A comprehensive evaluation of full-spectrum cell-free RNAs highlights cell-free RNA fragments for early-stage hepatocellular carcinoma detectionResearch in context
Chun Ning,
Peng Cai,
Xiaofan Liu,
Guangtao Li,
Pengfei Bao,
Lu Yan,
Meng Ning,
Kaichen Tang,
Yi Luo,
Hua Guo,
Yunjiu Wang,
Zhuoran Wang,
Lu Chen,
Zhi John Lu,
Jianhua Yin
Affiliations
Chun Ning
Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9 Dongdansantiao, Beijing, 100730, China; MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
Peng Cai
Department of Epidemiology, Naval Medical University, Key Laboratory of Biosafety Defense, Ministry of Education, Shanghai, 200433, China
Xiaofan Liu
MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
Guangtao Li
Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
Pengfei Bao
MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
Lu Yan
MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
Meng Ning
Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China
Kaichen Tang
Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9 Dongdansantiao, Beijing, 100730, China; MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
Yi Luo
Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
Hua Guo
Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
Yunjiu Wang
Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200433, China
Zhuoran Wang
Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, 200433, China
Lu Chen
Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China; Corresponding author. Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Huanhuxi Road, Tianjin, 300060, China.
Zhi John Lu
MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Corresponding author. MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Shuangqing Road 30, Beijing, 100084, China.
Jianhua Yin
Department of Epidemiology, Naval Medical University, Key Laboratory of Biosafety Defense, Ministry of Education, Shanghai, 200433, China; Corresponding author. Department of Epidemiology, Naval Medical University, Key Laboratory of Biosafety Defense, Ministry of Education, Xiangyin Road 800, Shanghai, 200433, China.
Summary: Background: Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently validated, and some results are contradictory. We provided a comprehensive evaluation of various types of cfRNA biomarkers and a full mining of the biomarker potential of new features of cfRNA. Methods: We first systematically reviewed reported cfRNA biomarkers and calculated dysregulated post-transcriptional events and cfRNA fragments. In 3 independent multicentre cohorts, we further selected 6 cfRNAs using RT-qPCR, built a panel called HCCMDP with AFP using machine learning, and internally and externally validated HCCMDP's performance. Findings: We identified 23 cfRNA biomarker candidates from a systematic review and analysis of 5 cfRNA-seq datasets. Notably, we defined the cfRNA domain to describe cfRNA fragments systematically. In the verification cohort (n = 183), cfRNA fragments were more likely to be verified, while circRNA and chimeric RNA candidates were neither abundant nor stable as qPCR-based biomarkers. In the algorithm development cohort (n = 287), we build and test the panel HCCMDP with 6 cfRNA markers and AFP. In the independent validation cohort (n = 171), HCCMDP can distinguish HCC patients from control groups (all: AUC = 0.925; CHB: AUC = 0.909; LC: AUC = 0.916), and performs well in distinguishing early-stage HCC patients (all: AUC = 0.936; CHB: AUC = 0.917; LC: AUC = 0.928). Interpretation: This study comprehensively evaluated full-spectrum cfRNA biomarker types for HCC detection, highlighted the cfRNA fragment as a promising biomarker type in HCC detection, and provided a panel HCCMDP. Funding: National Natural Science Foundation of China, and The National Key Basic Research Program (973 program).
