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Tracking Subclonal Mutation Frequencies Throughout Lymphomagenesis Identifies Cancer Drivers in Mouse Models of Lymphoma

Philip Webster, Joanna C. Dawes, Hamlata Dewchand, Katalin Takacs, Barbara Iadarola, Bruce J. Bolt, Juan J. Caceres, Jakub Kaczor, Laurence Game, Thomas Adejumo, James Elliott, Kikkeri Naresh, Ge Tan, Gopuraja Dharmalingam, Alberto Paccanaro, Anthony G. Uren
doi: https://doi.org/10.1101/157800
Philip Webster
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
3Imperial College Healthcare NHS Trust, London
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Joanna C. Dawes
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Hamlata Dewchand
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Katalin Takacs
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Barbara Iadarola
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Bruce J. Bolt
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Juan J. Caceres
4Centre for Systems and Synthetic Biology, Department of Computer Science, Royal Holloway, University of London
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Jakub Kaczor
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Laurence Game
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Thomas Adejumo
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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James Elliott
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Kikkeri Naresh
3Imperial College Healthcare NHS Trust, London
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Ge Tan
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Gopuraja Dharmalingam
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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Alberto Paccanaro
4Centre for Systems and Synthetic Biology, Department of Computer Science, Royal Holloway, University of London
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Anthony G. Uren
1MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN
2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN
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  • For correspondence: anthony.uren@imperial.ac.uk
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ABSTRACT

Determining 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 enabled identification of positively selected events, and the first demonstration of negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Customized sequencing and bioinformatics methodologies were developed to quantify subclonal mutations in both premalignant and malignant tissue, greatly expanding the statistical power for identifying driver mutations and yielding a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. Screening two BCL2 transgenic models confirms known drivers of human B-cell non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance such as co-stimulatory molecules 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.

Footnotes

  • ↵+ Denotes shared first authorship

  • The authors declare no potential conflicts of interest

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 29, 2017.
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Tracking Subclonal Mutation Frequencies Throughout Lymphomagenesis Identifies Cancer Drivers in Mouse Models of Lymphoma
Philip Webster, Joanna C. Dawes, Hamlata Dewchand, Katalin Takacs, Barbara Iadarola, Bruce J. Bolt, Juan J. Caceres, Jakub Kaczor, Laurence Game, Thomas Adejumo, James Elliott, Kikkeri Naresh, Ge Tan, Gopuraja Dharmalingam, Alberto Paccanaro, Anthony G. Uren
bioRxiv 157800; doi: https://doi.org/10.1101/157800
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Tracking Subclonal Mutation Frequencies Throughout Lymphomagenesis Identifies Cancer Drivers in Mouse Models of Lymphoma
Philip Webster, Joanna C. Dawes, Hamlata Dewchand, Katalin Takacs, Barbara Iadarola, Bruce J. Bolt, Juan J. Caceres, Jakub Kaczor, Laurence Game, Thomas Adejumo, James Elliott, Kikkeri Naresh, Ge Tan, Gopuraja Dharmalingam, Alberto Paccanaro, Anthony G. Uren
bioRxiv 157800; doi: https://doi.org/10.1101/157800

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