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

Research output: Contribution to journalArticle

225 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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