Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks.
p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19(ARF)-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.
Uren
Anthony G
AG
Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Kool
Jaap
J
Matentzoglu
Konstantin
K
de Ridder
Jeroen
J
Mattison
Jenny
J
van Uitert
Miranda
M
Lagcher
Wendy
W
Sie
Daoud
D
Tanger
Ellen
E
Cox
Tony
T
Reinders
Marcel
M
Hubbard
Tim J
TJ
Rogers
Jane
J
Jonkers
Jos
J
Wessels
Lodewyk
L
Adams
David J
DJ
van Lohuizen
Maarten
M
Berns
Anton
A
D000818:Animals; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53