Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates. / Webster, Philip; Dawes, Joanna; Dewchand, Hamlata; Takacs, Katalin; Iadarola, Barbara; Bolt, Bruce; Caceres Silva, Juan; Kaczor, Jakub; Dharmalingam, Gopuraja; Dore, Marian; Game, Laurence; Adejumo, Thomas; Elliott, James; Naresh, Kikkeri; Karimi, Mohammad; Rekopoulou, Katerina; Tan, Ge; Paccanaro, Alberto; Uren, Anthony.

In: Nature Communications, Vol. 9, 2649, 09.07.2018, p. 1-14.

Research output: Contribution to journalArticle

Published
  • Philip Webster
  • Joanna Dawes
  • Hamlata Dewchand
  • Katalin Takacs
  • Barbara Iadarola
  • Bruce Bolt
  • Juan Caceres Silva
  • Jakub Kaczor
  • Gopuraja Dharmalingam
  • Marian Dore
  • Laurence Game
  • Thomas Adejumo
  • James Elliott
  • Kikkeri Naresh
  • Mohammad Karimi
  • Katerina Rekopoulou
  • Ge Tan
  • Alberto Paccanaro
  • Anthony Uren

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.
Original languageEnglish
Article number2649
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume9
DOIs
StatePublished - 9 Jul 2018
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 30357781