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Nat Genet. 2017 May;49(5):730-741. doi: 10.1038/ng.3817. Epub 2017 Mar 20.

A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

Author information

1
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
2
Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
3
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
4
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
5
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain.
7
Unidad de Histopatología Molecular, Facultad de Medicina, IUOPA, Universidad de Oviedo, Oviedo, Spain.
8
School of Medicine, University of Western Australia, Crawley, Western Australia, Australia.
9
Centro de Investigación Biomédica en Red de Cáncer, Spain.

Abstract

The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

PMID:
28319090
PMCID:
PMC5409503
DOI:
10.1038/ng.3817
[Indexed for MEDLINE]
Free PMC Article

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