biostudies-literatureCampbell BBthe CIHR Joint Canada-Israel HealthFrank Fletcher Memorial FundNIEHS NIH HHSMcLaughlin CentreMeagan’s WalkSickKidsUniversity of TorontoCIHRStand Up to Cancer (SU2C) – Bristol-Myers Squibb Catalyst ResearchGovernment of OntarioNCI NIH HHSResearch ProgramGarron Family Cancer CentreSU2C – St. Baldrick’s Pediatric Dream Team Translational Research GrantSickKids Foundation1042-1056.e10https://www.ebi.ac.uk/biostudies/studies/S-EPMC5849393biostudies-literatureUnknown171(5)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 hypermutatCellComprehensive Analysis of Hypermutation in Human Cancer.PMC5849393SU2C-AACR-CT-07-17P50 CA097257MOP – 137899R00 ES016780MW-2014-10SU2C-AACR-DT1113R56 ES026821P01 CA118816R01 ES028271Issai VMMaris JMBowers DCElhasid RZatzman MHodel KPZiegler DSWimmer KFuligni FConstantini SGalati MAThomas GACole KACostello JFHuang AStorm PBTaylor MDZahurancik WJGrimmer MRYalon MDavidson SBouffet EHawkins CEdwards MMeyn MSJohanns TMToledano HLarouche VIrwin MSDunn GPde Borja RPursell ZFLight NGeorge BDirks PCampbell BBLaetsch TWElvin JAOpocher EMason GOsborn MRamaswamy VDurno CKratz CPRechavi GStearns DSmirnov IVRaman PMalkin DTabori UBronsema AChung JSuo ZLipman TShlien ADvir RFabrizio DSabel MAronson MLindhorst SFarah RSamuel DfalseComprehensive Analysis of Hypermutation in Human Cancer.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 hypermutat2017-01-01T00:00:00Z2017 Nov2026-04-07T20:43:39.695Z2019-03-26T23:37:33ZS-EPMC58493932905634410.1016/j.cell.2017.09.048