title: Angiopoietin pathway gene expression associated with poor breast cancer survival.
abstract: Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a "big data" approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA).
  
  
  
  A total of 888 patients with adequate gene expression, disease-free survival (DFS), and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated.
  
  
  
  The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology, and survival. High Ang2 gene expression was associated with not only decreased DFS (p = 0.05), but also decreased OS (p < 0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p < 0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS.
  
  
  
  This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data support the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.
authors.affiliation: Division of Surgical Oncology, Massey Cancer Center, Virginia Commonwealth University Medical Center, 1200 E. Broad St, Richmond VA 23298.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramanathan
authors.affiliation: Virginia Commonwealth University C. Kenneth and Diane Wright Center for Clinical and Translational Research, 1200 E. Clay St, Richmond VA 23298.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Olex
authors.affiliation: Virginia Commonwealth University C. Kenneth and Diane Wright Center for Clinical and Translational Research, 1200 E. Clay St, Richmond VA 23298.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Dozmorov
authors.affiliation: Division of Surgical Oncology, Massey Cancer Center, Virginia Commonwealth University Medical Center, 1200 E. Broad St, Richmond VA 23298.
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.affiliation: Division of Surgical Oncology, Massey Cancer Center, Virginia Commonwealth University Medical Center, 1200 E. Broad St, Richmond VA 23298.
authors.forename: Leopoldo Jose
authors.initials: LJ
authors.lastname: Fernandez
authors.affiliation: Breast Surgery Service, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo NY 14263.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
mesh_terms: D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D018426:SEER Program; D015398:Signal Transduction; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D042682:Angiopoietins; D042442:Vascular Endothelial Growth Factors; D042787:Receptor, TIE-2
keywords: ANGPT; Angiogenesis; Genomic; Outcomes; TCGA; TEK; The Cancer Genome Atlas