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2017 ; 49
(5
): 730-741
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A single-copy Sleeping Beauty transposon mutagenesis screen identifies new
PTEN-cooperating tumor suppressor genes
#MMPMID28319090
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-Otín C
; Bradley A
; Cadiñanos J
Nat Genet
2017[May]; 49
(5
): 730-741
PMID28319090
show ga
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.
|*Genes, Tumor Suppressor
[MESH]
|*Mutagenesis, Insertional
[MESH]
|Animals
[MESH]
|Cell Line
[MESH]
|Cell Movement/genetics
[MESH]
|DNA Transposable Elements/*genetics
[MESH]
|Epithelial Cells/cytology/metabolism
[MESH]
|Gene Dosage
[MESH]
|Genetic Predisposition to Disease/genetics
[MESH]