Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer

Grace O. Silva, Xiaping He, Joel S. Parker, Michael L. Gatza, Lisa A. Carey, Jack P. Hou, Stacy L. Moulder, Paul K. Marcom, Jian Ma, Jeffrey M. Rosen, Charles M. Perou

Research output: Contribution to journalArticlepeer-review

Abstract

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor ‘drivers’ (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15 % or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

Original languageEnglish (US)
Pages (from-to)347-356
Number of pages10
JournalBreast Cancer Research and Treatment
Volume152
Issue number2
DOIs
StatePublished - Jun 25 2015
Externally publishedYes

Keywords

  • Copy number alterations
  • Driver genes
  • Gene expression
  • Genetically engineered mouse
  • Intrinsic subtypes
  • Network analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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