1. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells
- Author
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Cynthia Hawkins, Daniel A. Morgenstern, Victoria J. Forster, Scott Lindhorst, Sumedha Sudhaman, Uri Tabori, An Van Damme, Eric Bouffet, Alexander Lossos, Ben George, Annika Bronsema, Anita Villani, Michael Osborn, Annie Huang, Yosef E. Maruvka, Melyssa Aronson, Patrick Tomboc, Michal Yalon-Oren, David S. Ziegler, Reid Hayes, Carol Durno, Vanessa Bianchi, Melissa Galati, Nuno Miguel Nunes, Magimairajan Issai Vanan, Vanja Cabric, Gregory Thomas, Nicholas Light, Scott Davidson, Matthew Zatzman, Michael D. Taylor, A. Sorana Morrissy, Martin Komosa, Melissa Edwards, Gary Mason, Jiil Chung, Adam Shlien, Gad Getz, Shriya Deshmukh, Alyssa Reddy, Karl P. Hodel, Zachary F. Pursell, Robert Siddaway, Maura Massimino, Enrico Opocher, Ledia Brunga, David Malkin, Ben Ho, Jacalyn Kelly, Daniel C. Bowers, Nathaniel D. Anderson, Valerie Larouche, Thomas A. Kunkel, Nicholas J. Haradhvala, Kristina A. Cole, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
- Subjects
0301 basic medicine ,DNA polymerase ,Somatic hypermutation ,DNA-Directed DNA Polymerase ,DNA Mismatch Repair ,Whole Exome Sequencing ,Article ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Exome Sequencing ,medicine ,Humans ,Exome ,Polymerase ,Genetics ,biology ,food and beverages ,Microsatellite instability ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Proofreading ,Microsatellite Instability ,DNA mismatch repair - Abstract
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 immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995
- Published
- 2020
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