title: The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis.
abstract: Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tumorigenesis, and observe marked differences in CNA prevalence between mouse mammary tumours initiated with distinct drivers. Some aberrations are recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumorigenesis. Synteny-based comparison of mouse and human tumours narrows critical regions in CNAs, thereby identifying candidate driver genes. We experimentally validate that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis to inform the pathogenesis of human cancer.
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Ben-David
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Prasidda
authors.initials: P
authors.lastname: Khadka
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Bang
authors.initials: B
authors.lastname: Wong
authors.affiliation: Department of Genetics, University of Groningen, Groningen 9711, The Netherlands.
authors.forename: Lude
authors.identifier: http://orcid.org/0000-0002-5159-8802
authors.initials: L
authors.lastname: Franke
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Harvard Medical School, Harvard University, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 208115, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005818:Genetic Engineering; D042822:Genomic Instability; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013045:Species Specificity
chemical_list: D048948:14-3-3 Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C499130:Sfn protein, mouse; C524056:Erbb2 protein, mouse