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

被引：44

作者：

de la Rosa, Jorge ^{[1
,2
,3
]}

Weber, Julia ^{[4
,5
]}

Friedrich, Mathias Josef ^{[1
]}

Li, Yilong ^{[1
]}

Rad, Lena ^{[1
]}

Ponstingl, Hannes ^{[1
]}

Liang, Qi ^{[1
]}

de Quiros, Sandra Bernaldo ^{[1
]}

Noorani, Imran ^{[1
]}

Metzakopian, Emmanouil ^{[1
]}

Strong, Alexander ^{[1
]}

Li, Meng Amy ^{[1
]}

Astudillo, Aurora ^{[6
]}

Fernadez-Garcia, Mara Teresa ^{[7
]}

Fernandez-Garcia, Maria Soledad ^{[7
]}

Hoffman, Gary J. ^{[1
,8
]}

Fuente, Rocio ^{[1
]}

Vassiliou, George S. ^{[1
]}

Rad, Roland ^{[1
,4
,5
]}

Lopez-Otin, Carlos ^{[3
,9
]}

Bradley, Allan ^{[1
]}

Cadinanos, Juan ^{[1
,2
]}

机构：

[1] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England

[2] IMOMA, Oviedo, Spain

[3] Univ Oviedo, Fac Med, Dept Bioquim & Biol Mol, Inst Univ Oncol IUOPA, Oviedo, Spain

[4] Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 2, Munich, Germany

[5] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[6] Hosp Univ Cent Asturias, Serv Anat Patol, Oviedo, Spain

[7] Univ Oviedo, IUOPA, Fac Med, Unidad Histopatol Mol, Oviedo, Spain

[8] Univ Western Australia, Sch Med, Crawley, WA, Australia

[9] Ctr Invest Biomed Red Canc, Madrid, Spain

来源：

NATURE GENETICS | 2017年 / 49卷 / 05期

基金：

英国惠康基金;

关键词：

GENOME-WIDE; PROSTATE; AUTOPHAGY; PROGRESSION; ACTIVATION; DISCOVERY; REVEALS; HAPLOINSUFFICIENCY; INACTIVATION; INITIATION;

D O I：

10.1038/ng.3817

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：730 / +

页数：14

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