@article{0c98bd924a674f05a8cd688b1faadae9,
title = "DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells",
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 immuno-therapy response prediction.",
author = "Jiil Chung and Maruvka, {Yosef E.} and Sumedha Sudhaman and Jacalyn Kelly and Haradhvala, {Nicholas J.} and Vanessa Bianchi and Melissa Edwards and Forster, {Victoria J.} and Nunes, {Nuno M.} and Galati, {Melissa A.} and Martin Komosa and Shriya Deshmukh and Vanja Cabric and Scott Davidson and Matthew Zatzman and Nicholas Light and Reid Hayes and Ledia Brunga and Anderson, {Nathaniel D.} and Ben Ho and Hodel, {Karl P.} and Robert Siddaway and Morrissy, {A. Sorana} and Bowers, {Daniel C.} and Val{\'e}rie Larouche and Annika Bronsema and Michael Osborn and Cole, {Kristina A.} and Enrico Opocher and Gary Mason and Thomas, {Gregory A.} and Ben George and Ziegler, {David S.} and Scott Lindhorst and Magimairajan Vanan and Michal Yalon-Oren and Reddy, {Alyssa T.} and Maura Massimino and Patrick Tomboc and {Van Damme}, An and Alexander Lossos and Carol Durno and Melyssa Aronson and Morgenstern, {Daniel A.} and Eric Bouffet and Annie Huang and Taylor, {Michael D.} and Anita Villani and David Malkin and Hawkins, {Cynthia E.} and Pursell, {Zachary F.} and Adam Shlien and Kunkel, {Thomas A.} and Gad Getz and Uri Tabori",
note = "Funding Information: The KiCS program is supported by the Garron Family Cancer Centre with funds from the SickKids Foundation. This research is supported by Meagan{\textquoteright}s Walk (MW-2014-10), b.r.a.i.n.child Canada, LivWise, an Enabling Studies Program grant from BioCanRx, Canada{\textquoteright}s Immunotherapy Network (a Network Centre of Excellence), the Canadian Institutes for Health Research (CIHR) grant (PJT-156006), the CIHR Joint Canada-Israel Health Research Program (108188), and a Stand Up To Cancer (SU2C)–Bristol Myers Squibb Catalyst Research (SU2C-AACR-CT07-17) research grant. Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. G. Getz and Y.E. Maruvka were partially funded by G. Getz funds at Massachusetts General Hospital. G. Getz was partially funded by the Paul C. Zamecnick Chair in Oncology at the Massachusetts General Hospital Cancer Center. Funding Information: The KiCS program is supported by the Garron Family Cancer Centre with funds from the SickKids Foundation. This research is supported by Meagan?s Walk (MW-2014-10), b.r.a.i.n.child Canada, LivWise, an Enabling Studies Program grant from BioCanRx, Canada?s Immunotherapy Network (a Network Centre of Excellence), the Canadian Institutes for Health Research (CIHR) grant (PJT-156006), the CIHR Joint Canada-Israel Health Research Program (108188), and a Stand Up To Cancer (SU2C)?Bristol Myers Squibb Catalyst Research (SU2C-AACR-CT07-17) research grant. Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. G. Getz and Y.E. Maruvka were partially funded by G. Getz funds at Massachusetts General Hospital. G. Getz was partially funded by the Paul C. Zamecnick Chair in Oncology at the Massachusetts General Hospital Cancer Center. Funding Information: Y.E. Maruvka reports MGH startup money grant outside the submitted work. N.J. Haradhvala reports personal fees from Constellation Pharmaceuticals outside the submitted work. M. Osborn reports nonfinancial support from Amgen, Pfizer, and Novartis outside the submitted work. G. Mason reports other support from Janssen Pharmaceuticals outside the submitted work. B. George reports grants and personal fees from Ipsen, BMS, Celgene, Taiho Oncology, and Roche/Genentech; personal fees from Foundation Medicine, Exelixis, Terumo Interventional Systems, and Eisai; and grants from Boehringer Ingelheim, Tolero Pharmaceuticals, Glyconex, and NGM Bio outside the submitted work. D.S. Ziegler reports personal fees from Bayer outside the submitted work. A. Van Damme reports other from BMS outside the submitted work. D.A. Morgenstern reports personal fees from Roche, Boehringer Ingelheim, Bayer, Clarity Pharmaceuticals, Y-mAbs Therapeutics, and EUSA Pharma outside the submitted work. E. Bouffet reports grants from Bristol Myers Squibb during the conduct of the study and grants from Roche outside the submitted work. G. Getz reports a patent for MSMuTect issued and a patent for MSIDetect pending. G. Getz also receives research funds from IBM and Pharmacyclics, and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, MSIDetect, POLYSOLVER, and TensorQTL. G. Getz is also a founder, consultant, and holds privately held equity in Scorpion Therapeutics. U. Tabori reports grants from AACR/SU2C BMS Catalyst during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2021",
month = may,
doi = "10.1158/2159-8290.CD-20-0790",
language = "English (US)",
volume = "11",
pages = "1176--1191",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}