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Comprehensive Analysis of Hypermutation in Human Cancer

Journal article
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
Published in Cell
Volume 171
Issue 5
Pages 1042-1056.e10
ISSN 0092-8674
Publication year 2017
Published at Institute of Clinical Sciences, Department of Pediatrics
Pages 1042-1056.e10
Language en
Keywords Cancer genomics, Cancer predisposition, DNA repair, DNA replication, Hypermutation, Immune checkpoint inhibitors, Mismatch repair, Mutator
Subject categories Molecular biology, Molecular medicine (genetics and pathology), Cancer and Oncology


© 2017 Elsevier Inc. 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.

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