title: Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer.
abstract: OBJECTIVE
  Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets.
  
  
  METHODS
  RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets.
  
  
  RESULTS
  We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines.
  
  
  CONCLUSIONS
  There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.
authors.affiliation: Structural and Computational Biology & Molecular Biophysics Graduate Program and Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Burstein
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Poage
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Pathology, Baylor College of Medicine, Houston, Texas.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Contreras
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.affiliation: Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Savage
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: The Methodist Hospital Research Institute, Houston, Texas.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas. phbrown@mdanderson.org cclau@txch.org.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, Texas. phbrown@mdanderson.org cclau@txch.org.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000401:mortality*