title: Transposon insertional mutagenesis in mice identifies human breast cancer susceptibility genes and signatures for stratification.
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.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.|Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671.
authors.forename: Piroon
authors.initials: P
authors.lastname: Jenjaroenpun
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.
authors.forename: Andrea Mun Ching
authors.initials: AM
authors.lastname: Pillai
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Ivshina
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671.
authors.forename: Ghim Siong
authors.initials: GS
authors.lastname: Ow
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671.
authors.forename: Motakis
authors.initials: M
authors.lastname: Efthimios
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671.
authors.forename: Tang
authors.initials: T
authors.lastname: Zhiqun
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors.forename: Tuan Zea
authors.identifier: 0000-0001-6624-1593
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.
authors.forename: Song-Choon
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.
authors.forename: Keith
authors.initials: K
authors.lastname: Rogers
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Japanese Foundation of Cancer Research, Tokyo 1358550, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.affiliation: Experimental Cancer Genetics, Hinxton Campus, Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.|Cancer Biology Program, Methodist Hospital Research Institute, Houston, TX 77030.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673; vladimirk@bii.a-star.edu.sg bchtjp@nus.edu.sg ncopeland@houstonmethodist.org.|Cancer Biology Program, Methodist Hospital Research Institute, Houston, TX 77030.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Kenneth Hon-Kim
authors.initials: KH
authors.lastname: Ban
authors.affiliation: Division of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore 138671; vladimirk@bii.a-star.edu.sg bchtjp@nus.edu.sg ncopeland@houstonmethodist.org.|School of Computer Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kuznetsov
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673; vladimirk@bii.a-star.edu.sg bchtjp@nus.edu.sg ncopeland@houstonmethodist.org.|Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009154:Mutation; D011379:Prognosis; D015203:Reproducibility of Results; D012306:Risk; D015398:Signal Transduction; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: D004251:DNA Transposable Elements
keywords: Sleeping Beauty; breast cancer; cancer susceptibility; prognostic gene signature; survival prediction analysis