Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset

Jiil Chung, Logine Negm, Vanessa Bianchi, Lucie Stengs, Anirban Das, Zhihui Amy Liu, Sumedha Sudhaman, Melyssa Aronson, Ledia Brunga, Melissa Edwards, Victoria Forster, Martin Komosa, Scott Davidson, Jodi Lees, Patrick Tomboc, David Samuel, Roula Farah, Anne Bendel, Jeffrey Knipstein, Kami Wolfe SchneiderAgnes Reschke, Shayna Zelcer, Alexandra Zorzi, Robert McWilliams, William D. Foulkes, Raymond Bedgood, Lindsay Peterson, Sara Rhode, An Van Damme, Isabelle Scheers, Sharon Gardner, Gabriel Robbins, Magimairajan Issai Vanan, M. Stephen Meyn, Rebecca Auer, Brandie Leach, Carol Burke, Anita Villani, David Malkin, Eric Bouffet, Annie Huang, Michael D. Taylor, Carol Durno, Adam Shlien, Cynthia Hawkins, Gad Getz, Yosef E. Maruvka, Uri Tabori

Research output: Contribution to journalArticlepeer-review


PURPOSEDiagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD.PATIENTS AND METHODSWe developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation.RESULTSOverall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P <.0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5).CONCLUSIONLOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Original languageEnglish (US)
Pages (from-to)766-777
Number of pages12
JournalJournal of Clinical Oncology
Issue number4
StatePublished - Feb 1 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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