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Insertional mutagenesis identifies multiple networks of co-operating genes driving intestinal tumorigenesis

H. N. March,A. Rust,N. Wright,J. T. Hoeve,J. de Ridder,Matthew Eldridge,L. van der Weyden,A. Berns,J. Gadiot,A. Uren,Richard Kemp,M. Arends,L. Wessels,D. Winton,D. Adams

Published 2011 in Nature Genetics

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.

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