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Nat Genet. 2015 Jan;47(1):47-56. doi: 10.1038/ng.3164. Epub 2014 Dec 8.

A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer.

Author information

1
1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [3] The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
2
The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK.
3
Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
4
1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
6
Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
7
Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC-SODERCAN), Santander, Spain.
8
Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
9
Biostatistics and Bioinformatics Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
10
Bioinformatics and Statistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
11
Institute of Virology, Technische Universität München, Munich, Germany.
12
Institute of Pathology, Ludwig Maximilians Universität München, München, Germany.
13
Institute of Pathology, Universität Regensburg, Regensburg, Germany.
14
Institute of Pathology, Technische Universität Dresden, Dresden, Germany.
15
Department of Surgery, Technische Universität Dresden, Dresden, Germany.
16
Institute of Pathology, Medizinische Universität Insbruck, Insbruck, Austria.

Abstract

Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.

PMID:
25485836
DOI:
10.1038/ng.3164
[Indexed for MEDLINE]

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