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Angiopoietin pathway gene expression associated with poor breast cancer survival

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Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

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Funding

This study was funded by CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences; NIH/NCI grant R01CA160688; and Susan G. Komen Investigator Initiated Research Grant IIR12222224.

Author information

Author notes

    Authors and Affiliations

    1. Division of Surgical Oncology, Massey Cancer Center, Virginia Commonwealth University Medical Center, 1200 E. Broad St, Richmond, VA, 23298, USA

      Rajesh Ramanathan, Harry D. Bear & Leopoldo Jose Fernandez

    2. Virginia Commonwealth University C. Kenneth and Diane Wright Center for Clinical and Translational Research, 1200 E. Clay St, Richmond, VA, 23298, USA

      Amy L. Olex

    3. Department of Biostatistics, Virginia Commonwealth University, One Capitol Square, 830 E Main Street, Richmond, VA, 23298, USA

      Mikhail Dozmorov

    4. Breast Surgery Service, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

      Kazuaki Takabe

    5. Department of Surgery, University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, 131 Biomedical Education Building, Buffalo, NY, 14260, USA

      Kazuaki Takabe

    Authors
    1. Rajesh Ramanathan
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    2. Amy L. Olex
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    4. Harry D. Bear
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    Corresponding author

    Correspondence to Kazuaki Takabe.

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    Conflict of interest

    All authors declare that he/she has no conflict of interest.

    Ethics Approval

    This article does not contain any studies with human participants or animals performed by any of the authors. Ethics approval was waived by the Virginia Commonwealth University Institutional Review Board.

    Additional information

    Rajesh Ramanathan and Amy L. Olex have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary Fig. 1

    Gene-specific expression level thresholds for generating survival plots. Gene-specific thresholds for each gene and survival type (overall and disease-free) were generated as described in Methods. Each plot here shows the density of gene expression values for each of the interrogated genes (listed in top left corner). Black line: the mean expression value across all 1092 breast cancer patients with gene expression data. Red line: The expression cutoff chosen from the overall survival analysis. Blue line: The expression cutoff chosen from the disease-free survival analysis. Gene expression values are reported as the normalized log2 transformed RSEM-derived transcripts per million (PDF 41 kb)

    Supplementary Fig. 2

    Stage-specific survival analysis by Ang2 expression. Survival based on high or low Ang2 expression is shown with significant decrease in OS and DFS by stage in tissues with high and low Ang2 expression. (a) DFS in samples with low Ang2 expression. (b) DFS in samples with high Ang2 expression. (c) OS in samples with low Ang2 expression. (d) OS in samples with high Ang2 expression (EPS 71 kb)

    Supplementary Fig. 3

    SynTarget survival analyses for microarray data sets. SynTarget was used to assess the synergistic survival relationships resulting from gene expression of combinations of Ang2, Tie2 and VEGFA genes in the METABRIC data set. After choosing the data set, official gene symbols were entered and the analysis was run. All figures shown are from the METABRIC data set. (a) OS for Ang2 expression. (b) OS for low Ang2 and high Tie. (c) OS for high VEGFA and high Ang2. (d) OS for low VEGFA and low Ang2 (PDF 117 kb)

    Supplementary Tables 1–8

    Gene expression cutoffs tested for each gene (DOCX 187 kb)

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    Ramanathan, R., Olex, A.L., Dozmorov, M. et al. Angiopoietin pathway gene expression associated with poor breast cancer survival. Breast Cancer Res Treat 162, 191–198 (2017). https://doi.org/10.1007/s10549-017-4102-2

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    • DOI: https://doi.org/10.1007/s10549-017-4102-2

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