Webster, PhilipPhilipWebsterDawes, JoannaJoannaDawesDewchand, hamlatahamlataDewchandTakacs, katalinkatalinTakacsiadarola, barbarabarbaraiadarolabolt, brucebruceboltcaceres, JuanJuancacereskaczor, JakubJakubkaczordharmalingham, GopurajaGopurajadharmalinghamdore, marianmariandoreGame, laurencelaurenceGameadejumo, thomasthomasadejumoElliott, JamesJamesElliottNaresh, KikkeriKikkeriNareshKarimi, MohammadMohammadKarimirekopoulou, KaterinaKaterinarekopouloutan, gegetanpaccanaro, albertoalbertopaccanaroUren, AnthonyAnthonyUren2018-05-112018-07-092018-07-09Nature Communications, 2018, 92041-1723http://hdl.handle.net/10044/1/59052Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of retrovirus driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel, novel statistical approaches for identifying driver mutations and yields a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening two BCL2 transgenic models confirms known drivers of human B-cell non- Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features also gives robust identification of known cancer genes independently of local variance in mutation density. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.© 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsB-CELL LYMPHOMAACUTE LYMPHOBLASTIC-LEUKEMIACHRONIC LYMPHOCYTIC-LEUKEMIAGENOME-WIDE ASSOCIATIONINSERTIONAL MUTAGENESISFOLLICULAR LYMPHOMASUSCEPTIBILITY LOCIINTEGRATION SITEGENE DISCOVERYRECURRENTMD MultidisciplinaryJournal Articlehttps://www.dx.doi.org/10.1038/s41467-018-05069-9DMAID_P13593