Chia-Chun Chen1, Pi-Yueh Chang2, Yu-Sun Chang3, Jeng-Fu You4, Err-Cheng Chan5, Jinn-Shiun Chen4, Wen-Sy Tsai4, Yen-Lin Huang6, Chung-Wei Fan7, Hung-Chih Hsu8, Jy-Ming Chiang9. 1. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Colorectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. 2. Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan. 3. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 4. Department of Colorectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. 5. Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan. 6. College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. 7. Department of Colorectal Surgery, Chang Gung Memorial Hospital at Keelung, Taiwan. 8. College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. 9. Department of Colorectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. Electronic address: jmjiang@cgmh.org.tw.
Abstract
BACKGROUND: Colorectal cancer (CRC) is still among the most lethal and prevalent malignancies in the world. Despite continuous efforts, the diagnosis and prognosis of CRC have never been satisfying, especially the non-invasive assays. METHODS: Our study comprised three independent cohorts of 835 qualified stool samples. From 46 literature-identified miRNA candidates, four miRNA ratios were selected and developed into a miRNA-based signature after applied to the training and test sets. The clinical performances of this signature were further evaluated in the prospective cohorts. RESULTS: Four miRNA ratios with significant alterations and the highest discriminating power between the CRC and control groups in the training set were successfully validated in the test set. In the training dataset, combining these four miRNA ratios using a logistic regression model improved the area under the curve value to 0.821 and obtained a sensitivity of 73.6% and specificity of 78.9%. This miRNA signature showed consistent performances in the other two sample cohorts, with the highest sensitivity of 85.7% in the prospective cohort. Additionally, the higher miRNA signature was associated with worse disease-free survival (hazard ratio = 2.27) and overall survival (hazard ratio = 1.83) of CRC patients. For fecal immunochemical test (FIT)-positive populations, the positive predictive value for CRC detection in miRNA-positive subjects was 3.43-fold higher in the prospective cohort, compared to FIT alone. CONCLUSION: This stool miRNA signature is highly associated with poor outcome of CRC and can be added to FIT tests to help identify the most at-risk group to receive prompt colonoscopy examination.
BACKGROUND: Colorectal cancer (CRC) is still among the most lethal and prevalent malignancies in the world. Despite continuous efforts, the diagnosis and prognosis of CRC have never been satisfying, especially the non-invasive assays. METHODS: Our study comprised three independent cohorts of 835 qualified stool samples. From 46 literature-identified miRNA candidates, four miRNA ratios were selected and developed into a miRNA-based signature after applied to the training and test sets. The clinical performances of this signature were further evaluated in the prospective cohorts. RESULTS: Four miRNA ratios with significant alterations and the highest discriminating power between the CRC and control groups in the training set were successfully validated in the test set. In the training dataset, combining these four miRNA ratios using a logistic regression model improved the area under the curve value to 0.821 and obtained a sensitivity of 73.6% and specificity of 78.9%. This miRNA signature showed consistent performances in the other two sample cohorts, with the highest sensitivity of 85.7% in the prospective cohort. Additionally, the higher miRNA signature was associated with worse disease-free survival (hazard ratio = 2.27) and overall survival (hazard ratio = 1.83) of CRC patients. For fecal immunochemical test (FIT)-positive populations, the positive predictive value for CRC detection in miRNA-positive subjects was 3.43-fold higher in the prospective cohort, compared to FIT alone. CONCLUSION: This stool miRNA signature is highly associated with poor outcome of CRC and can be added to FIT tests to help identify the most at-risk group to receive prompt colonoscopy examination.