Comparison of the clinical prediction model PREMM_1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer

Background: Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM_1,2,6 model predicts the likelihood of a MMR gene mutation based on personal and family cancer history. Objective: To compare strategies using PREMM_1,2,6 and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers. Design: Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2 , MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM_1,2,6 predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM_1,2,6, (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM _1,2,6+MSI, (6) PREMM_1,2,6+IHC, (7) PREMM _1,2,6+IHC+MSI. Results: Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM_1,2,6 discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM _1,2,6 was slightly greater than PREMM_1,2,6+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM_1,2,6+IHC did not improve discrimination. Conclusion: PREMM_1,2,6 and IHC showed excellent performance in distinguishing mutation carriers from noncarriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM _1,2,6 scores where genetic evaluation does not disclose a MMR mutation.