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Tang B, Zhu J, Zhao Z, Lu C, Liu S, Fang S, Zheng L, Zhang N, Chen M, Xu M, Yu R, Ji J. Diagnosis and prognosis models for hepatocellular carcinoma patient's management based on tumor mutation burden. J Adv Res 2021; 33:153-165. [PMID: 34603786 PMCID: PMC8463909 DOI: 10.1016/j.jare.2021.01.018] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023] Open
Abstract
Introduction The development and prognosis of HCC involve complex molecular mechanisms, which affect the effectiveness of its treatment strategies. Tumor mutational burden (TMB) is related to the efficacy of immunotherapy, but the prognostic role of TMB-related genes in HCC has not yet been determined clearly. Objectives In this study, we identified TMB-specific genes with good prognostic value to build diagnostic and prognostic models and provide guidance for the treatment of HCC patients. Methods Weighted gene co-expression network analysis (WGCNA) was applied to identify the TMB-specific genes. And LASSO method and Cox regression were used in establishing the prognostic model. Results The prognostic model based on SMG5 and MRPL9 showed patients with higher prognostic risk had a remarkedly poorer survival probability than their counterparts with lower prognostic risk in both a TCGA cohort (P < 0.001, HR = 1.93) and an ICGC cohort (P < 0.001, HR = 3.58). In addition, higher infiltrating fractions of memory B cells, M0 macrophages, neutrophils, activated memory CD4 + T cells, follicular helper T cells and regulatory T cells and higher expression of B7H3, CTLA4, PD1, and TIM3 were present in the high-risk group than in the low-risk group (P < 0.05). Patients with high prognostic risk had higher resistance to some chemotherapy and targeted drugs, such as methotrexate, vinblastine and erlotinib, than those with low prognostic risk (P < 0.05). And a diagnostic model considering two genes was able to accurately distinguish patients with HCC from normal samples and those with dysplastic nodules. In addition, knockdown of SMG5 and MRPL9 was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion Our study helps to select patients suitable for chemotherapy, targeted drugs and immunotherapy and provide new ideas for developing treatment strategies to improve disease outcomes in HCC patients.
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Affiliation(s)
- Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinyu Zhu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Chenying Lu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Siyu Liu
- Department of Laboratory, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Shiji Fang
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Liyun Zheng
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Nannan Zhang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.,Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
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Zhu J, Tang B, Gao Y, Xu S, Tu J, Wang Y, Yang W, Fang S, Weng Q, Zhao Z, Xu M, Yang Y, Chen M, Lu C, Ji J. Predictive Models for HCC Prognosis, Recurrence Risk, and Immune Infiltration Based on Two Exosomal Genes: MYL6B and THOC2. J Inflamm Res 2021; 14:4089-4109. [PMID: 34466015 PMCID: PMC8403029 DOI: 10.2147/jir.s315957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC. Objective The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis. Methods Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2. Results The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P<0.001), the ICGC cohort (HR=3.15, P<0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P<0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P<0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules. Conclusion Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.
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Affiliation(s)
- Jinyu Zhu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
| | - Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People's Republic of China
| | - Yang Gao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Suqin Xu
- Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People's Republic of China
| | - Jianfei Tu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yajie Wang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Weibin Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Shiji Fang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Qiaoyou Weng
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yang Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Chenying Lu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
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Sparchez Z, Mocan T. Contemporary role of liver biopsy in hepatocellular carcinoma. World J Hepatol 2018; 10:452-461. [PMID: 30079131 PMCID: PMC6068845 DOI: 10.4254/wjh.v10.i7.452] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/29/2018] [Accepted: 06/26/2018] [Indexed: 02/06/2023] Open
Abstract
A correct diagnosis of hepatocellular carcinoma (HCC) in cirrhotic patients with focal liver lesions is one of the most important issues nowadays. Probably one of the oldest debates in the hepatology community is whether to perform liver biopsy (LB) in all cirrhotic patients with focal liver lesions. We now face a time when oncology is moving towards personalized medicine. According to the current European Association for the study of Liver diseases HCC guidelines, LB has only a minor role in the management of HCC. However, the current recommendations were made more than five years ago. As time has passed, the development of high-throughput molecular technologies has helped reveal the main molecular mechanism involved in HCC development and progression. Several subtypes of HCC, with both molecular and histological characterization, have been described. Importantly, some of these subtypes have prognostic impact. In the context of personalized treatment, the role of LB will be carefully reconsidered. Until then, it is mandatory to know the various techniques of LB, their performances, complications and limitations. The balance of risk and benefit defines many of the decisions that we make as providers of medical care. In this review, we discuss not only the risks associated with LB, but also the benefits of biopsy in various clinical scenarios. Not long from now, the role of LB will be reconsidered. It is possible that we will go back in time and once again use biopsy for HCC diagnosis. Then again, we may move back to the future to try to improve the use of liquid biopsy in the follow-up of HCC patients after various treatment modalities.
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Affiliation(s)
- Zeno Sparchez
- 3 Medical Department, Institute for Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
| | - Tudor Mocan
- 3 Medical Department, Institute for Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania.
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