Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm₅ Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing.

Abstract

Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM₅ prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM₅ scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM₅ score ≥ 2.5%. MSI/IHC and PREMM₅ had comparable sensitivity for identifying LS carriers in high-risk (89.3% <i>v</i> 85.7%; <i>P</i> = .712) and oncology clinic patients (96.6% <i>v</i> 96.6%; <i>P</i> = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% <i>v</i> 20.1%; <i>P</i> < .001; 92.3% <i>v</i> 24.3%; <i>P</i> < .001). In both cohorts, PREMM₅ had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM₅ identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. MSI/IHC and PREMM₅ effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM₅ identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM₅ score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.