2model is useful to identify MLH1/MSH2 mutation carriers among unselected colorectal cancer patients. Quantitative assessment of the genetic risk might be useful to decide on subsequent tumor MMR and germline testing.

Additional Metadata
Persistent URL dx.doi.org/10.1053/j.gastro.2007.10.042, hdl.handle.net/1765/29083
Note Free full text at PubMed
Citation
Balaguer, F., Balmana, J., Castellví-Bel, S., Steyerberg, E.W., Andreu, H., Llor, X., … Castells, S.. (2008). Validation and Extension of the PREMM1,2 Model in a Population-Based Cohort of Colorectal Cancer Patients. Gastroenterology, 134(1), 39–46. doi:10.1053/j.gastro.2007.10.042