Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma
Background/Aims Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost...
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Korean Association for the Study of the Liver
2025-01-01
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| Series: | Clinical and Molecular Hepatology |
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| Online Access: | http://e-cmh.org/upload/pdf/cmh-2024-0527.pdf |
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| author | Yang Liu Fan Peng Siyuan Wang Huanmin Jiao Kaixiang Zhou Wenjie Guo Shanshan Guo Miao Dang Huanqin Zhang Weizheng Zhou Xu Guo Jinliang Xing |
| author_facet | Yang Liu Fan Peng Siyuan Wang Huanmin Jiao Kaixiang Zhou Wenjie Guo Shanshan Guo Miao Dang Huanqin Zhang Weizheng Zhou Xu Guo Jinliang Xing |
| author_sort | Yang Liu |
| collection | DOAJ |
| description | Background/Aims Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and high-risk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients. |
| format | Article |
| id | doaj-art-abd3a3ba948448f59dd84d33b688fa0c |
| institution | DOAJ |
| issn | 2287-2728 2287-285X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj-art-abd3a3ba948448f59dd84d33b688fa0c2025-08-20T03:16:42ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2025-01-0131119621210.3350/cmh.2024.05272069Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinomaYang Liu0Fan Peng1Siyuan Wang2Huanmin Jiao3Kaixiang Zhou4Wenjie Guo5Shanshan Guo6Miao Dang7Huanqin Zhang8Weizheng Zhou9Xu Guo10Jinliang Xing11 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China Department of General Surgery, Changhai Hospital, Navy Medical University, Shanghai, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, ChinaBackground/Aims Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and high-risk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.http://e-cmh.org/upload/pdf/cmh-2024-0527.pdfhepatocellular carcinomacirculating cell free mitochondrial dnafragmentomicsearly diagnosisprognosis |
| spellingShingle | Yang Liu Fan Peng Siyuan Wang Huanmin Jiao Kaixiang Zhou Wenjie Guo Shanshan Guo Miao Dang Huanqin Zhang Weizheng Zhou Xu Guo Jinliang Xing Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma Clinical and Molecular Hepatology hepatocellular carcinoma circulating cell free mitochondrial dna fragmentomics early diagnosis prognosis |
| title | Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma |
| title_full | Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma |
| title_fullStr | Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma |
| title_full_unstemmed | Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma |
| title_short | Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma |
| title_sort | aberrant fragmentomic features of circulating cell free mitochondrial dna enable early detection and prognosis prediction of hepatocellular carcinoma |
| topic | hepatocellular carcinoma circulating cell free mitochondrial dna fragmentomics early diagnosis prognosis |
| url | http://e-cmh.org/upload/pdf/cmh-2024-0527.pdf |
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