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Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma
OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESI...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872444/ https://www.ncbi.nlm.nih.gov/pubmed/31358576 http://dx.doi.org/10.1136/gutjnl-2019-318882 |
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author | Cai, Jiabin Chen, Lei Zhang, Zhou Zhang, Xinyu Lu, Xingyu Liu, Weiwei Shi, Guoming Ge, Yang Gao, Pingting Yang, Yuan Ke, Aiwu Xiao, Linlin Dong, Ruizhao Zhu, Yanjing Yang, Xuan Wang, Jiefei Zhu, Tongyu Yang, Deping Huang, Xiaowu Sui, Chengjun Qiu, Shuangjian Shen, Feng Sun, Huichuan Zhou, Weiping Zhou, Jian Nie, Ji Zeng, Chang Stroup, Emily Kunce Zhang, Xu Chiu, Brian C-H Lau, Wan Yee He, Chuan Wang, Hongyang Zhang, Wei Fan, Jia |
author_facet | Cai, Jiabin Chen, Lei Zhang, Zhou Zhang, Xinyu Lu, Xingyu Liu, Weiwei Shi, Guoming Ge, Yang Gao, Pingting Yang, Yuan Ke, Aiwu Xiao, Linlin Dong, Ruizhao Zhu, Yanjing Yang, Xuan Wang, Jiefei Zhu, Tongyu Yang, Deping Huang, Xiaowu Sui, Chengjun Qiu, Shuangjian Shen, Feng Sun, Huichuan Zhou, Weiping Zhou, Jian Nie, Ji Zeng, Chang Stroup, Emily Kunce Zhang, Xu Chiu, Brian C-H Lau, Wan Yee He, Chuan Wang, Hongyang Zhang, Wei Fan, Jia |
author_sort | Cai, Jiabin |
collection | PubMed |
description | OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESIGN: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection. RESULTS: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history). CONCLUSION: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals. |
format | Online Article Text |
id | pubmed-6872444 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-68724442019-12-04 Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma Cai, Jiabin Chen, Lei Zhang, Zhou Zhang, Xinyu Lu, Xingyu Liu, Weiwei Shi, Guoming Ge, Yang Gao, Pingting Yang, Yuan Ke, Aiwu Xiao, Linlin Dong, Ruizhao Zhu, Yanjing Yang, Xuan Wang, Jiefei Zhu, Tongyu Yang, Deping Huang, Xiaowu Sui, Chengjun Qiu, Shuangjian Shen, Feng Sun, Huichuan Zhou, Weiping Zhou, Jian Nie, Ji Zeng, Chang Stroup, Emily Kunce Zhang, Xu Chiu, Brian C-H Lau, Wan Yee He, Chuan Wang, Hongyang Zhang, Wei Fan, Jia Gut Hepatology OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESIGN: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection. RESULTS: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history). CONCLUSION: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals. BMJ Publishing Group 2019-12 2019-07-29 /pmc/articles/PMC6872444/ /pubmed/31358576 http://dx.doi.org/10.1136/gutjnl-2019-318882 Text en © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Hepatology Cai, Jiabin Chen, Lei Zhang, Zhou Zhang, Xinyu Lu, Xingyu Liu, Weiwei Shi, Guoming Ge, Yang Gao, Pingting Yang, Yuan Ke, Aiwu Xiao, Linlin Dong, Ruizhao Zhu, Yanjing Yang, Xuan Wang, Jiefei Zhu, Tongyu Yang, Deping Huang, Xiaowu Sui, Chengjun Qiu, Shuangjian Shen, Feng Sun, Huichuan Zhou, Weiping Zhou, Jian Nie, Ji Zeng, Chang Stroup, Emily Kunce Zhang, Xu Chiu, Brian C-H Lau, Wan Yee He, Chuan Wang, Hongyang Zhang, Wei Fan, Jia Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title | Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title_full | Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title_fullStr | Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title_full_unstemmed | Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title_short | Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma |
title_sort | genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free dna as a non-invasive approach for early detection of hepatocellular carcinoma |
topic | Hepatology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872444/ https://www.ncbi.nlm.nih.gov/pubmed/31358576 http://dx.doi.org/10.1136/gutjnl-2019-318882 |
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