Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis

H Nikki March, Alistair G Rust, Nicholas A Wright, Jelle ten Hoeve, Jeroen de Ridder, Matthew Eldridge, Louise van der Weyden, Anton Berns, Jules Gadiot, Anthony Uren, Richard Kemp, Mark J Arends, Lodewyk F A Wessels, Douglas J Winton, David J Adams

Research output: Contribution to journalArticlepeer-review

Abstract

The evolution of colorectal cancer suggests the involvement of many genes. To identify new drivers of intestinal cancer, we performed insertional mutagenesis using the Sleeping Beauty transposon system in mice carrying germline or somatic Apc mutations. By analyzing common insertion sites (CISs) isolated from 446 tumors, we identified many hundreds of candidate cancer drivers. Comparison to human data sets suggested that 234 CIS-targeted genes are also dysregulated in human colorectal cancers. In addition, we found 183 CIS-containing genes that are candidate Wnt targets and showed that 20 CISs-containing genes are newly discovered modifiers of canonical Wnt signaling. We also identified mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included those encoding members of the FGF signaling cascade. Some 70 genes had co-occurrence of CIS pairs, clustering into 38 sub-networks that may regulate tumor development.
Original languageEnglish
Pages (from-to)1202-9
Number of pages8
JournalNature Genetics
Volume43
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Adenomatous Polyposis Coli Protein
  • Animals
  • Cell Transformation, Neoplastic
  • Epistasis, Genetic
  • Genes, Neoplasm
  • Humans
  • Intestinal Neoplasms
  • Intracellular Signaling Peptides and Proteins
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Monte Carlo Method
  • Mutagenesis, Insertional
  • Signal Transduction
  • Transposases
  • Tumor Burden
  • beta Catenin

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