Sung Hwan Lee1,2,3, Sun Young Yim1,4, Yun Seong Jeong1, Qi-Xiang Li5, Sang-Hee Kang1,6, Bo Hwa Sohn1, Shwetha V Kumar7, Ji-Hyun Shin1, You Rhee Choi1, Jae-Jun Shim8, Hayeon Kim9, Ji Hoon Kim4, Shin Kim1,10, 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, Ju-Seog Lee1. 1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 2. Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Yonsei, Korea. 3. Division of Hepatobiliary and Pancreas, Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea. 4. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea. 5. Crown Bioscience, Inc., Santa Clara, California, USA. 6. Department of Surgery, Korea University Guro Hospital, Seoul, Korea. 7. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 8. Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea. 9. Department of Pathology, Korea University Guro Hospital, Seoul, Korea. 10. Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea. 11. Crown Bioscience (Suzhou), Inc., Suzhou, China. 12. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 13. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 14. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Keimyung University Dongsan Medical Center, Daegu, Korea. 15. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 16. Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA. 17. Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea. 18. Department of Health Informatics & Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea. 19. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. 20. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Abstract
BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a 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 five 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 hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft 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 preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.
BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a 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 five 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 hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft 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 preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.
Authors: Wing-Kin Sung; Hancheng Zheng; Shuyu Li; Ronghua Chen; Xiao Liu; Yingrui Li; Nikki P Lee; Wah H Lee; Pramila N Ariyaratne; Chandana Tennakoon; Fabianus H Mulawadi; Kwong F Wong; Angela M Liu; Ronnie T Poon; Sheung Tat Fan; Kwong L Chan; Zhuolin Gong; Yujie Hu; Zhao Lin; Guan Wang; Qinghui Zhang; Thomas D Barber; Wen-Chi Chou; Amit Aggarwal; Ke Hao; Wei Zhou; Chunsheng Zhang; James Hardwick; Carolyn Buser; Jiangchun Xu; Zhengyan Kan; Hongyue Dai; Mao Mao; Christoph Reinhard; Jun Wang; John M Luk Journal: Nat Genet Date: 2012-05-27 Impact factor: 38.330
Authors: Scott L Carter; Kristian Cibulskis; Elena Helman; Aaron McKenna; Hui Shen; Travis Zack; Peter W Laird; Robert C Onofrio; Wendy Winckler; Barbara A Weir; Rameen Beroukhim; David Pellman; Douglas A Levine; Eric S Lander; Matthew Meyerson; Gad Getz Journal: Nat Biotechnol Date: 2012-05 Impact factor: 54.908