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Efficacy of ginseng-based Renshenguben oral solution for cancer-related fatigue among patients with advanced-stage Hepatocellular carcinoma:A prospective multicenter cohort study

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 249-256页

作者： Ming-Da Wang Chen Yuan Ke-Chun Wang Nan-Ya Wang Ying-Jian Liang Hong Zhu Xiang-Min Tong Tian Yang Department of Hepatobiliary and Pancreatic Surgery General Surgery CenterFirst Hospital of Jilin UniversityChangchun 130021China Department of Hepatobiliary Surgery Eastern Hepatobiliary Surgery HospitalSecond Military Medical University(Naval Medical University)Shanghai 200438China Department of Clinical Laboratory Laboratory Medicine CenterZhejiang Provincial People’s HospitalHangzhou Medical CollegeHangzhou 310000China Department of Hepatobiliary Surgery First Affiliated Hospital of Harbin Medical UniversityHarbin 150007China Department of Medical Oncology First Affiliated Hospital of Soochow UniversitySuzhou 215006China fDepartment of Central Laboratory Affiliated Hangzhou First People’s HospitalWestlake University School of MedicineHangzhou 310006China

Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and safety of Renshenguben(RSGB)oral solution,a ginseng-based traditional Chinese medicine,in alleviating CRF in patients with advanced Hepatocellular carcinoma(HCC)receiving antitumor treatment.Methods:In this prospective,open-label,controlled,multicenter study,patients with advanced HCC at BCLC stage C and a brief fatigue inventory(BFI)score of≥4 were enrolled.Participants were assigned to the RSGB group(RSGB,10 mL twice daily)or the control group(with supportive care).Primary and secondary endpoints were the change in multidimensional fatigue inventory(MFI)score,and BFI and functional assessment of cancer therapy-hepatobiliary(FACT-Hep)scores at weeks 4 and 8 after enrollment.Adverse events(AEs)and toxicities were assessed.Results:A total of 409 participants were enrolled,with 206 assigned to the RSGB group.At week 4,there was a trend towards improvement,but the differences were not statistically significant.At week 8,the RSGB group exhibited a significantly lower MFI score(P<0.05)compared to the control group,indicating improved fatigue levels.Additionally,the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8(P<0.05).Subgroup analyses among patients receiving various antitumor treatments showed similar results.Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI,BFI,and FACT-Hep scores at week 8.No serious drug-related AEs or toxicities were observed.Conclusions:RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period,with no discernible toxicities.These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.

关键词： Cancer-related fatigue Hepatocellular carcinoma Renshenguben oral solution Efficacy Safety Ginseng

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Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity

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Chinese Journal of Integrative Medicine 2024年第2期30卷 115-124页

作者： LUO Zhi-yi TIAN Qi CHENG Niang-mei LIU Wen-han YANG Ye CHEN Wei ZHANG Xiang-zhi ZHENG Xiao-yuan CHEN Ming-sheng ZHUANG Qiu-yu ZHAO Bi-xing LIU Cong-sheng LIU Xiao-long LI Qin WANG Ying-chao The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co.Ltd.ZhangzhouFujian Province(363099)China College of Biological Science and Engineering and Mengchao Med-X Center Fuzhou UniversityFuzhou(350116)China Department of Internal Medicine Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China

Objective:To investigate the effects of Pien Tze Huang(PZH) on the migration and invasion of HCC cells and underlying molecular mechanism.Methods:Cell counting kit-8(CCK-8) was applied to evaluate the cell viabilities of SMMC-7721,SK-Hep-1,C3A and HL-7702(6 × 10^(3)cells/well) co-incubated with different concentrations of PZH(0,0.2,0.4,0.6,0.8 mg/mL) for 24 h.Transwell,wound healing assay,CCK-8and Annexin V-FITC/PI staining were conducted to investigate the effects of PZH on the migration,invasion,proliferation and apoptosis of SK-Hep-1 and SMMC-7721 cells(650 μg/mL for SK-Hep-1 cells and 330 μg/mL for SMMC-7721 cells),respectively.In vivo,lung metastasis mouse model constructed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of PZH.SK-Hep-1 cells(10^(6)cells/200 μL per mice) were injected into B-NDG mice via tail vein.Totally 8 mice were randomly divided into PZH and control groups,4 mice in each group.After 2-d inoculation,mice in the PZH group were administered with PZH(250 mg/kg,daily) and mice in the control group received only vehicle(PBS) from the 2nd day after xenograft to day 17.Transcriptome analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of PZH.Quantitative real-time polymerase chain reaction(qRT-PCR) and Western blot were applied to verify RNA-seq results.Luciferase reporter assay was performed to examine the transcriptional activity of yes-associated protein(YAP).Results:PZH treatment significantly inhibited the migration,invasion,proliferation and promoted the apoptosis of HCC cells in vitro and in vivo(P<0.01).Transcriptome analysis indicated that Hippo signaling pathway was associated with anti-metastasis function of PZH.Mechanical study showed PZH significantly inhibited the expressions of platelet derived growth factor receptor beta(PDGFRB),YAP,connective tissue growth factor(CCN2),N-cadherin,vimentin and matrix metallopeptidase 2(MMP2,P<0.01).Meanwhile,the phosphorylation of YAP was also enhanced by PZH treatment in v

关键词： PienTzeHuang Hepatocellular carcinoma RNA-seq Hippo yes-associated protein

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Proteomics of adjacent-to-tumor samples uncovers clinically relevant biological events in Hepatocellular carcinoma

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National Science Review 2023年第8期10卷 88-104页

作者： Hongwen Zhu Youpei Lin Dayun Lu Shisheng Wang Yuejia Liu Liangqing Dong Qian Meng Jing Gao Yuqiu Wang Nixue Song Yuying Suo Li Ding Pei Wang Bing Zhang Daming Gao Jia Fan Qiang Gao Hu Zhou Department of Analytical Chemistry State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica Chinese Academy of Sciences 2. Department of Liver Surgery and TransplantationLiver Cancer InstituteZhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Fudan University School of Chinese Materia Medica Nanjing University of Chinese Medicine Institutes for Systems Genetics and NHC Key Lab of Transplant Engineering and Immunology Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application West China Hospital Sichuan University University of Chinese Academy of Sciences Department of Medicine McDonnell Genome Institute Siteman Cancer Center Washington University Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai Lester and Sue Smith Breast Center Department of Molecular and Human Genetics Baylor College of Medicine State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences

Normal adjacent tissues(NATs) of Hepatocellular carcinoma(HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes(Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence. The pathway and immune features of these two subtypes were characterized. Proteomic differences between the two NAT subtypes and healthy liver tissues were further investigated using data-independent acquisition mass spectrometry, revealing the early molecular alterations associated with the progression from healthy livers to NATs. This study provides a high-quality resource for HCC researchers and clinicians and may significantly expand the knowledge of tumor NATs to eventually benefit clinical practice.

关键词： proteomics Hepatocellular carcinoma normal tissue adjacent to tumor heterogeneity

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Computed tomography radiomic features and clinical factors predicting the response to first transarterial chemoembolization in intermediate-stage Hepatocellular carcinoma

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HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL 2024年第4期23卷 361-369页

作者： Shi, Zhong-Xing Li, Chang -Fu Zhao, Li-Feng Sun, Zhong-Qi Cui, Li -Ming Xin, Yan-Jie Wang, Dong-Qing Kang, Tan-Rong Jiang, Hui-Jie Harbin Med Univ Affiliated Hosp 2 Dept Intervent Radiol Harbin 150086 Peoples R China Daqing Longnan Hosp Dept Digest Med Daqing 163453 Peoples R China Daqing Longnan Hosp Dept Radiol Daqing 163453 Peoples R China Harbin Med Univ Affiliated Hosp 2 Dept Radiol Harbin 150086 Peoples R China

Background: According to clinical practice guidelines, transarterial chemoembolization (TACE) is the standard treatment modality for patients with intermediate -stage Hepatocellular carcinoma (HCC). Early prediction of treatment response can help patients choose a reasonable treatment plan. This study aimed to investigate the value of the radiomic-clinical model in predicting the efficacy of the first TACE treatment for HCC to prolong patient survival. Methods: A total of 164 patients with HCC who underwent the first TACE from January 2017 to September 2021 were analyzed. The tumor response was assessed by modified response evaluation criteria in solid tumors (mRECIST), and the response of the first TACE to each session and its correlation with overall survival were evaluated. The radiomic signatures associated with the treatment response were identified by the least absolute shrinkage and selection operator (LASSO), and four machine learning models were built with different types of regions of interest (ROIs) (tumor and corresponding tissues) and the model with the best performance was selected. The predictive performance was assessed with receiver operating characteristic (ROC) curves and calibration curves. Results: Of all the models, the random forest (RF) model with peritumor ( + 10 mm) radiomic signatures had the best performance [area under ROC curve (AUC) = 0.964 in the training cohort, AUC = 0.949 in the validation cohort]. The RF model was used to calculate the radiomic score (Rad-score), and the optimal cutoff value (0.34) was calculated according to the Youden's index. Patients were then divided into a high -risk group (Rad-score > 0.34) and a low -risk group (Rad-score <= 0.34), and a nomogram model was successfully established to predict treatment response. The predicted treatment response also allowed for significant discrimination of Kaplan -Meier curves. Multivariate Cox regression identified six independent prognostic factors for overall survival, including male [hazard ratio (HR) = 0.500, 95% c

关键词： Hepatocellular carcinoma Transarterial chemoembolization Radiomics Treatment response Prediction PROGNOSIS

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Targeting stroma and tumor,silencing galectin 1 treats orthotopic mouse Hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2024年第1期14卷 292-303页

作者： Tahereh Setayesh Ying Hu Farzam Vaziri Xin Chen Jinping Lai Dongguang Wei Yu-Jui Yvonne Wan Department of Medical Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Cancer Biology Program the University of Hawaii Cancer CenterHonoluluHI 96813USA Department of Pathology and Laboratory Medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825USA

This study examines inhibiting galectin 1(Gal1)as a treatment option for Hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting roles.Our data showed that Gal1 was highly expressed in human and mouse HCC.The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival.The roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by AAV9.Prior to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor load.The treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body weight.Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing.Within the tumors,silencing Gal1 inhibited translational initiation,elongation,and termination.Furthermore,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas CD8-dependent.Overall,Gal1 silencing has a promising potential for HCC treatment.

关键词： Liver Hepatocellular carcinoma Carbohydrate-binding lectin Galectin 1 Extracellular matrix Translation Spatial transcriptomics Tumor-margin

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Conversion therapy in liver transplantation for Hepatocellular carcinoma:What's new in the era of molecular and immune therapy?

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Hepatobiliary & Pancreatic Diseases International 2023年第1期22卷 7-13页

作者： Chao Jiang Xiao-Dong Sun Wei Qiu Yu-Guo Chen Da-Wei Sun Guo-Yue Lv General Surgery Center Department of Hepatobiliary and Pancreatic Surgerythe First Hospital of Jilin UniversityChangchun 130021China

Background:Hepatocellular carcinoma(HCC)is the sixth most common cancer globally,with limited therapies and unsatisfactory prognosis once in the advanced stages.With promising advances in locoregional and systematic treatments,fast development of targeted drugs,the success of immunotherapy,as well as the emergence of the therapeutic alliance,conversion therapy has recently become more well developed and an effective therapeutic strategy.This article aimed to review recent developments in conversion therapy in liver transplantation(LT)for HCC.Data sources:We searched for relevant publications on Pub Med before September 2022,using the terms“HCC”,“liver transplantation”,“downstaging”,“bridging treatment”and“conversion therapy.”Results:Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT.Although combining various local and systematic treatments in conversion therapy is still controversial,growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time,which ultimately increases the opportunities for LT.Moreover,the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors.Conclusions:In the era of targeted therapy and immunotherapy,applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients.With the expansion of conversion therapy concepts,further investigation and research is required to realize the full potential of conversion treatment strategies,including accurately selecting candidates,determining the timing of surgery,improving the conversion rate,and guaranteeing the safety and long-term efficacy of treatment.

关键词： Liver transplantation Hepatocellular carcinoma Conversion therapy Targeted therapy Immunotherapy Combination therapy

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Response Evaluation Using Contrast-Enhanced Ultrasound for Unresectable Advanced Hepatocellular carcinoma Treated With Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy

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Ultrasound in Medicine and Biology 2024年第1期50卷 142-149页

作者： Zhao C.-K. Guan X. Pu Y.-Y. Zhou B.-Y. Wang L.-F. Sun Y.-K. Yin H.-H. Xia H.-S. Wang X. Han H. Xu H.-X. Department of Ultrasound Zhongshan Hospital Institute of Ultrasound in Medicine and Engineering Fudan University Shanghai China Shanghai Institute of Medical Imaging Shanghai China Central Laboratory and Department of Medical Ultrasound Sichuan Academy of Medical Sciences Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu China

Objective: The aim of the work described here was to evaluate the role of contrast-enhanced ultrasound (CEUS) in response evaluation for unresectable advanced Hepatocellular carcinoma (HCC) treated with tyrosine kinase inhibitors (TKIs) plus anti-programmed cell death protein-1 (PD-1) antibody therapy. Methods: A prospective cohort of consecutive patients with HCC who received combined TKI/anti-PD-1 antibody treatment for unresectable HCC between January 2022 and October 2022 was included in this study. The patients underwent unenhanced ultrasound (US) and CEUS examinations before treatment and at follow-up. Changes in the largest diameters of the target tumor on unenhanced US and the largest diameters of the enhancing target tumors on CEUS were evaluated. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with unenhanced US and magnetic resonance imaging/computed tomography (MRI/CT) and modified RECIST (mRECIST) with CEUS and CEMRI/CT were used to assess treatment response. Results: A total of 24 HCC patients (23 men and 1 woman; mean age: 56.5 ± 8.5 y; Barcelona Clinic Liver Cancer stage C, 62.5%; 29 intrahepatic target tumors) were studied. Calculations of degree of necrosis in the target tumors revealed no significant differences between CEUS and CEMRI/CT (44.5 ± 36.2% vs. 45.3 ± 36.8%, p = 0.862). As for the differentiation of responders from non-responders, the agreement between RECIST version 1.1 of unenhanced US and mRECIST-CEUS was poor (κ coefficient = 0.233). Meanwhile, there was a high degree of concordance between mRECIST-CEUS and mRECIST-CEMRI/CT (κ coefficient = 0.812). Conclusion: CEUS proved to be superior to baseline US and is comparable to CEMRI/CT in defining treatment outcome for combined TKI/anti-PD-1 antibody therapy. © 2023 World Federation for Ultrasound in Medicine & Biology

关键词： Anti-angiogenic therapy Anti-PD-1 antibody Contrast-enhanced ultrasound Hepatocellular carcinoma

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Indications of pro-inflammatory cytokines in laparoscopic and open liver resection for early-stage Hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 257-264页

作者： Kevin Tak-Pan Ng Li Pang Jia-Qi Wang Wong Hoi She Simon Hing-Yin Tsang Chung Mau Lo Kwan Man Tan To Cheung Department of Surgery HKU-SZH&School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina State Key Laboratory of Liver Research The University of Hong KongHong KongChina

Background:Our clinical practice of laparoscopic liver resection(LLR)had achieved better short-term and long-term benefits for patients with Hepatocellular carcinoma(HCC)over open liver resection(OLR),but the underlying mechanisms are not clear.This study was to find out whether systemic inflammation plays an important role.Methods:A total of 103 patients with early-stage HCC under liver resection were enrolled(LLR group,n=53;OLR group,n=50).The expression of 9 inflammatory cytokines in patients at preoperation,postoperative day 1(POD1)and POD7 was quantified by Luminex Multiplex assay.The relationships of the cytokines and the postoperative outcomes were compared between LLR and OLR.Results:Seven of the circulating cytokines were found to be significantly upregulated on POD1 after LLR or OLR compared to their preoperative levels.Compared to OLR,the POD1 levels of granulocytemacrophage colony-stimulating factor(GM-CSF),interleukin-6(IL-6),IL-8,and monocyte chemoattractant protein-1(MCP-1)in the LLR group were significantly lower.Higher POD1 levels of these cytokines were significantly correlated with longer operative time and higher volume of blood loss during operation.The levels of these cytokines were positively associated with postoperative liver injury,and the length of hospital stay.Importantly,a high level of IL-6 at POD1 was a risk factor for HCC recurrence and poor disease-free survival after liver resection.Conclusions:Significantly lower level of GM-CSF,IL-6,IL-8,and MCP-1 after liver resection represented a milder systemic inflammation which might be an important mechanism to offer better short-term and long-term outcomes in LLR over OLR.

关键词： Laparoscopic liver resection Open liver resection Hepatocellular carcinoma Postoperative cytokines Inflammatory responses

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Non-anatomical liver resection for Hepatocellular carcinoma:the SegSubTe classification to overcome the problem of heterogeneity

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 265-271页

作者： Mattia Garancini Alessandro Fogliati Mauro Alessandro Scotti Cristina Ciulli Francesca Carissimi Antonio Rovere Luca Gianotti Fabrizio Romano Unit of Hepatobiliopancreatic Surgery Department of SurgeryASST-MonzaSan Gerardo HospitalUniversity of Milano-Bicoccavia Pergolesi 33MonzaMB 20052Italy Interventional Radiology Department of RadiologyASST-MonzaSan Gerardo HospitalMilano-Bicocca Universityvia Pergolesi 33MonzaMB 20052Italy

Background:The superiority of anatomical resection(AR)vs.non-anatomical resection(NAR)in the surgical management of Hepatocellular carcinoma(HCC)is debated.ARs are well-defined procedures,whereas the lack of NAR standardization results in heterogeneous outcomes.This study aimed to introduce the SegSubTe classification for NAR detailing the appropriateness of the level of surgical section of the Glissonean pedicles feeding the tumor.Methods:A single-center retrospective analysis of pre-and postoperative imaging of consecutive patients treated with NAR for single HCC between 2012 and 2020 was conducted.The quality of surgery was assessed classifying the type of vascular supply and the level of surgical section(segmental,subsegmental or terminal next to the tumor)of vascular pedicles feeding the HCCs;then,the population was divided in“SegSubTe-IN”or“SegSubTe-OUT”groups,and the tumor recurrence and survival were analyzed.Results:Ninety-seven patients who underwent NAR were included;76%were SegSubTe-IN and 24%were SegSubTe-OUT.Total disease recurrence,local recurrence and cut-edge recurrence in the SegSubTe-IN vs.SegSubTe-OUT groups were 50%vs.83%(P=0.006),20%vs.52%(P=0.003)and 16%vs.39%(P=0.020),respectively.SegSubTe-OUT odds ratio for local recurrence was 4.1 at univariate regression analysis.One-,three-,and five-year disease-free survival rates in the SegSubTe-IN vs.SegSubTe-OUT groups were 81%,58%and 35%vs.46%,21%and 11%,respectively(P<0.001).Conclusions:The SegSubTe classification is a useful tool to stratify and standardize NAR for HCC,aiming at improving long-term oncological outcomes and reducing the heterogeneity of quality of NAR for HCC.

关键词： Hepatocellular carcinoma Intraoperative ultrasound Liver surgery Computed tomography Surgical procedure

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

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National Science Review 2022年第3期9卷 96-109页

作者： 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 Division of Pathology National Cancer Institute Department of Surgery Faculty of Medicine University of Malaya Department of Surgery and Center for Liver Disease Management and Transplantation The Medical City 13. Department of Laboratories The Medical City Department of Pathology Singapore General Hospital Institute for Infocomm Research ASTAR Department of Pathology National University Health System Translational Immunology Institute (TII) Sing Health Duke-NUS Academic Medical Centre Division of Gastroenterology and Hepatology University Medicine Cluster National University Hospital Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Genome Institute of Singapore Agency for Science Technology and Research Cancer Science Institute of Singapore National University of Singapore Division of Medical Oncology National Cancer Center Singapore Cardiovascular Research Institute National University of Singapore National University Healthcare System Singhealth-Duke-NUS Academic Surgery Program Duke-NUS Graduate Medical School Institute of Molecular and Cell Biology Agency for Science Technology and Research Key Laboratory of Zoological Systematics and Evolution Institute of Zoology Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences School of Biological Sciences Nanyang Technological University Division of Biosciences Faculty of Life Sciences Division of Surgery and Surgical Oncology National Cancer Centre Department of Hepato-Pancreato-Biliary and Transplant Surgery Singapore General Hospital Division of Hepatobiliary and Pancreatic Surgery Department of Surgery University Surgical Cluster National University Health System Hepato-Pancreato-Biliary Surgery Unit Department of Surgery National Cancer Institute

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.

关键词： Hepatocellular carcinoma intra-tumor heterogeneity phenotypic evolution tumor evolution

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