Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis : Nature Genetics : Nature Publishing Group

Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis

• H Nikki March,¹
• Alistair G Rust,²
• Nicholas A Wright,³
• Jelle ten Hoeve,⁴
• Jeroen de Ridder,^{4, 5}
• Matthew Eldridge,¹
• Louise van der Weyden,²
• Anton Berns,⁶
• Jules Gadiot,⁶
• Anthony Uren,⁶
• Richard Kemp,¹
• Mark J Arends,⁷
• Lodewyk F A Wessels,^{4, 5}
• Douglas J Winton¹
• & David J Adams²

• Affiliations
• Contributions
• Corresponding author

Journal name:Nature Genetics

Year published:(2011)

DOI:doi:10.1038/ng.990

Received28 January 2011

Accepted03 October 2011

Published online06 November 2011

Abstract

• Abstract
• Author information
• Supplementary information

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.