Comprehensive Analysis of Hypermutation in Human Cancer.

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.

• Authors: 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 Grimmer, Ivan 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
• Journal: Cell (Cell) Vol. 171 Issue 5 Pg. 1042-1056.e10 (Nov 16 2017) ISSN: 1097-4172 [Electronic] United States
• PMID: 29056344 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Poly-ADP-Ribose Binding Proteins
• POLD1 protein, human
• DNA Polymerase II
• DNA Polymerase III
• POLE protein, human

Topics

• Adult
• Child
• Cluster Analysis
• DNA Polymerase II (genetics)
• DNA Polymerase III (genetics)
• DNA Replication
• Humans
• Mutation
• Neoplasms (classification, genetics, pathology, therapy)
• Poly-ADP-Ribose Binding Proteins (genetics)