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 stages,phenotypic ITH had a very different trajectory and quickly diversified in stage Ⅱ patients.Most strikingly,30％of 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.

Weiwei Zhai;Hannah Lai;Neslihan Arife Kaya;Jianbin Chen;Hechuan Yang;Bingxin Lu;Jia Qi Lim;Siming Ma;Sin Chi Chew;Khi Pin Chua;Jacob Josiah Santiago Alvarez;Pauline Jieqi Chen;Mei Mei Chang;Lingyan Wu;Brian K.P.Goh;Alexander Yaw-Fui Chung;Chung Yip Chan;Peng Chung Cheow;Ser Yee Lee;Juinn Huar Kam;Alfred Wei-Chieh Kow;Iyer Shridhar Ganpathi;Rawisak Chanwat;Jidapa Thammasiri;Boon Koon Yoong;Diana Bee-Lan Ong;Vanessa H.de Villa;Rouchelle D.Dela Cruz;Tracy Jiezhen Loh;Wei Keat Wan;Zeng Zeng;Anders Jacobsen Skanderup;Yin Huei Pang;Krishnakumar Madhavan;Tony Kiat-Hon Lim;Glenn Bonney;Wei Qiang Leow;Valerie Chew;Yock Young Dan;Wai Leong Tam;Han Chong Toh;Roger Sik-Yin Foo;Pierce Kah-Hoe Chow

Genome Institute of Singapore,Agency for Science,Technology and Research,Singapore 138672,Singapore;Key Laboratory of Zoological Systematics and Evolution,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;Center for Excellence in Animal Evolution and Genetics,Chinese Academy of Sciences,Kunming 650223,China;School of Biological Sciences,Nanyang Technological University,Singapore 637551,Singapore;Cell and Developmental Biology,Division of Biosciences,Faculty of Life Sciences,Bloomsbury,London WC1E 6AP,UK;Division of Surgery and Surgical Oncology,National Cancer Centre,Singapore 169610,Singapore;Department of Hepato-Pancreato-Biliary and Transplant Surgery,Singapore General Hospital,Singapore 169608,Singapore;Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,University Surgical Cluster,National University Health System,Singapore 119228,Singapore;Hepato-Pancreato-Biliary Surgery Unit,Department of Surgery,National Cancer Institute,Bangkok 10310,Thailand;Division of Pathology,National Cancer Institute,Bangkok 10400,Thailand;Department of Surgery,Faculty of Medicine,University of Malaya,Kuala Lumpur 59100,Malaysia;Department of Surgery and Center for Liver Disease Management and Transplantation,The Medical City,Pasig City,Metro Manila,Philippines;Department of Laboratories,The Medical City,Pasig City,Metro Manila,Philippines;Department of Pathology,Singapore General Hospital,Singapore 169608,Singapore;Institute for Infocomm Research,A*STAR,Singapore 138632,Singapore;Department of Pathology,National University Health System,Singapore 119228,Singapore;Translational Immunology Institute(TⅡ),SingHealth Duke-NUS Academic Medical Centre,Singapore 168753,Singapore;Division of Gastroenterology and Hepatology,University Medicine Cluster,National University Hospital,Singapore 119228,Singapore;Department of Biochemistiy,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 117597,Singapore;Cancer Science Institute of Singapore,National University of Singapore,Singapore 117599,Singapore;Division of Medical Oncology,National Cancer Center Singapore,Singapore 169610,Singapore;Cardiovascular Research Institute,National University of Singapore,National University Healthcare System,Singapore 119228,Singapore;Singhealth-Duke-NUS Academic Surgery Program,Duke-NUS Graduate Medical School,Singapore 169857,Singapore;Institute of Molecular and Cell Biology,Agency for Science,Technology and Research,Singapore 138673,Singapore

国家科学评论（英文版）

[1]Weiwei Zhai;Hannah Lai;Neslihan Arife Kaya;Jianbin Chen;Hechuan Yang;Bingxin Lu;Jia Qi Lim;Siming Ma;Sin Chi Chew;Khi Pin Chua;Jacob Josiah Santiago Alvarez;Pauline Jieqi Chen;Mei Mei Chang;Lingyan Wu;Brian K.P.Goh;Alexander Yaw-Fui Chung;Chung Yip Chan;Peng Chung Cheow;Ser Yee Lee;Juinn Huar Kam;Alfred Wei-Chieh Kow;Iyer Shridhar Ganpathi;Rawisak Chanwat;Jidapa Thammasiri;Boon Koon Yoong;Diana Bee-Lan Ong;Vanessa H.de Villa;Rouchelle D.Dela Cruz;Tracy Jiezhen Loh;Wei Keat Wan;Zeng Zeng;Anders Jacobsen Skanderup;Yin Huei Pang;Krishnakumar Madhavan;Tony Kiat-Hon Lim;Glenn Bonney;Wei Qiang Leow;Valerie Chew;Yock Young Dan;Wai Leong Tam;Han Chong Toh;Roger Sik-Yin Foo;Pierce Kah-Hoe Chow-.Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma:the PLANET study)[J].国家科学评论（英文版）,2022(03):92-105

PLANET

Dynamic,phenotypic,heterogeneity,evolution,multiple,subtypes,hepatocellular,carcinoma,Intra,tumor,ITH,is,key,challenge,cancer,treatment,but,previous,studies,have,focused,mainly,genomic,alterations,without,exploring,transcriptomic,immune,Using,one,largest,prospective,surgical,cohorts,HCC,region,sampling,sequenced,whole,genomes,paired,transcriptomes,from,patients,samples,We,found,that,while,was,rather,constant,across,stages,had,very,different,trajectory,quickly,diversified,Most,strikingly,were,contain,more,than,within,single,Such,be,much,informative,predicting,survival,explains,poor,efficacy,target,systemic,therapies,Taken,together,only,revealed,unprecedentedly,dynamic,landscape,also,highlighted,importance,studying

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