Comprehensive Analysis of Hypermutation in Human Cancer

Brittany B. Campbell, Nicholas Light, David Fabrizio, Matthew Zatzman, Fabio Fuligni, Richard de Borja, Scott Davidson, Melissa Edwards, Julia A. Elvin, Karl P. Hodel, Walter J. Zahurancik, Zucai Suo, Tatiana Lipman, Katharina Wimmer, Christian P. Kratz, Daniel C. Bowers, Theodore W. Laetsch, Gavin P. Dunn, Tanner M. Johanns, Matthew R. GrimmerIvan V. Smirnov, Valérie Larouche, David Samuel, Annika Bronsema, Michael Osborn, Duncan Stearns, Pichai Raman, Kristina A. Cole, Phillip B. Storm, Michal Yalon, Enrico Opocher, Gary Mason, Gregory A. Thomas, Magnus Sabel, Ben George, David S. Ziegler, Scott Lindhorst, Vanan Magimairajan Issai, Shlomi Constantini, Helen Toledano, Ronit Elhasid, Roula Farah, Rina Dvir, Peter Dirks, Annie Huang, Melissa A. Galati, Jiil Chung, Vijay Ramaswamy, Meredith S. Irwin, Melyssa Aronson, Carol Durno, Michael D. Taylor, Gideon Rechavi, John M. Maris, Eric Bouffet, Cynthia Hawkins, Joseph F. Costello, M. Stephen Meyn, Zachary F. Pursell, David Malkin, Uri Tabori*, Adam Shlien

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

Original languageEnglish
Pages (from-to)1042-1056.e10
JournalCell
Volume171
Issue number5
DOIs
StatePublished - 16 Nov 2017

Funding

FundersFunder number
Bristol-Myers Squibb Catalyst Research
Meagan's Walk
SickKids Foundation
LivWise
Janssen Pharmaceutical Companies of Johnson & Johnson
Entertainment Industry Foundation
SickKids Research Training Competition
Ministero dell’Istruzione, dell’Università e della Ricerca
Garron Family Cancer Centre
Government of Ontario
SU2C – St. Baldrick’s Pediatric Dream Team Translational Research
McLaughlin Centre
Weill Cornell Medical College
National Institute of Environmental Health SciencesR56ES026821, R00ES016780, R01ES028271
National Institute of Environmental Health Sciences
Stand Up To CancerSU2C-AACR-CT-07-17, SU2C-AACR-DT1113
Stand Up To Cancer
Associazione Italiana per la Ricerca sul Cancro20417
Associazione Italiana per la Ricerca sul Cancro
Canadian Institutes of Health ResearchMOP – 137899, 137899, unidentified
Canadian Institutes of Health Research
National Cancer InstituteP01CA118816, R01CA169316, P50CA097257
National Cancer Institute
Meagan’s WalkMW-2014-10
Ministero della SaluteRF_GR-2011-02351355
Ministero della Salute

    Keywords

    • DNA repair
    • DNA replication
    • cancer genomics
    • cancer predisposition
    • hypermutation
    • immune checkpoint inhibitors
    • mismatch repair
    • mutator

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