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DNA POLYMERASE AND MISMATCH REPAIR EXERT DISTINCT MICROSATELLITE INSTABILITY SIGNATURES IN NOMRAL AND MALIGNANT HUMAN CELLS
- Jiil Chung, Canada
- Yosef E. Maruvka, United States of America
- Sumedha Sudhaman, Canada
- Jacalyn Kelly, Canada
- Nicholas J. Haradhvala, United States of America
- Vanessa J Bianchi, Canada
- Melissa Edwards, Canada
- Victoria J. Forster, Canada
- Nuno M. Nunes, Canada
- Melissa A. Galati, Canada
- Martin Komosa, Canada
- Shriya Deshmukh, Canada
- Vanja Cabric, Canada
- Scott Davidson, Canada
- Matthew Zatzman, Canada
- Nicholas Light, Canada
- Reid Hayes, Canada
- Ledia Brunga, Canada
- Nathaniel Anderson, Canada
- Ben Ho, Canada
- Karl Hodel, United States of America
- Robert Siddaway, Canada
- A. Sorana Morrissy, Canada
- Daniel Bowers, United States of America
- Valerie Larouche, Canada
- Annika Bronsema, Germany
- Michael Osborn, Australia
- Kristina Cole, United States of America
- Enrico Opocher, Italy
- Gary Mason, United States of America
- Gregory A. Thomas, United States of America
- Ben George, United States of America
- David S. Ziegler, Australia
- Scott Lindhorst, United States of America
- Vanan Magimairajan Issai, Canada
- Michal Oren, Israel
- Alyssa Reddy, United States of America
- Maura Massimino, Italy
- Patrick Tomboc, United States of America
- An Van Damme, Belgium
- Alexander Lossos, Israel
- Carol Durno, Canada
- Melyssa Aronson, Canada
- Daniel Morgenstern, Canada
- Eric Bouffet, Canada
- Annie Huang, Canada
- Michael D. Taylor, Canada
- Anita Vilani, Canada
- David D. Malkin, Canada
- Cynthia Hawkins, Canada
- Zachary F. Pursell, United States of America
- Adam Shlien, Canada
- Thomas A. Kunkel, United States of America
- Gad Getz, United States of America
- Uri Tabori, Canada
Abstract
Background and Aims
Replication Repair Deficiency (RRD) results in mistakes during DNA replication, and is hallmarked by aggressive hypermutant cancers. RRD is the dysfunction of either, or both, of the Mismatch Repair (MMR) and the exonuclease/proofreading domain of DNA polymerase. Currently, it is generally understood that both systems repair substitution mutations, but microsatellite insertion/deletions (MS-indels) are solely repaired by the MMR system. The role of the polymerase in repairing MS-indels is currently unclear, so we used next-generation sequencing data of 69 exomes and 45 genomes of normal-matched RRD tumors to investigate the >20,000,000 genomic microsatellite loci in each tumor and germline sample.
Methods
We applied MSMuTect to all RRD samples, and compared their MS-indels to adult RRD tumors and pediatric replication repair-proficient tumors.
Results
The number of MS-indels in pediatric RRD cancers were comparable to adult MMR-deficient cancers, and significantly higher than all MMR-proficient cancers (p<2.2x10-15). We developed novel MS-indel signatures (MS-sig) where MMR-deficiency was associated with -1 deletions (p<2.2e-16), and polymerase-exonuclease-mutant tumours had a significant increase of +1 insertion mutations (p<5.7e-7). These findings led to insights to a strand-bias model of MS-indel repair. Furthermore, we found that MS-deletions in adults tended to converge the MS-loci to a specific length, suggesting a non-stochastic model of MS-indel accumulation. Clinically, MS-sigs were able to stratify patients based on the variants of RRD. These unique signatures were also observed in non-malignant/germline tissues, which enables the detection of RRD prior to cancer, and specific signatures were associated with improved response to immune checkpoint inhibitors.
Conclusions
We uncovered key biological and clinical insights in RRD tumourigenesis. We are the first to uncover the impact of polymerase proofreading in MS-indel gains, as revealed by unique MS-sigs. The discovery of MS-sigs has also enabled pre-cancer diagnosis and immunotherapy response prediction in RRD individuals, which can improve the clinical management of this high-risk patient group.