Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

Ruidong Xue; Lu Chen; Chong Zhang; Masashi Fujita; Ruoyan Li; Shu-Mei Yan; Choon Kiat Ong; Xiwen Liao; Qiang Gao; Shota Sasagawa; Yanmeng Li; Jincheng Wang; Hua Guo; Qi-Tao Huang; Qian Zhong; Jing Tan; Lisha Qi; Wenchen Gong; Zhixian Hong; Meng Li; Jingmin Zhao; Tao Peng; Yinying Lu; Kiat Hon Tony Lim; Arnoud Boot; Atushi Ono; Kazuaki Chayama; Zemin Zhang; Steve George Rozen; Bin Tean Teh; Xin Wei Wang; Hidewaki Nakagawa; Mu-Sheng Zeng; Fan Bai; Ning Zhang

doi:10.1016/j.ccell.2019.04.007

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

Cancer Cell. 2019 Jun 10;35(6):932-947.e8. doi: 10.1016/j.ccell.2019.04.007. Epub 2019 May 23.

Authors

Ruidong Xue¹, Lu Chen², Chong Zhang¹, Masashi Fujita³, Ruoyan Li¹, Shu-Mei Yan⁴, Choon Kiat Ong⁵, Xiwen Liao⁶, Qiang Gao⁷, Shota Sasagawa³, Yanmeng Li¹, Jincheng Wang¹, Hua Guo⁸, Qi-Tao Huang⁴, Qian Zhong⁴, Jing Tan⁴, Lisha Qi⁹, Wenchen Gong⁹, Zhixian Hong¹⁰, Meng Li¹¹, Jingmin Zhao¹², Tao Peng⁶, Yinying Lu¹³, Kiat Hon Tony Lim¹⁴, Arnoud Boot¹⁵, Atushi Ono¹⁶, Kazuaki Chayama¹⁶, Zemin Zhang¹, Steve George Rozen¹⁵, Bin Tean Teh¹⁷, Xin Wei Wang¹⁸, Hidewaki Nakagawa¹⁹, Mu-Sheng Zeng²⁰, Fan Bai²¹, Ning Zhang²²

Affiliations

¹ Biomedical Pioneering Innovation Center (BIOPIC) and Translational Cancer Research Center, School of Life Sciences, First Hospital, Peking University, Beijing 100871, China.
² Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
³ Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
⁴ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
⁵ Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
⁶ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
⁷ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai 200032, China.
⁸ Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
⁹ Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
¹⁰ Department of Hepatobiliary Surgery, Beijing 302 Hospital, Beijing 100039, China.
¹¹ Department of Ultrasonography, Beijing 302 Hospital, Beijing 100039, China.
¹² Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing 100039, China.
¹³ Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing 100039, China.
¹⁴ Department of Anatomical Pathology, Singapore General Hospital, Singapore 169608, Singapore.
¹⁵ Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
¹⁶ Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
¹⁷ Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore 169610, Singapore.
¹⁸ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁹ Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. Electronic address: hidewaki@ims.u-tokyo.ac.jp.
²⁰ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China. Electronic address: zengmsh@mail.sysu.edu.cn.
²¹ Biomedical Pioneering Innovation Center (BIOPIC) and Translational Cancer Research Center, School of Life Sciences, First Hospital, Peking University, Beijing 100871, China. Electronic address: fbai@pku.edu.cn.
²² Biomedical Pioneering Innovation Center (BIOPIC) and Translational Cancer Research Center, School of Life Sciences, First Hospital, Peking University, Beijing 100871, China; Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. Electronic address: zhangning@bjmu.edu.cn.

Abstract

We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.

Keywords: Allen and Lisa; Nestin; bilinear differentiation; clonal origin; intratumor heterogeneity; liver cancer; metastatic route; molecular subtype; phenotypic transition; single nucleus sequencing.

Publication types

Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Asia
Bile Duct Neoplasms / chemistry
Bile Duct Neoplasms / classification
Bile Duct Neoplasms / genetics*
Bile Duct Neoplasms / pathology
Biomarkers, Tumor / analysis
Biomarkers, Tumor / genetics*
Carcinoma, Hepatocellular / chemistry
Carcinoma, Hepatocellular / classification
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / pathology
Cholangiocarcinoma / chemistry
Cholangiocarcinoma / classification
Cholangiocarcinoma / genetics*
Cholangiocarcinoma / pathology
Databases, Genetic
Female
Gene Expression Profiling*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Immunohistochemistry
Liver Neoplasms / chemistry
Liver Neoplasms / classification
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Male
Neoplasms, Complex and Mixed / chemistry
Neoplasms, Complex and Mixed / classification
Neoplasms, Complex and Mixed / genetics*
Neoplasms, Complex and Mixed / pathology
Nestin / analysis
Nestin / genetics*
Predictive Value of Tests
Prognosis
Transcriptome*
Up-Regulation

Substances

Biomarkers, Tumor
NES protein, human
Nestin

Grants and funding

ZIA BC010313/ImNIH/Intramural NIH HHS/United States