Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors

Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors

Klijn, C.
Koudijs, M.J.
Kool, J.
Ten Hoeve, J.
Boer, M.
De Moes, J.
Akhtar, W.
Van Miltenburg, M.
Vendel-Zwaagstra, A.
Reinders, M.J.T.
Adams, D.J.
Van Lohuizen, M.
Hilkens, J.
Wessels, L.F.A.
Jonkers, J.

Electrical Engineering, Mathematics and Computer Science

Computer Science

2013-05-14

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.

http://resolver.tudelft.nl/uuid:04cecd5a-c418-47b0-bb77-3f810e39ca23

https://doi.org/10.1371/journal.pone.0062113

Public Library of Science

1932-6203

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0062113

Plos One, 8 (5), 2013

Institutional Repository

journal article

(c) 2013 Klijn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.