Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma

被引:230
作者
Cai, Jiabin [1 ,2 ,3 ,4 ]
Chen, Lei [5 ,6 ]
Zhang, Zhou [7 ]
Zhang, Xinyu [1 ,2 ,3 ]
Lu, Xingyu [8 ]
Liu, Weiwei [9 ]
Shi, Guoming [1 ,2 ,3 ]
Ge, Yang [10 ]
Gao, Pingting [1 ,2 ,3 ]
Yang, Yuan [11 ]
Ke, Aiwu [1 ,2 ,3 ]
Xiao, Linlin [12 ]
Dong, Ruizhao [1 ,2 ,3 ]
Zhu, Yanjing [5 ]
Yang, Xuan [1 ,2 ,3 ]
Wang, Jiefei [13 ]
Zhu, Tongyu [13 ]
Yang, Deping [14 ]
Huang, Xiaowu [1 ,2 ,3 ]
Sui, Chengjun [11 ]
Qiu, Shuangjian [1 ,2 ,3 ]
Shen, Feng [11 ]
Sun, Huichuan [1 ,2 ,3 ]
Zhou, Weiping [11 ]
Zhou, Jian [1 ,2 ,3 ,4 ]
Nie, Ji [15 ]
Zeng, Chang [7 ,16 ]
Stroup, Emily Kunce [16 ]
Zhang, Xu [17 ]
Chiu, Brian C-H [18 ]
Lau, Wan Yee [19 ]
He, Chuan [15 ,20 ,21 ,22 ]
Wang, Hongyang [3 ,5 ,6 ,23 ]
Zhang, Wei [7 ,24 ]
Fan, Jia [1 ,2 ,3 ,4 ]
机构
[1] Fudan Univ, Zhongshan Hosp, Dept Liver Surg & Transplantat, Liver Canc Inst, Shanghai, Peoples R China
[2] Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China
[3] Minist Educ, Shanghai, Peoples R China
[4] Fudan Univ, Inst Biomed Sci, Key Lab Med Epigenet & Metab, Shanghai, Peoples R China
[5] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Int Cooperat Lab Signal Transduct, Shanghai 200433, Peoples R China
[6] Natl Ctr Liver Canc, Shanghai, Peoples R China
[7] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA
[8] Shanghai Epican Genetech Co Ltd, Shanghai, Peoples R China
[9] Tongji Univ, Peoples Hosp Shanghai 10, Dept Lab Med, Shanghai, Peoples R China
[10] Shanghai Jiao Tong Univ, Sch Publ Hlth, Sch Med, Shanghai, Peoples R China
[11] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Hepatobiliary Surg, Shanghai, Peoples R China
[12] Shanghai Jiao Tong Univ, Dept Lab Med, Shanghai, Peoples R China
[13] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China
[14] Shanghai Univ Med & Hlth Sci, Zhoupu Hosp, Dept Lab Med, Shanghai, Peoples R China
[15] Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA
[16] Northwestern Univ, Driskill Grad Program Life Sci, Feinberg Sch Med, Chicago, IL 60611 USA
[17] Univ Illinois, Dept Med, Chicago, IL USA
[18] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA
[19] Chinese Univ Hong Kong, Fac Med, Hong Kong, Peoples R China
[20] Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA
[21] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA
[22] Univ Chicago, Howard Hughes Med Inst, 5841 S Maryland Ave, Chicago, IL 60637 USA
[23] Second Mil Med Univ, Lab Signaling Regulat & Targeting Therapy Liver C, Shanghai, Peoples R China
[24] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
PAN-CANCER ANALYSIS; ALPHA-FETOPROTEIN; HEPATITIS; EXPRESSION; BIOMARKERS; TUMORS;
D O I
10.1136/gutjnl-2019-318882
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 alpha-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.
引用
收藏
页码:2195 / 2205
页数:11
相关论文
共 46 条
[1]  
[Anonymous], 2013, R LANG ENV STAT COMP
[2]   Tumour heterogeneity in the clinic [J].
Bedard, Philippe L. ;
Hansen, Aaron R. ;
Ratain, Mark J. ;
Siu, Lillian L. .
NATURE, 2013, 501 (7467) :355-364
[3]   Uncovering the role of 5-hydroxymethylcytosine in the epigenome [J].
Branco, Miguel R. ;
Ficz, Gabriella ;
Reik, Wolf .
NATURE REVIEWS GENETICS, 2012, 13 (01) :7-13
[4]   Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma [J].
Bruix, Jordi ;
Reig, Maria ;
Sherman, Morris .
GASTROENTEROLOGY, 2016, 150 (04) :835-853
[5]  
Cai J, BIORXIV
[6]   Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma [J].
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, 2019, 68 (12) :2195-2205
[7]   ALDH3A1 is overexpressed in a subset of hepatocellular carcinoma characterised by activation of the Wnt/β-catenin pathway [J].
Calderaro, Julien ;
Nault, Jean-Charles ;
Bioulac-Sage, Paulette ;
Laurent, Alexis ;
Blanc, Jean-Frederic ;
Decaens, Thomas ;
Zucman-Rossi, Jessica .
VIRCHOWS ARCHIV, 2014, 464 (01) :53-60
[8]   Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing [J].
Chan, K. C. Allen ;
Jiang, Peiyong ;
Chan, Carol W. M. ;
Sun, Kun ;
Wong, John ;
Hui, Edwin P. ;
Chan, Stephen L. ;
Chan, Wing Cheong ;
Hui, David S. C. ;
Ng, Simon S. M. ;
Chan, Henry L. Y. ;
Wong, Cesar S. C. ;
Ma, Brigette B. Y. ;
Chan, Anthony T. C. ;
Lai, Paul B. S. ;
Sun, Hao ;
Chiu, Rossa W. K. ;
Lo, Y. M. Dennis .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (47) :18761-18768
[9]   A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples [J].
Chen, Han ;
Li, Chunyan ;
Peng, Xinxin ;
Zhou, Zhicheng ;
Weinstein, John N. ;
Liang, Han .
CELL, 2018, 173 (02) :386-+
[10]   Cancer Statistics in China, 2015 [J].
Chen, Wanqing ;
Zheng, Rongshou ;
Baade, Peter D. ;
Zhang, Siwei ;
Zeng, Hongmei ;
Bray, Freddie ;
Jemal, Ahmedin ;
Yu, Xue Qin ;
He, Jie .
CA-A CANCER JOURNAL FOR CLINICIANS, 2016, 66 (02) :115-132