Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study-Reference-Cited by-同舟云学术

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study

Published:2021-10-29 Issue: Volume: Page:
ISSN:2095-5138
Container-title:National Science Review
language:en
Short-container-title:

Author:

Zhai Weiwei¹²³,Lai Hannah¹,Kaya Neslihan Arife¹⁴,Jianbin Chen¹^ORCID,Yang Hechuan¹²,Lu Bingxin¹⁵^ORCID,Lim Jia Qi¹,Ma Siming¹,Chew Sin Chi⁶,Chua Khi Pin¹,Alvarez Jacob Josiah Santiago¹,Chen Pauline Jieqi¹,Chang Mei Mei¹,Wu Lingyan⁶,Goh Brian K P⁷,Chung Alexander Yaw-Fui⁷,Chan Chung Yip⁷,Cheow Peng Chung⁷,Lee Ser Yee⁷,Kam Juinn Huar⁷,Kow Alfred Wei-Chieh⁸,Iyer Shridhar Ganpathi⁸^ORCID,Chanwat Rawisak⁹,Thammasiri Jidapa¹⁰,Yoong Boon Koon¹¹,Ong Diana Bee-Lan¹¹,de Villa Vanessa H¹²,Dela Cruz Rouchelle D¹³,Loh Tracy Jiezhen¹⁴,Wan Wei Keat¹⁴,Zeng Zeng¹⁵,Skanderup Anders Jacobsen¹,Pang Yin Huei¹⁶,Madhavan Krishnakumar⁸,Lim Tony Kiat-Hon¹⁴,Bonney Glenn⁸,Leow Wei Qiang¹⁴,Chew Valerie¹⁷,Dan Yock Young¹⁸,Tam Wai Leong¹⁴¹⁹²⁰,Toh Han Chong²¹,Foo Roger Sik-Yin¹²²,Chow Pierce Kah-Hoe¹⁶⁷²³²⁴

Affiliation:

1. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore

2. Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

3. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China

4. School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore

5. Cell & Developmental Biology, Division of Biosciences, Faculty of Life Sciences, Bloomsbury, London WC1E 6AP, UK

6. Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore

7. Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore

8. Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Singapore

9. Hepato-Pancreato-Biliary Surgery Unit, Department of Surgery, National Cancer Institute, Bangkok, Thailand

10. Division of Pathology, National Cancer Institute, Thailand

11. Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

12. Department of Surgery and Center for Liver Disease Management and Transplantation, The Medical City, Pasig City, Metro Manila, Philippines

13. Department of Laboratories, The Medical City, Pasig City, Metro Manila, Philippines

14. Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore

15. Institute for Infocomm Research, A*STAR, Singapore 138632, Singapore

16. Department of Pathology, National University Health System, Singapore 119228, Singapore

17. Translational Immunology Institute (TII), SingHealth Duke-NUS Academic Medical Centre, Singapore

18. Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore

19. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597

20. Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599

21. Division of Medical Oncology, National Cancer Center Singapore, 169610 Singapore, Singapore

22. Cardiovascular Research Institute, National University of Singapore, National University Healthcare System, Singapore 119228, Singapore

23. Singhealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore

24. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore

Abstract

Abstract Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for Hepatocellular Carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across TNM stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.

Publisher

Oxford University Press (OUP)

Subject

Multidisciplinary

Link

http://academic.oup.com/nsr/advance-article-pdf/doi/10.1093/nsr/nwab192/41009894/nwab192.pdf

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