| Literature DB >> 29056344 |
Brittany B Campbell1, Nicholas Light2, David Fabrizio3, Matthew Zatzman4, Fabio Fuligni5, Richard de Borja5, Scott Davidson6, Melissa Edwards5, Julia A Elvin3, Karl P Hodel7, Walter J Zahurancik8, Zucai Suo8, Tatiana Lipman5, Katharina Wimmer9, Christian P Kratz10, Daniel C Bowers11, Theodore W Laetsch11, Gavin P Dunn12, Tanner M Johanns13, Matthew R Grimmer14, Ivan V Smirnov15, Valérie Larouche16, David Samuel17, Annika Bronsema18, Michael Osborn19, Duncan Stearns20, Pichai Raman21, Kristina A Cole21, Phillip B Storm22, Michal Yalon23, Enrico Opocher24, Gary Mason25, Gregory A Thomas26, Magnus Sabel27, Ben George28, David S Ziegler29, Scott Lindhorst30, Vanan Magimairajan Issai31, Shlomi Constantini32, Helen Toledano32, Ronit Elhasid33, Roula Farah34, Rina Dvir35, Peter Dirks36, Annie Huang37, Melissa A Galati5, Jiil Chung5, Vijay Ramaswamy38, Meredith S Irwin38, Melyssa Aronson39, Carol Durno40, Michael D Taylor36, Gideon Rechavi41, John M Maris21, Eric Bouffet38, Cynthia Hawkins42, Joseph F Costello43, M Stephen Meyn44, Zachary F Pursell7, David Malkin45, Uri Tabori46, Adam Shlien47.
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.Entities:
Keywords: DNA repair; DNA replication; cancer genomics; cancer predisposition; hypermutation; immune checkpoint inhibitors; mismatch repair; mutator
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Year: 2017 PMID： 29056344 PMCID： PMC5849393 DOI： 10.1016/j.cell.2017.09.048
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582