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Transposon insertional mutagenesis in mice identifies human breast cancer susceptibility genes and signatures for stratification

Authors :
Tuan Zea Tan
Jerrold M. Ward
Seiichi Mori
Anna V. Ivshina
Keith Rogers
Jean Paul Thiery
Andrea Mun Ching Pillai
Neal G. Copeland
Song-Choon Lee
Motakis Efthimios
Nancy A. Jenkins
Piroon Jenjaroenpun
Vladimir A. Kuznetsov
Kenneth Hon Kim Ban
David J. Adams
Tang Zhiqun
Ghim Siong Ow
Liming Chen
School of Computer Science and Engineering
Source :
Proceedings of the National Academy of Sciences. 114
Publication Year :
2017
Publisher :
Proceedings of the National Academy of Sciences, 2017.

Abstract

Robust prognostic gene signatures and therapeutic targets are difficult to derive from expression profiling because of the significant heterogeneity within breast cancer (BC) subtypes. Here, we performed forward genetic screening in mice using Sleeping Beauty transposon mutagenesis to identify candidate BC driver genes in an unbiased manner, using a stabilized N-terminal truncated β-catenin gene as a sensitizer. We identified 134 mouse susceptibility genes from 129 common insertion sites within 34 mammary tumors. Of these, 126 genes were orthologous to protein-coding genes in the human genome (hereafter, human BC susceptibility genes, hBCSGs), 70% of which are previously reported cancer-associated genes, and ∼16% are known BC suppressor genes. Network analysis revealed a gene hub consisting of E1A binding protein P300 (EP300), CD44 molecule (CD44), neurofibromin (NF1) and phosphatase and tensin homolog (PTEN), which are linked to a significant number of mutated hBCSGs. From our survival prediction analysis of the expression of human BC genes in 2,333 BC cases, we isolated a six-gene-pair classifier that stratifies BC patients with high confidence into prognostically distinct low-, moderate-, and high-risk subgroups. Furthermore, we proposed prognostic classifiers identifying three basal and three claudin-low tumor subgroups. Intriguingly, our hBCSGs are mostly unrelated to cell cycle/mitosis genes and are distinct from the prognostic signatures currently used for stratifying BC patients. Our findings illustrate the strength and validity of integrating functional mutagenesis screens in mice with human cancer transcriptomic data to identify highly prognostic BC subtyping biomarkers. ASTAR (Agency for Sci., Tech. and Research, S’pore)

Details

ISSN :
10916490 and 00278424
Volume :
114
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi.dedup.....58eb46eb9d82ab8876c08f9c3b356668
Full Text :
https://doi.org/10.1073/pnas.1701512114