title: Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival.
abstract: Breast cancer is a heterogeneous disease with known expression-defined tumor subtypes. DNA copy number studies have suggested that tumors within gene expression subtypes share similar DNA Copy number aberrations (CNA) and that CNA can be used to further sub-divide expression classes. To gain further insights into the etiologies of the intrinsic subtypes, we classified tumors according to gene expression subtype and next identified subtype-associated CNA using a novel method called SWITCHdna, using a training set of 180 tumors and a validation set of 359 tumors. Fisher's exact tests, Chi-square approximations, and Wilcoxon rank-sum tests were performed to evaluate differences in CNA by subtype. To assess the functional significance of loss of a specific chromosomal region, individual genes were knocked down by shRNA and drug sensitivity, and DNA repair foci assays performed. Most tumor subtypes exhibited specific CNA. The Basal-like subtype was the most distinct with common losses of the regions containing RB1, BRCA1, INPP4B, and the greatest overall genomic instability. One Basal-like subtype-associated CNA was loss of 5q11-35, which contains at least three genes important for BRCA1-dependent DNA repair (RAD17, RAD50, and RAP80); these genes were predominantly lost as a pair, or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability and poor patient survival. RNAi knockdown of RAD17, or RAD17/RAD50, in immortalized human mammary epithelial cell lines caused increased sensitivity to a PARP inhibitor and carboplatin, and inhibited BRCA1 foci formation in response to DNA damage. These data suggest a possible genetic cause for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this breast cancer subtype.
authors: Bioinformatics and Computational Biology Program, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Victor J
authors: VJ
authors: Weigman
authors: Hann-Hsiang
authors: HH
authors: Chao
authors: Andrey A
authors: AA
authors: Shabalin
authors: Xiaping
authors: X
authors: He
authors: Joel S
authors: JS
authors: Parker
authors: Silje H
authors: SH
authors: Nordgard
authors: Tatyana
authors: T
authors: Grushko
authors: Dezheng
authors: D
authors: Huo
authors: Chika
authors: C
authors: Nwachukwu
authors: Andrew
authors: A
authors: Nobel
authors: Vessela N
authors: VN
authors: Kristensen
authors: Anne-Lise
authors: AL
authors: Børresen-Dale
authors: Olufunmilayo I
authors: OI
authors: Olopade
authors: Charles M
authors: CM
authors: Perou
mesh_terms: D017766:Acid Anhydride Hydrolases; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D042822:Genomic Instability; D006801:Humans; D018295:Neoplasms, Basal Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C113575:Rad17 protein, human; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes