Home LiteratureArticle Details
PMID: 22057237 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis.

Nature genetics ·Vol. 43 ·No. 12 ·2011-11-06 ·Pages 1202-9

March HN, Rust AG, Wright NA, ten Hoeve J, de Ridder J, Eldridge M, van der Weyden L, Berns A, Gadiot J, Uren A, Kemp R, Arends MJ, Wessels LF, Winton DJ, Adams DJ

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.

MeSH Terms
Adenomatous Polyposis Coli Protein/genetics Animals Cell Transformation, Neoplastic/genetics,metabolism Epistasis, Genetic Genes, Neoplasm Humans Intestinal Neoplasms/genetics,metabolism Intracellular Signaling Peptides and Proteins/genetics Kaplan-Meier Estimate Mice Mice, Transgenic Models, Genetic Monte Carlo Method Mutagenesis, Insertional Signal Transduction Transposases Tumor Burden beta Catenin/metabolism
Chemicals
Adenomatous Polyposis Coli Protein Intracellular Signaling Peptides and Proteins beta Catenin Transposases sleeping beauty transposase, human
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
March H Nikki
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, UK.
Rust Alistair G
Wright Nicholas A
ten Hoeve Jelle
de Ridder Jeroen
Eldridge Matthew
van der Weyden Louise
Berns Anton
Gadiot Jules
Uren Anthony
Kemp Richard
Arends Mark J
Wessels Lodewyk F A
Winton Douglas J
Adams David J
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.990
Published
2011-11-06
Epub
2011-00-06
Pages
1202-9
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3233530
Subset
IM
Grants
Cancer Research UK · 13031 · United Kingdom
Cancer Research UK · A6997 · United Kingdom
Medical Research Council · MC_UP_A652_1001 · United Kingdom
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1038/ng.990 PMC Full Text View journal details
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