DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells

Jiil Chung, Yosef E. Maruvka, Sumedha Sudhaman, Jacalyn Kelly, Nicholas J. Haradhvala, Vanessa Bianchi, Melissa Edwards, Victoria J. Forster, Nuno M. Nunes, Melissa A. Galati, Martin Komosa, Shriya Deshmukh, Vanja Cabric, Scott Davidson, Matthew Zatzman, Nicholas Light, Reid Hayes, Ledia Brunga, Nathaniel D. Anderson, Ben HoKarl P. Hodel, Robert Siddaway, A. Sorana Morrissy, Daniel C. Bowers, Valérie Larouche, Annika Bronsema, Michael Osborn, Kristina A. Cole, Enrico Opocher, Gary Mason, Gregory A. Thomas, Ben George, David S. Ziegler, Scott Lindhorst, Magimairajan Vanan, Michal Yalon-Oren, Alyssa T. Reddy, Maura Massimino, Patrick Tomboc, An Van Damme, Alexander Lossos, Carol Durno, Melyssa Aronson, Daniel A. Morgenstern, Eric Bouffet, Annie Huang, Michael D. Taylor, Anita Villani, David Malkin, Cynthia E. Hawkins, Zachary F. Pursell, Adam Shlien, Thomas A. Kunkel, Gad Getz, Uri Tabori

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome-and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immuno-therapy response prediction.

Original languageEnglish (US)
Pages (from-to)1176-1191
Number of pages16
JournalCancer discovery
Issue number5
StatePublished - May 2021

ASJC Scopus subject areas

  • Oncology


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