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

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.

journal_name

Nat Genet

journal_title

Nature genetics

authors

de la Rosa J,Weber J,Friedrich MJ,Li Y,Rad L,Ponstingl H,Liang Q,de Quirós SB,Noorani I,Metzakopian E,Strong A,Li MA,Astudillo A,Fernández-García MT,Fernández-García MS,Hoffman GJ,Fuente R,Vassiliou GS,Rad R,López-O

doi

10.1038/ng.3817

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

730-741

issue

5

eissn

1061-4036

issn

1546-1718

pii

ng.3817

journal_volume

49

pub_type

杂志文章

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