Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates
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Published version
Author(s)
Type
Journal Article
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 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.
Date Issued
2018-07-09
Online Publication Date
2018-07-09
Date Acceptance
2018-04-12
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
9
Copyright Statement
© 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/
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/
Source Database
manual-entry
Sponsor
Medical Research Council (MRC)
Grant Number
DMAID_P13593
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
B-CELL LYMPHOMA
ACUTE LYMPHOBLASTIC-LEUKEMIA
CHRONIC LYMPHOCYTIC-LEUKEMIA
GENOME-WIDE ASSOCIATION
INSERTIONAL MUTAGENESIS
FOLLICULAR LYMPHOMA
SUSCEPTIBILITY LOCI
INTEGRATION SITE
GENE DISCOVERY
RECURRENT
MD Multidisciplinary
Publication Status
Published
Article Number
ARTN 2649