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Hepatology, First published: 29 March 2022 | https://doi.org/10.1002/hep.32490 Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes

Sung Hwan Lee^1,2,3,*, Sun Young Yim^1,4,*, Yun Seong Jeong^1,*, Qi-Xiang Li^5,*, Sang-Hee Kang^1,6,*, Bo Hwa Sohn^1,*, Shwetha V. Kumar⁷, Ji-Hyun Shin¹, You Rhee Choi¹, Jae-Jun Shim⁸, Hayeon Kim⁹, Jihoon Kim⁴, Shin Kim^1,10, Sheng Guo¹¹, Randy L. Johnson¹², Ahmed Kaseb¹³, Koo Jeong Kang¹⁴, Yun Shin Chun¹⁵, Hee Jin Jang¹⁶, Byoung Gill Lee¹⁷, Hyun Goo Woo¹⁷, Min Jin Ha¹⁸, Rehan Akbani⁷, Lewis R. Roberts¹⁹, David A. Wheeler²⁰, and Ju-Seog Lee¹

¹Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
²Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Korea
³Division of Hepatobiliary and Pancreas, Department of Surgery, CHA Bundang Medical Center, CHA University, Korea.
⁴Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
⁵Crown Bioscience, Inc., 3375 Scott Blvd, Suite 108, Santa Clara, CA, USA.
⁶Department of Surgery, Korea University Guro Hospital, Seoul, Korea.
⁷Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
⁸Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea.
⁹Department of Pathology, Korea University Guro Hospital, Seoul, Korea.
¹⁰Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea.
¹¹Crown Bioscience (Suzhou), Inc., 218 Xinhu St, Suzhou, China.
¹²Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Keimyung University Dongsan Medical Center, Daegu, Korea.
¹⁵Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
¹⁶Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
¹⁷Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
¹⁸Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
¹⁹Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
²⁰Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

^*These authors contributed equally.
Correspondence: Ju-Seog Lee

Abstract

Background & aims
While many studies revealed transcriptomic subtypes of hepatocellular carcinoma (HCC), concordance of the subtypes are not fully examined. We aim to examine consensus of transcriptomic subtypes and correlate them with clinical outcomes.

Approach and results
By integrating 16 previously established genomic signatures for HCC subtypes, we identified 5 clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high HNF4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes (PICS100) and demonstrated that 5 subtypes were well conserved in patient derived xenograft (PDX) models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes.

Conclusions
Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in pre-clinical models, providing a framework for selecting the most appropriate models for preclinical studies.

논문정보

형식Research article
게재일2022년 03월 (BRIC 등록일 2022-04-08)
연구진국내+국외 연구진
분야 의약학 > 종양의학

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