Tstutomu Kawaguchi1,2, Li Yan3, Qianya Qi3, Xuan Peng3, Stephen B Edge1,4, Jessica Young1,4, Song Yao5, Song Liu3, Eigo Otsuji2, Kazuaki Takabe6,7,8,9,10,11. 1. Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 2. Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. 3. Department of Biostatistics and Bioinformatics, University at Buffalo, The State University of New York Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA. 4. Department of Surgery, University at Buffalo, The State University of New York Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA. 5. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA. 6. Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Kazuaki.Takabe@roswellpark.org. 7. Department of Surgery, University at Buffalo, The State University of New York Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA. Kazuaki.Takabe@roswellpark.org. 8. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Kazuaki.Takabe@roswellpark.org. 9. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan. Kazuaki.Takabe@roswellpark.org. 10. Department of Surgery, Yokohama City University, Yokohama, Japan. Kazuaki.Takabe@roswellpark.org. 11. Breast Surgery, Fukushima Medical University, Fukushima, Japan. Kazuaki.Takabe@roswellpark.org.
Abstract
BACKGROUND: The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer. METHODS: An integrated unbiased approach was applied to derive a composite risk score for prognosis based on miRNA expression in primary breast tumors in 1051 breast cancer patients from The Cancer Genome Atlas (TCGA). Further analysis of the risk score with metastasis/recurrence was performed using the TCGA data set and validated in a separate patient population using small RNA sequencing. RESULTS: The three-miRNAs risk score (miR-19a, miR-93, and miR-106a) was developed using the TCGA cohort, which predicted poor prognosis (p = 0.0005) independently of known clinical risk factors. The prognostic value was validated in another three following independent cohorts: GSE19536 (p = 0.0009), GSE22220 (p = 0.0003), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (p = 0.0023). The three-miRNAs risk score predicted bone recurrence in TCGA (p = 0.0052), and the findings were validated in another independent population of patients who experienced bone recurrence and age/stage-matched patients without any recurrence. The three-miRNAs risk score enriched multiple metastasis-related gene sets such as angiogenesis and epithelial mesenchymal transition in a gene-set-enrichment analysis. CONCLUSIONS: The authors developed the novel miRNA-based risk score, which is a promising biomarker for prediction of worse survival and bone recurrence potential in breast cancer.
BACKGROUND: The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer. METHODS: An integrated unbiased approach was applied to derive a composite risk score for prognosis based on miRNA expression in primary breast tumors in 1051 breast cancerpatients from The Cancer Genome Atlas (TCGA). Further analysis of the risk score with metastasis/recurrence was performed using the TCGA data set and validated in a separate patient population using small RNA sequencing. RESULTS: The three-miRNAs risk score (miR-19a, miR-93, and miR-106a) was developed using the TCGA cohort, which predicted poor prognosis (p = 0.0005) independently of known clinical risk factors. The prognostic value was validated in another three following independent cohorts: GSE19536 (p = 0.0009), GSE22220 (p = 0.0003), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (p = 0.0023). The three-miRNAs risk score predicted bone recurrence in TCGA (p = 0.0052), and the findings were validated in another independent population of patients who experienced bone recurrence and age/stage-matched patients without any recurrence. The three-miRNAs risk score enriched multiple metastasis-related gene sets such as angiogenesis and epithelial mesenchymal transition in a gene-set-enrichment analysis. CONCLUSIONS: The authors developed the novel miRNA-based risk score, which is a promising biomarker for prediction of worse survival and bone recurrence potential in breast cancer.
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