TY - JOUR
T1 - Analysis of Tumor Heterogeneity and Cancer Gene Networks Using Deep Sequencing of MMTV-Induced Mouse Mammary Tumors
AU - Klijn, Christiaan
AU - Koudijs, Marco J.
AU - Kool, Jaap
AU - ten Hoeve, Jelle
AU - Boer, Mandy
AU - de Moes, Joost
AU - Akhtar, Waseem
AU - van Miltenburg, Martine
AU - Vendel-Zwaagstra, Annabel
AU - Reinders, Marcel J T
AU - Adams, David J.
AU - van Lohuizen, Maarten
AU - Hilkens, John
AU - Wessels, Lodewyk F A
AU - Jonkers, Jos
PY - 2013/5/14
Y1 - 2013/5/14
N2 - Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV) as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs) and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution.
AB - Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV) as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs) and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution.
UR - http://www.scopus.com/inward/record.url?scp=84877764646&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0062113
DO - 10.1371/journal.pone.0062113
M3 - Article
C2 - 23690930
AN - SCOPUS:84877764646
SN - 1932-6203
VL - 8
JO - PLoS ONE [E]
JF - PLoS ONE [E]
IS - 5
M1 - e62113
ER -