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 language | English |
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Pages (from-to) | 1042-1056.e10 |
Journal | Cell |
Volume | 171 |
Issue number | 5 |
DOIs | |
State | Published - 16 Nov 2017 |
Funding
Funders | Funder number |
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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 Sciences | R56ES026821, R00ES016780, R01ES028271 |
Stand Up To Cancer | SU2C-AACR-CT-07-17, SU2C-AACR-DT1113 |
Associazione Italiana per la Ricerca sul Cancro | 20417 |
Canadian Institutes of Health Research | MOP – 137899, 137899, unidentified |
National Cancer Institute | P01CA118816, R01CA169316, P50CA097257 |
Meagan’s Walk | MW-2014-10 |
Ministero della Salute | RF_GR-2011-02351355 |
Keywords
- DNA repair
- DNA replication
- cancer genomics
- cancer predisposition
- hypermutation
- immune checkpoint inhibitors
- mismatch repair
- mutator