Comparison of colorectal and endometrial microsatellite instability tumor analysis and premm5 risk assessment for predicting pathogenic germline variants on multigene panel testing

Alessandro Mannucci, C. Sloane Furniss, Chinedu Ukaegbu, Miki Horiguchi, Tara Fehlmann, Hajime Uno, Matthew B. Yurgelun, Sapna Syngal

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE 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. PATIENTS AND METHODS 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%. RESULTS MSI/IHC and PREMM5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P 5.712) and oncology clinic patients (96.6% v 96.6%; P 5 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P,.001; 92.3% v 24.3%; P,.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. CONCLUSION 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.

Original languageEnglish
Pages (from-to)4086-4094
Number of pages9
JournalJournal of Clinical Oncology
Volume38
Issue number34
DOIs
Publication statusPublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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