The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

Uri Ben-David, Gavin Ha, Prasidda Khadka, Xin Jin, Bang Wong, Lude Franke and Todd R. Golub ()
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Uri Ben-David: Cancer Program, Broad Institute of Harvard and MIT
Gavin Ha: Cancer Program, Broad Institute of Harvard and MIT
Prasidda Khadka: Cancer Program, Broad Institute of Harvard and MIT
Xin Jin: Cancer Program, Broad Institute of Harvard and MIT
Bang Wong: Cancer Program, Broad Institute of Harvard and MIT
Lude Franke: University of Groningen
Todd R. Golub: Cancer Program, Broad Institute of Harvard and MIT

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12160

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