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Abstract
Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0–81.4% and 74.6–78% respectively (rfm, ACC 63.2–65.5%, AUC 61.9–74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10–8) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.
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1 Taoyuan Armed Forces General Hospital, Division of Colorectal Surgery, Department of Surgery, Taoyuan, Taiwan (GRID:grid.413912.c) (ISNI:0000 0004 1808 2366); National Central University, Department of Biomedical Sciences and Engineering, Taoyuan, Taiwan (GRID:grid.37589.30) (ISNI:0000 0004 0532 3167)
2 National Defense Medical Center, Division of General Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); Songshan Branch of Tri-Service General Hospital, National Defense Medical Center, Department of Surgery, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); National Defense Medical Center, Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
3 Taichung Armed Forces General Hospital, Division of Gastroenterology, Department of Medicine, Taichung, Taiwan (GRID:grid.416826.f) (ISNI:0000 0004 0572 7495)
4 Chang Gung University, School of Nursing, College of Medicine, Taoyuan, Taiwan (GRID:grid.145695.a); Chang Gung Memorial Hospital, Department of Pediatrics, Taoyuan, Taiwan (GRID:grid.413801.f) (ISNI:0000 0001 0711 0593); Chang Gung Memorial Hospital, Department of Nursing, Tao-Yuan, Taiwan (GRID:grid.454210.6) (ISNI:0000 0004 1756 1461)
5 National Defense Medical Center, Division of Medical Informatics, Department of Epidemiology, School of Public Health, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); Fu-Jen Catholic University, Big Data Research Center, College of Medicine, New Taipei City, Taiwan (GRID:grid.256105.5) (ISNI:0000 0004 1937 1063); Fu-Jen Catholic University, Department of Public Health, College of Medicine, New Taipei City, Taiwan (GRID:grid.256105.5) (ISNI:0000 0004 1937 1063); China Medical University, Department of Public Health, Taichung City, Taiwan (GRID:grid.254145.3) (ISNI:0000 0001 0083 6092); Kaohsiung Medical University, Department of Healthcare Administration and Medical Informatics College of Health Sciences, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696)
6 Taipei Medical University, Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Taipei Medical University, Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481)
7 National Defense Medical Center, Division of General Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
8 National Defense Medical Center, Division of Medical Informatics, Department of Epidemiology, School of Public Health, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
9 Fu-Jen Catholic University, Big Data Research Center, College of Medicine, New Taipei City, Taiwan (GRID:grid.256105.5) (ISNI:0000 0004 1937 1063)
10 Chang Gung University, School of Nursing, College of Medicine, Taoyuan, Taiwan (GRID:grid.145695.a); Chang Gung Memorial Hospital, Department of Nursing, Tao-Yuan, Taiwan (GRID:grid.454210.6) (ISNI:0000 0004 1756 1461)
11 National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
12 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
13 National Central University, Department of Biomedical Sciences and Engineering, Taoyuan, Taiwan (GRID:grid.37589.30) (ISNI:0000 0004 0532 3167); National Central University, Center for Biotechnology and Biomedical Engineering, Taoyuan, Taiwan (GRID:grid.37589.30) (ISNI:0000 0004 0532 3167)
14 National Defense Medical Center, Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); Hualien Armed Forces General Hospital, Xincheng, Hualien, Taiwan (GRID:grid.413601.1) (ISNI:0000 0004 1797 2578)
15 National Defense Medical Center, Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); National Defense Medical Center, Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, Taipei City, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); National Defense Medical Center, School of Medicine, Taipei City, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356)
16 National Defense Medical Center, Division of Medical Informatics, Department of Epidemiology, School of Public Health, Taipei, Taiwan (GRID:grid.260565.2) (ISNI:0000 0004 0634 0356); Fu-Jen Catholic University, Big Data Research Center, College of Medicine, New Taipei City, Taiwan (GRID:grid.256105.5) (ISNI:0000 0004 1937 1063)