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Hu D, Zhang Z, Wang Y, Li S, Zhang J, Wu Z, Sun M, Jiang J, Liu D, Ji X, Wang S, Wang Y, Luo X, Huang W, Xia L. Transcription factor ELF4 in physiology and diseases: Molecular roles and clinical implications. Genes Dis 2025; 12:101394. [PMID: 40083328 PMCID: PMC11904542 DOI: 10.1016/j.gendis.2024.101394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/21/2024] [Accepted: 07/28/2024] [Indexed: 03/16/2025] Open
Abstract
Transcription factor E74 like ETS transcription factor 4 (ELF4), a member of the ETS family, is highly expressed in normal human hematopoietic tissue, ovary, placenta, colon, and certain pathological cell lines. During normal physiological processes, ELF4 regulates differentiation in osteogenic, adipocyte, and neuronal types. It also exerts a critical impact on the development of the immune system. However, its function is dysregulated through posttranslational modifications, gene fusions, and complex signaling crosstalk under pathological conditions. Furthermore, serving as a double-edged sword in cancer, ELF4 exhibits both tumor-suppressing and tumor-promoting effects. Specifically, ELF4 plays a critical role in cancer metastasis, proliferation, and modulation of the tumor microenvironment. This review provides an in-depth overview of the molecular structure and post-translational modifications of ELF4. It also summarizes the hallmarks of ELF4 in physiology and diseases, with a particular focus on its significance in oncology. Notably, this review underscores the potential of ELF4 as a prognostic biomarker, highlighting its clinical relevance. Finally, it discusses unresolved questions and future research directions of ELF4. An in-depth understanding of ELF4 biology could facilitate its clinical translation and offer promising targeted therapeutic strategies.
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Affiliation(s)
- Dian Hu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Zerui Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yijun Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Siwen Li
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Jiaqian Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Zhangfan Wu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Mengyu Sun
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Junqing Jiang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Danfei Liu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaoyu Ji
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, China
| | - Yufei Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiangyuan Luo
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, China
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shannxi 710032, China
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Lindblad KE, Donne R, Liebling I, Barcena-Varela M, Lozano A, de Galarreta MR, Dhainaut M, Param NJ, Giotti B, Cappuyns S, Kodama T, Wang Y, Kamphorst AO, Tsankov AM, Lujambio A. NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma. Cancer Discov 2025; 15:495-510. [PMID: 39560425 PMCID: PMC11875915 DOI: 10.1158/2159-8290.cd-24-1215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/28/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024]
Abstract
Hepatocellular carcinoma presents strong sexual dimorphism, being two to three times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic antitumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced antitumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in dendritic cell (DC)-mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC-CD8+ T-cell axis with CD40 agonism to improve outcomes. Significance: Although HCC presents strong sexual dimorphism, the role of sex in response to immunotherapies remains elusive. With a novel HCC mouse model and validation in patients with HCC, we demonstrate that NOTCH1 disrupts antitumor immunity specifically in females through a mechanism mediated by sex chromosome genes, which is reversed with CD40 agonism. See related commentary by Zhu and Koltsova, p. 452.
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Affiliation(s)
- Katherine E. Lindblad
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA
| | - Romain Donne
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Ian Liebling
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marina Barcena-Varela
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Anthony Lozano
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marina Ruiz de Galarreta
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Maxime Dhainaut
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York
| | - Nesteene J. Param
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA
| | - Bruno Giotti
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York
| | - Sarah Cappuyns
- Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yulei Wang
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
| | - Alice O. Kamphorst
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Alexander M. Tsankov
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York
| | - Amaia Lujambio
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA
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Barcena-Varela M, Monga SP, Lujambio A. Precision models in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:191-205. [PMID: 39663463 DOI: 10.1038/s41575-024-01024-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 12/13/2024]
Abstract
Hepatocellular carcinoma (HCC) represents a global health challenge, and ranks among one of the most prevalent and deadliest cancers worldwide. Therapeutic advances have expanded the treatment armamentarium for patients with advanced HCC, but obstacles remain. Precision oncology, which aims to match specific therapies to patients who have tumours with particular features, holds great promise. However, its implementation has been hindered by the existence of numerous 'HCC influencers' that contribute to the high inter-patient heterogeneity. HCC influencers include tumour-related characteristics, such as genetic alterations, immune infiltration, stromal composition and aetiology, and patient-specific factors, such as sex, age, germline variants and the microbiome. This Review delves into the intricate world of HCC, describing the most innovative model systems that can be harnessed to identify precision and/or personalized therapies. We provide examples of how different models have been used to nominate candidate biomarkers, their limitations and strategies to optimize such models. We also highlight the importance of reproducing distinct HCC influencers in a flexible and modular way, with the aim of dissecting their relative contribution to therapy response. Next-generation HCC models will pave the way for faster discovery of precision therapies for patients with advanced HCC.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Satdarshan P Monga
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Gao Y, Chen X, Zhu Y, Zhou S, Zhang L, Wu Q, Zhang H, Wang Z, Chen X, Xia X, Pu L, Wang X. Establishment of two novel organoid lines from patients with combined hepatocellular cholangiocarcinoma. Hum Cell 2024; 38:27. [PMID: 39643731 DOI: 10.1007/s13577-024-01148-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/01/2024] [Indexed: 12/09/2024]
Abstract
Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a unique subtype of primary liver cancer displaying both hepatocytic and cholangiocytic differentiation. The development of effective treatments for cHCC-CCA remains challenging because of its high heterogeneity and lack of a suitable model system. Using a three-dimensional culture system, we successfully established two novel cHCC-CCA organoid lines from patients undergoing surgical resection for primary liver cancer. cHCC-CCA organoid lines were authenticated by fingerprint analysis, and their morphology, growth kinetics, and anchorage-independent growth were also characterized. Hematoxylin and eosin staining and immunohistochemical analysis showed that the cHCC-CCA organoids preserved the growth pattern, differentiation grade, and phenotypic characteristics of their parental tumors. Whole-exome sequencing demonstrated that patient-derived cHCC-CCA organoid lines retained the genetic alterations identified in their original tumors. Subcutaneous tumors developed in immunodeficient mice after injection of cHCC-CCA organoids. Histologically, the xenografts recapitulated the features of the original cHCC-CCA tumors, harboring both HCC and intrahepatic cholangiocarcinoma components within the same tumor. The establishment of patient-derived cHCC-CCA organoid lines with high tumorigenicity provides a valuable resource for the mechanistic investigation and drug development of this disease.
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Affiliation(s)
- Yun Gao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China
| | - Xiaoyun Chen
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Yuerong Zhu
- Department of Clinical Laboratory, Affiliated Hospital of Medical School, Jinling Hospital, Nanjing University, Nanjing, China
| | - Suiqing Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China
| | - Long Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China
| | - Qiuyue Wu
- Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China
- State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Hui Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China
| | - Ziyi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China
| | - Xuejiao Chen
- Department of General Surgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng, China
| | - Xinyi Xia
- Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China.
- State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China.
| | - Liyong Pu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China.
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
- NHC Key Laboratory of Hepatobiliary Cancers, The First Affiliated Hospital of Nanjing Medical University), Nanjing, China.
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Huang CF, Awad MH, Gal-Tanamy M, Yu ML. Unmet needs in the post-direct-acting antivirals era: The risk and molecular mechanisms of hepatocellular carcinoma after hepatitis C virus eradication. Clin Mol Hepatol 2024; 30:326-344. [PMID: 38665034 PMCID: PMC11261227 DOI: 10.3350/cmh.2024.0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 07/20/2024] Open
Abstract
Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Ph.D. Program in Translational Medicine, College of Medicine, Kaohsiung Medical University and Academia Sinica, Kaohsiung, Taiwan
| | - Manar Hijaze Awad
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Meital Gal-Tanamy
- Molecular Virology Lab, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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Kasuga R, Taniki N, Chu PS, Tamura M, Tabuchi T, Yamaguchi A, Hayatsu S, Koizumi J, Ojiro K, Hoshi H, Kaneko F, Morikawa R, Noguchi F, Yamataka K, Usui S, Ebinuma H, Itano O, Hasegawa Y, Abe Y, Kitago M, Inoue M, Nakatsuka S, Jinzaki M, Kitagawa Y, Kanai T, Nakamoto N. Multiple asynchronous recurrence as a predictive factor for refractoriness against locoregional and surgical therapy in patients with intermediate-stage hepatocellular carcinoma. Sci Rep 2024; 14:10896. [PMID: 38740983 DOI: 10.1038/s41598-024-61611-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child-Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child-Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44-2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3-5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes.
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Affiliation(s)
- Ryosuke Kasuga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masashi Tamura
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Takaya Tabuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Akihiro Yamaguchi
- Division of Gastroenterology, Department of Internal Medicine, National Hospital Organization Saitama National Hospital, Saitama, Japan
| | - Shigeo Hayatsu
- Department of Surgery, National Hospital Organization Saitama National Hospital, Saitama, Japan
| | - Jun Koizumi
- Department of Diagnostic Radiology and Radiation Oncology, School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Ojiro
- Department of Gastroenterology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Hitomi Hoshi
- Department of Gastroenterology and Hepatology, Saitama City Hospital, Saitama, Japan
| | - Fumihiko Kaneko
- Department of Gastroenterology and Hepatology, Saitama City Hospital, Saitama, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Fumie Noguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Karin Yamataka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shingo Usui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Department of Gastroenterology, School of Medicine, International University of Health and Welfare, Chiba, Japan
| | - Osamu Itano
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare School of Medicine, Chiba, Japan
| | - Yasushi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuta Abe
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Minoru Kitago
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masanori Inoue
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Seishi Nakatsuka
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Xu A, Sun M, Li Z, Chu Y, Fang K, Zhang Y, Lian J, Zhang L, Chen T, Xu M. ELF4 contributes to esophageal squamous cell carcinoma growth and metastasis by augmenting cancer stemness via FUT9. Acta Biochim Biophys Sin (Shanghai) 2024; 56:129-139. [PMID: 37674363 PMCID: PMC10875363 DOI: 10.3724/abbs.2023225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) commonly has aggressive properties and a poor prognosis. Investigating the molecular mechanisms underlying the progression of ESCC is crucial for developing effective therapeutic strategies. Here, by performing transcriptome sequencing in ESCC and adjacent normal tissues, we find that E74-like transcription factor 4 (ELF4) is the main upregulated transcription factor in ESCC. The results of the immunohistochemistry show that ELF4 is overexpressed in ESCC tissues and is significantly correlated with cancer staging and prognosis. Furthermore, we demonstrate that ELF4 could promote cancer cell proliferation, migration, invasion, and stemness by in vivo assays. Through RNA-seq and ChIP assays, we find that the stemness-related gene fucosyltransferase 9 ( FUT9) is transcriptionally activated by ELF4. Meanwhile, ELF4 is verified to affect ESCC cancer stemness by regulating FUT9 expression. Overall, we first discover that the transcription factor ELF4 is overexpressed in ESCC and can promote ESCC progression by transcriptionally upregulating the stemness-related gene FUT9.
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Affiliation(s)
- Aiping Xu
- Endoscopy CenterZhongshan HospitalSchool of MedicineFudan UniversityShanghai200032China
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
- Department of Gastroenterology and HepatologyJing’an District Centre HospitalFudan UniversityShanghai20032China
| | - Mingchuang Sun
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Zhaoxing Li
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Yuan Chu
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Kang Fang
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Yunwei Zhang
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Jingjing Lian
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Li Zhang
- Department of PathologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Tao Chen
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
| | - Meidong Xu
- Endoscopy CenterDepartment of GastroenterologyShanghai East HospitalSchool of MedicineTongji UniversityShanghai200120China
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8
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Lin D, Luo R, Ye Z, Wei Q, Bae H, Juon HS, Hann HW, Posey J, Wang C. Genomic characterization of early-stage hepatocellular carcinoma patients with Hepatitis B using circulating tumor DNA. Clin Res Hepatol Gastroenterol 2023; 47:102161. [PMID: 37307947 DOI: 10.1016/j.clinre.2023.102161] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology worldwide. Effective early detection strategies may facilitate curative therapies and improve survival. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as potential diagnostic markers of HCC in HBV-infected patients. METHODS We identified early stage (BCLC 0-A) HCC cases (n = 21) and patients without HCC (n = 14) from a cohort of Asian patients with HBV, undergoing surveillance between 2013 and 2017. Circulating cell-free DNA was isolated from blood samples, and assayed by next-generation sequencing of 23 genes implicated in HCC pathogenesis. Somatic mutations were identified using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic (ROC) analysis, we evaluated gene alterations and clinical factors in an exploratory early HCC detection model. RESULTS Mutant ARID1A, CTNNB1, TP53 genes were increased in HCC cases vs. non-HCC patients (85.7% vs 42.9%, P = 0.011; 42.9% vs 0%, P = 0.005; 100% vs 71.4%, P = 0.019, respectively). Using these three genes, AUC for discriminating HCC from non-HCC patients was 0.844 (95% confidence interval [CI]: 0.7317-0.9553). When combining these genes with clinical factors in an exploratory early HCC detection model, AUC increased from 0.7415 (using clinical factors alone) to 0.9354 (P = 0.041). CONCLUSION Genomic aberrations in ctDNA were more prevalent in HBV-infected HCC patients compared with patients without HCC. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant validation in future studies.
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Affiliation(s)
- Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
| | - Rui Luo
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Zhong Ye
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Qiang Wei
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Ho Bae
- Asia-Pacific Liver Center, Los Angeles, CA, USA
| | - Hee-Soon Juon
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hie Won Hann
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
| | - James Posey
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Chun Wang
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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9
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Perez S, Lavi-Itzkovitz A, Gidoni M, Domovitz T, Dabour R, Khurana I, Davidovich A, Tobar A, Livoff A, Solomonov E, Maman Y, El-Osta A, Tsai Y, Yu ML, Stemmer SM, Haviv I, Yaari G, Gal-Tanamy M. High-Resolution Genomic Profiling of Liver Cancer Links Etiology With Mutation and Epigenetic Signatures. Cell Mol Gastroenterol Hepatol 2023; 16:63-81. [PMID: 36965814 PMCID: PMC10212990 DOI: 10.1016/j.jcmgh.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/27/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a model of a diverse spectrum of cancers because it is induced by well-known etiologies, mainly hepatitis C virus (HCV) and hepatitis B virus. Here, we aimed to identify HCV-specific mutational signatures and explored the link between the HCV-related regional variation in mutations rates and HCV-induced alterations in genome-wide chromatin organization. METHODS To identify an HCV-specific mutational signature in HCC, we performed high-resolution targeted sequencing to detect passenger mutations on 64 HCC samples from 3 etiology groups: hepatitis B virus, HCV, or other. To explore the link between the genomic signature and genome-wide chromatin organization we performed chromatin immunoprecipitation sequencing for the transcriptionally permissive H3K4Me3, H3K9Ac, and suppressive H3K9Me3 modifications after HCV infection. RESULTS Regional variation in mutation rate analysis showed significant etiology-dependent regional mutation rates in 12 genes: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, and ARSD. We found an enrichment of C->T transversion mutations in the HCV-associated HCC cases. Furthermore, these cases showed regional variation in mutation rates associated with genomic intervals in which HCV infection dictated epigenetic alterations. This signature may be related to the HCV-induced decreased expression of genes encoding key enzymes in the base excision repair pathway. CONCLUSIONS We identified novel distinct HCV etiology-dependent mutation signatures in HCC associated with HCV-induced alterations in histone modification. This study presents a link between cancer-causing mutagenesis and the increased predisposition to liver cancer in chronic HCV-infected individuals, and unveils novel etiology-specific mechanisms leading to HCC and cancer in general.
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Affiliation(s)
- Shira Perez
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Cancer Personalized Medicine, Diagnostic Genomics Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Anat Lavi-Itzkovitz
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Bioengineering, Faculty of Engineering, Bar-Ilan University, Ramat-Gan, Israel
| | - Moriah Gidoni
- Bioengineering, Faculty of Engineering, Bar-Ilan University, Ramat-Gan, Israel
| | - Tom Domovitz
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Roba Dabour
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Ishant Khurana
- Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Ateret Davidovich
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Ana Tobar
- Institute of Pathology, Rabin Medical Center, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alejandro Livoff
- Department of Pathology, Barzilay Medical Center, Faculty of Medicine, Ben Gurion University, Beer Sheva, Israel
| | | | - Yaakov Maman
- The Laboratory of Genomic Instability and Cancer, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Assam El-Osta
- Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia; Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Yishan Tsai
- Hepatobiliary Division, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine and Hepatitis Research Center, College of Medicine, Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine and Hepatitis Research Center, College of Medicine, Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Salomon M Stemmer
- Davidoff Center, Rabin Medical Center, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Izhak Haviv
- Cancer Personalized Medicine, Diagnostic Genomics Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; AID Genomics, Ltd, Rehovot, Israel.
| | - Gur Yaari
- Bioengineering, Faculty of Engineering, Bar-Ilan University, Ramat-Gan, Israel; Bar-Ilan Institute of Nanotechnologies and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel.
| | - Meital Gal-Tanamy
- Molecular Virology Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
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10
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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11
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Identification of Prognostic Factors in Cholangiocarcinoma Based on Integrated ceRNA Network Analysis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7102736. [PMID: 36158120 PMCID: PMC9499749 DOI: 10.1155/2022/7102736] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 08/08/2022] [Accepted: 08/13/2022] [Indexed: 12/03/2022]
Abstract
This study is aimed at screening prognostic biomarkers in cholangiocarcinoma (CHOL) based on competitive endogenous RNA (ceRNA) regulatory network analysis. Microarray data for lncRNAs, mRNA, and miRNAs were downloaded from the GEO and TCGA databases. Differentially expressed RNAs (DERs) were identified in CHOL and normal liver tissue samples. WGCNA was used to identify disease-related gene modules. By integrating the information from the starBase and DIANA-LncBasev2 databases, we constructed a ceRNA network. Survival analysis was performed, and a prognostic gene-based prognostic score (PS) model was generated. The correlation between gene expression and immune cell infiltration or immune-related feature genes was analyzed using TIMER. Finally, real-time quantitative PCR (RT-qPCR) was used to verify the expression of the 10 DERs with independent prognosis. A large cohort of DERs was identified in the CHOL and control samples. The ceRNA network consisted of 6 lncRNAs, 2 miRNAs, 90 mRNAs, and 98 nodes. Ten genes were identified as prognosis-related genes, and a ten-gene signature PS model was constructed, which exhibited a good prognosis predictive ability for risk assessment of CHOL patients (AUC value = 0.975). Four genes, ELF4, AGXT, ABCG2, and LDHD, were associated with immune cell infiltration and closely correlated with immune-related feature genes (CD14, CD163, CD33, etc.) in CHOL. Additionally, the consistency rate of the RT-qPCR results and bioinformatics analysis was 80%, implying a relatively high reliability of the bioinformatic analysis results. Our findings suggest that the ten-signature gene PS model has significant prognostic predictive value for patients with CHOL. These four immune-related DERs are involved in the progression of CHOL and may be useful prognostic biomarkers for CHOLs.
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12
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Kiyose H, Nakagawa H, Ono A, Aikata H, Ueno M, Hayami S, Yamaue H, Chayama K, Shimada M, Wong JH, Fujimoto A. Comprehensive analysis of full-length transcripts reveals novel splicing abnormalities and oncogenic transcripts in liver cancer. PLoS Genet 2022; 18:e1010342. [PMID: 35926060 PMCID: PMC9380957 DOI: 10.1371/journal.pgen.1010342] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/16/2022] [Accepted: 07/14/2022] [Indexed: 12/24/2022] Open
Abstract
Genes generate transcripts of various functions by alternative splicing. However, in most transcriptome studies, short-reads sequencing technologies (next-generation sequencers) have been used, leaving full-length transcripts unobserved directly. Although long-reads sequencing technologies would enable the sequencing of full-length transcripts, the data analysis is difficult. In this study, we developed an analysis pipeline named SPLICE and analyzed cDNA sequences from 42 pairs of hepatocellular carcinoma (HCC) and matched non-cancerous livers with an Oxford Nanopore sequencer. Our analysis detected 46,663 transcripts from the protein-coding genes in the HCCs and the matched non-cancerous livers, of which 5,366 (11.5%) were novel. A comparison of expression levels identified 9,933 differentially expressed transcripts (DETs) in 4,744 genes. Interestingly, 746 genes with DETs, including the LINE1-MET transcript, were not found by a gene-level analysis. We also found that fusion transcripts of transposable elements and hepatitis B virus (HBV) were overexpressed in HCCs. In vitro experiments on DETs showed that LINE1-MET and HBV-human transposable elements promoted cell growth. Furthermore, fusion gene detection showed novel recurrent fusion events that were not detected in the short-reads. These results suggest the efficiency of full-length transcriptome studies and the importance of splicing variants in carcinogenesis. Genes generate transcripts of various functions by alternative splicing. However, in most transcriptome studies, short-reads sequencing technologies (next-generation sequencers) have been used, leaving full-length transcripts unobserved directly. In this study, we developed an analysis pipeline named SPLICE for long-read transcriptome sequencing and analyzed cDNA sequences from 42 pairs of hepatocellular carcinoma (HCC), and matched non-cancerous livers with an Oxford Nanopore sequencer. Our analysis detected 5,366 novel transcripts and 9,933 differentially expressed transcripts in 4,744 genes between HCCs and non-cancerous livers. An analysis of hepatitis B virus (HBV) transcripts showed that fusion transcripts of the HBV gene and human transposable elements were overexpressed in HBV-infected HCCs. We also identified fusion genes that were not found in the short-reads. These results suggest that long-reads sequencing technologies provide a fuller understanding of cancer transcripts and that our method contributes to the analysis of transcriptome sequences by such technologies.
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Affiliation(s)
- Hiroki Kiyose
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masaki Ueno
- Department of Surgery II, Wakayama Medical University, Wakayama, Japan
| | - Shinya Hayami
- Department of Surgery II, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Yamaue
- Department of Surgery II, Wakayama Medical University, Wakayama, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mihoko Shimada
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jing Hao Wong
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akihiro Fujimoto
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
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13
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Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report. Brain Tumor Pathol 2022; 39:171-178. [PMID: 35596897 DOI: 10.1007/s10014-022-00435-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 04/27/2022] [Indexed: 11/02/2022]
Abstract
BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.
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14
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Oe N, Takeda H, Eso Y, Takai A, Marusawa H. Clinical and Molecular Basis of Hepatocellular Carcinoma after Hepatitis C Virus Eradication. Pathogens 2022; 11:pathogens11040430. [PMID: 35456105 PMCID: PMC9028726 DOI: 10.3390/pathogens11040430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) arises in the background of chronic liver diseases, including hepatitis and liver cirrhosis caused by hepatitis C virus (HCV) infection. It is well known that HCV eradication using antiviral drugs can efficiently inhibit hepatocarcinogenesis. Recent advances in and development of direct-acting antiviral (DAA) drugs has revolutionized the treatment of HCV infection, and the vast majority of HCV patients can achieve HCV eradication using DAAs. However, mounting evidence clearly indicates that HCC inevitably occurs in a subset of patients after successful viral eradication using DAA therapy. Cancer is a genetic disease, and the accumulation of genetic and epigenetic aberrations may cause hepatocarcinogenesis in chronically damaged liver, even after virus elimination. In this review, we highlight HCC development after HCV eradication and discuss the current understanding of the molecular mechanisms of tumorigenesis after virus elimination, focusing on the genetic and epigenetic background of chronically damaged liver tissues.
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Affiliation(s)
- Natsumi Oe
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
- Correspondence: ; Tel.: +81-6-6774-5111; Fax: +81-6-6774-5131
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15
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Takeda H, Takai A, Eso Y, Takahashi K, Marusawa H, Seno H. Genetic Landscape of Multistep Hepatocarcinogenesis. Cancers (Basel) 2022; 14:568. [PMID: 35158835 PMCID: PMC8833551 DOI: 10.3390/cancers14030568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/22/2021] [Accepted: 01/15/2022] [Indexed: 12/04/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Although several targeted therapy agents are available for advanced HCC, their antitumor efficacy remains limited. As the complex genetic landscape of HCC would compromise the antitumor efficacy of targeted therapy, a deeper understanding of the genetic landscape of hepatocarcinogenesis is necessary. Recent comprehensive genetic analyses have revealed the driver genes of HCC, which accumulate during the multistage process of hepatocarcinogenesis, facilitating HCC genetic heterogeneity. In addition, as early genetic changes may represent key therapeutic targets, the genetic landscapes of early HCC and precancerous liver tissues have been characterized in recent years, in parallel with the advancement of next-generation sequencing analysis. In this review article, we first summarize the landscape of the liver cancer genome and its intratumor heterogeneity. We then introduce recent insight on early genetic alterations in hepatocarcinogenesis, especially those in early HCC and noncancerous liver tissues. Finally, we summarize the multistep accumulation of genetic aberrations throughout cancer progression and discuss the future perspective towards the clinical application of this genetic information.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (H.T.); (Y.E.); (K.T.); (H.S.)
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (H.T.); (Y.E.); (K.T.); (H.S.)
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (H.T.); (Y.E.); (K.T.); (H.S.)
| | - Ken Takahashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (H.T.); (Y.E.); (K.T.); (H.S.)
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka 543-8555, Japan;
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (H.T.); (Y.E.); (K.T.); (H.S.)
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16
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Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas. Mod Pathol 2021; 34:2200-2210. [PMID: 34302054 DOI: 10.1038/s41379-021-00873-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 12/28/2022]
Abstract
BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.
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Yim SY, Lee JS. An Overview of the Genomic Characterization of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:1077-1088. [PMID: 34522690 PMCID: PMC8434863 DOI: 10.2147/jhc.s270533] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/18/2021] [Indexed: 02/03/2023] Open
Abstract
Tumor classifications based on alterations in the genome, epigenome, or proteome have revealed distinct tumor subgroups that are associated with clinical outcomes. Several landmark studies have demonstrated that such classifications can significantly improve patient outcomes by enabling tailoring of therapy to specific alterations in cancer cells. Since cancer cells accumulate numerous alterations in many cancer-related genes, it is a daunting task to find and confirm important cancer-promoting alterations as therapeutic targets or biomarkers that can predict clinical outcomes such as survival and response to treatments. To aid further advances, we provide here an overview of the current understanding of molecular and genomic subtypes of hepatocellular carcinoma (HCC). System-level integration of data from multiple studies and development of new technical platforms for analyzing patient samples hold great promise for the discovery of new targets for treatment and correlated biomarkers, leading to personalized medicine for treatment of HCC patients.
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Affiliation(s)
- Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
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18
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Li YT, Wu HL, Liu CJ. Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1. Int J Mol Sci 2021; 22:9380. [PMID: 34502289 PMCID: PMC8431721 DOI: 10.3390/ijms22179380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis.
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Affiliation(s)
- Yung-Tsung Li
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Hui-Lin Wu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
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19
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Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13092095. [PMID: 33926021 PMCID: PMC8123716 DOI: 10.3390/cancers13092095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/15/2021] [Accepted: 04/22/2021] [Indexed: 12/19/2022] Open
Abstract
Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005-2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163-3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990-2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
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20
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Molina-Sánchez P, Ruiz de Galarreta M, Yao MA, Lindblad KE, Bresnahan E, Bitterman E, Martin TC, Rubenstein T, Nie K, Golas J, Choudhary S, Bárcena-Varela M, Elmas A, Miguela V, Ding Y, Kan Z, Grinspan LT, Huang KL, Parsons RE, Shields DJ, Rollins RA, Lujambio A. Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma. Gastroenterology 2020; 159:2203-2220.e14. [PMID: 32814112 PMCID: PMC7726023 DOI: 10.1053/j.gastro.2020.08.015] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/29/2020] [Accepted: 08/11/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. METHODS By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. RESULTS Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. CONCLUSIONS This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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Affiliation(s)
- Pedro Molina-Sánchez
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marina Ruiz de Galarreta
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Melissa A Yao
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York
| | - Katherine E Lindblad
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York
| | - Erin Bresnahan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Elizabeth Bitterman
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tiphaine C Martin
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Troy Rubenstein
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kai Nie
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | - Marina Bárcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Abdulkadir Elmas
- Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Veronica Miguela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ying Ding
- Oncology R&D, Pfizer Inc, San Diego, California
| | | | - Lauren Tal Grinspan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Ramon E Parsons
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York.
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21
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Takeda H, Takai A, Kumagai K, Iguchi E, Arasawa S, Eso Y, Shimizu T, Ueda Y, Taura K, Uemoto S, Kita R, Haga H, Marusawa H, Fujimoto A, Seno H. Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution. J Pathol 2020; 252:398-410. [PMID: 32815153 DOI: 10.1002/path.5533] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/22/2020] [Accepted: 08/10/2020] [Indexed: 01/04/2025]
Abstract
Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eriko Iguchi
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryuichi Kita
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Akihiro Fujimoto
- Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
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22
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Abstract
Adenosarcoma can mimic high-grade endometrial stromal sarcoma with ZC3H7B-BCOR fusion that may show entrapped glands and often exhibits diffuse BCOR expression. We encountered diffuse BCOR expression in rare adenosarcomas and sought to define its frequency among a larger cohort of these tumors. BCOR immunohistochemistry was performed on archival formalin-fixed paraffin-embedded tumor tissue in 13 of 14 adenosarcomas with and without stromal overgrowth arising in the uterus or ovary. The staining intensity and percentage of positive tumor nuclei in the mesenchymal component were evaluated. Eleven cases with sufficient tumoral tissue were subjected to fluorescence in situ hybridization for the detection of BCOR, BCORL1, NUTM1, ZC3H7B, and JAZF1 rearrangement. Three cases were subjected to targeted RNA sequencing. BCOR was expressed in 9 of 13 (70%) tumors, including 6 with and 3 without stromal overgrowth. Moderate to strong staining in >70% of cells was seen throughout in 1 low-grade and 6 high-grade tumors, 5 of which had stromal overgrowth. No staining was seen in 3 low-grade and 1 high-grade tumors with stromal overgrowth. One tumor demonstrating extensive sex cord-like differentiation and diffuse BCOR expression harbored JAZF1 and BCORL1 rearrangements. No BCOR or BCORL1 rearrangement was identified in the remaining tumors. BCOR expression is seen in most adenosarcomas with and without stromal overgrowth. BCORL1 rearrangement is seen in rare tumors with diffuse BCOR expression. Assessment of BCOR or BCORL1 rearrangement status is required in adenosarcomas demonstrating BCOR expression.
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Abstract
Primary liver cancer (PLC) is a fatal disease that affects millions of lives worldwide. PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades. PLC can be categorized into three major histological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC. These subtypes are distinct with respect to epidemiology, clinicopathological features, genetic alterations, and clinical managements, which are thoroughly summarized in this review. The state of treatment strategies for each subtype, including the currently approved drugs and the potential novel therapies, are also discussed.
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Affiliation(s)
- Mei Feng
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Yisheng Pan
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Ruirui Kong
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
| | - Shaokun Shu
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of Biomedical Engineering, Peking University, Beijing 100871, China
- Peking University Cancer Hospital, Beijing 100142, China
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24
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Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M, Goldani F, Parizadeh SMR, Hassanian SM, Ghayour-Mobarhan M, Ferns GA, Avan A. MicroRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma. Curr Drug Targets 2020; 20:1129-1140. [PMID: 30848198 DOI: 10.2174/1389450120666190307095720] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the second most common cause of cancer-associated death globally. One of the major reasons for this high rate of mortality is a failure to make an early diagnosis. The average survival in untreated HCC patients is estimated to be approximately three months. The 5-year overall survival rate after radical resection is about 15-40% and within two years, more than two third of patients experience a relapse. To date, the most common biomarker which has been used for the diagnosis of HCC is serum alpha-fetoprotein (AFP). However, there is a lack of sensitive and specific tumor biomarkers for the early diagnosis of HCC. MicroRNAs are a class of short endogenous RNA with crucial role in many biological activities and cellular pathways and can be found in various tissues and body fluids. The aim of this review was to summarize the results of recent studies investigating miRNAs as novel biomarkers for the early diagnosis and prognostic risk stratification of patients with this type of liver cancer.
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Affiliation(s)
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Ghandehari
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of medical sciences, Mashhad, Iran
| | - Fatemeh Goldani
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of medical sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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25
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Han XJ, Ma XL, Yang L, Wei YQ, Peng Y, Wei XW. Progress in Neoantigen Targeted Cancer Immunotherapies. Front Cell Dev Biol 2020; 8:728. [PMID: 32850843 PMCID: PMC7406675 DOI: 10.3389/fcell.2020.00728] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/14/2020] [Indexed: 02/05/2023] Open
Abstract
Immunotherapies that harness the immune system to kill cancer cells have showed significant therapeutic efficacy in many human malignancies. A growing number of studies have highlighted the relevance of neoantigens in recognizing cancer cells by intrinsic T cells. Cancer neoantigens are a direct consequence of somatic mutations presenting on the surface of individual cancer cells. Neoantigens are fully cancer-specific and exempt from central tolerance. In addition, neoantigens are important targets for checkpoint blockade therapy. Recently, technological innovations have made neoantigen discovery possible in a variety of malignancies, thus providing an impetus to develop novel immunotherapies that selectively enhance T cell reactivity for the destruction of cancer cells while leaving normal tissues unharmed. In this review, we aim to introduce the methods of the identification of neoantigens, the mutational patterns of human cancers, related clinical trials, neoantigen burden and sensitivity to immune checkpoint blockade. Moreover, we focus on relevant challenges of targeting neoantigens for cancer treatment.
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26
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Shi HS, Wang S, Li MJ, Wu LQ. A Hepatocellular Carcinoma Patient with TSC1 Mutations Benefits from Treatment with Everolimus: A Case Report. Visc Med 2020; 37:116-119. [PMID: 33981751 DOI: 10.1159/000505950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 01/14/2020] [Indexed: 11/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high degree of malignancy and poor prognosis. Treatment options for patients with advanced HCC are limited. There is currently no evidence to approve the accumulation of targeted therapies for HCC to support the inhibition of the PI3K/Akt/mTOR signaling pathway as an effective therapeutic strategy. We report on a patient with advanced HCC carrying the TSC1 gene mutation who responded well to the mammalian target of rapamycin inhibitor everolimus. Computed tomography revealed tumor shrinkage and maintenance of partial remission after everolimus treatment for >12.3 months. To the best of our knowledge, this is the first clinical case report showing benefit from everolimus treatment in HCC patients with TSC1 gene mutations. Therefore, everolimus may be used as a potential targeted therapy for HCC with TSC1 gene mutation.
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Affiliation(s)
- Hua-Sheng Shi
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China.,Medical College of Qingdao University, Qingdao University, Qingdao, China
| | - Shuo Wang
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China.,Medical College of Qingdao University, Qingdao University, Qingdao, China
| | - Man-Jiang Li
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China.,Medical College of Qingdao University, Qingdao University, Qingdao, China
| | - Li-Qun Wu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China.,Medical College of Qingdao University, Qingdao University, Qingdao, China
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27
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Zhou Q, Li Z, Song L, Mu D, Wang J, Tian L, Liao Y. Whole-exome mutational landscape of metastasis in patient-derived hepatocellular carcinoma cells. Genes Dis 2020; 7:380-391. [PMID: 32884992 PMCID: PMC7452411 DOI: 10.1016/j.gendis.2020.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/29/2020] [Accepted: 05/09/2020] [Indexed: 02/06/2023] Open
Abstract
In order to explore the genomic basis for liver cancer metastasis, whole-exome sequencing (WES) was performed on patient-derived hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials and analyzed their clonal evolution relationships. An evolutionary tree based on genomic single nucleotide polymorphism (SNP) was constructed in MegaX software. The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55% (range, 15.38%–18.17%). C: G > T: A and T: A > C: G somatic transitions were the two most frequent substitutions. In these metastatic HCC cell lines, non-silent gene mutations were found in 21.88% of known driver genes and 10 classical signaling pathways. The protein interaction network was constructed by STRING, and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively. In cBioPortal database, some of the selected hub genes were found to be associated with poor overall survival (OS) of HCC patients. Among the mutated HCC driver genes, a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells. In conclusion, WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo, and they do indeed have a genetic relationship at the genomic level.
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Key Words
- BTB, Broad-complex, Tramtrack, and Bric-a-brac
- CDS, coding for amino acids in protein
- CNC, cap’n’collar
- CTR, C-terminal region
- CUL3, Cullin3
- Clonal evolution
- DGR, DC domain harboring six Kelch-repeat domain
- Encyclopedia of genes and genomes (KEGG)
- FA, fatty acid
- GO, Gene Ontology
- Gene ontology (GO)
- Genome-wide association
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- IVR, intervening region
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- Metastatic potentiality
- NTR, N-terminal region
- OS, overall survival
- SNP, single nucleotide polymorphism
- Somatic gene mutation
- WES, whole exome sequencing
- Whole exome sequencing
- bZIP, basic-region leucine zipper
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Affiliation(s)
- Qian Zhou
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zuli Li
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Linlan Song
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Di Mu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jin Wang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Tian
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yong Liao
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China.,Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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28
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Li T, Zhang G, Wang L, Li S, Xu X, Gao Y. Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:225. [PMID: 32363190 PMCID: PMC7182440 DOI: 10.3389/fcell.2020.00225] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 03/16/2020] [Indexed: 02/05/2023] Open
Abstract
Background and Aims Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of non-inflammatory HCC remains unclear. Methods Spontaneous non-inflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific TSC1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results We showed that LTsc1KO in mice triggered spontaneous non-inflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated non-cirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1, and fibroblast growth factor 21), and mTORC1-signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of non-inflammatory HCC. Conclusion Our findings reveal the mechanisms of mTORC1-driven non-inflammatory HCC and provide insight into further development of a protective strategy against non-inflammatory HCC.
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Affiliation(s)
- Ting Li
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Guohong Zhang
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Shantou University Medical College, Shantou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linlin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Susu Li
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaoping Xu
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Artificial Organs and Tissue Engineering Centre of Guangdong Province, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Artificial Organs and Tissue Engineering Centre of Guangdong Province, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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29
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Rao BC, Lou JM, Wang WJ, Li A, Cui GY, Yu ZJ, Ren ZG. Human microbiome is a diagnostic biomarker in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2020; 19:109-115. [PMID: 32037278 DOI: 10.1016/j.hbpd.2020.01.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 01/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Increasing evidence indicates a close relationship between HCC and the human microbiota. Herein, we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC. DATA SOURCES Several innovative studies have investigated the characteristics of the gut and oral microbiomes in patients with HCC and proposed that the human microbiome has the potential to be a diagnostic biomarker of HCC. Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords "microbiota" or "microbiome" or "microbe" and "liver cancer" or "hepatocellular carcinoma", and the results of clinical and experimental studies were analyzed. RESULTS Specific changes occur in the human microbiome of patients with HCC. Moreover, the gut microbiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC. Furthermore, they also have certain diagnostic potential for precancerous diseases of HCC. The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future. CONCLUSIONS The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC. The human microbiome may be widely used in the diagnosis, treatment and prognosis for multiple system diseases or cancers in the future.
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Affiliation(s)
- Ben-Chen Rao
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jia-Min Lou
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Wei-Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Ang Li
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Guang-Ying Cui
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhi-Gang Ren
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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30
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Lu L, Daigle BJ. Prognostic analysis of histopathological images using pre-trained convolutional neural networks: application to hepatocellular carcinoma. PeerJ 2020; 8:e8668. [PMID: 32201640 PMCID: PMC7073245 DOI: 10.7717/peerj.8668] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Histopathological images contain rich phenotypic descriptions of the molecular processes underlying disease progression. Convolutional neural networks, state-of-the-art image analysis techniques in computer vision, automatically learn representative features from such images which can be useful for disease diagnosis, prognosis, and subtyping. Hepatocellular carcinoma (HCC) is the sixth most common type of primary liver malignancy. Despite the high mortality rate of HCC, little previous work has made use of CNN models to explore the use of histopathological images for prognosis and clinical survival prediction of HCC. We applied three pre-trained CNN models-VGG 16, Inception V3 and ResNet 50-to extract features from HCC histopathological images. Sample visualization and classification analyses based on these features showed a very clear separation between cancer and normal samples. In a univariate Cox regression analysis, 21.4% and 16% of image features on average were significantly associated with overall survival (OS) and disease-free survival (DFS), respectively. We also observed significant correlations between these features and integrated biological pathways derived from gene expression and copy number variation. Using an elastic net regularized Cox Proportional Hazards model of OS constructed from Inception image features, we obtained a concordance index (C-index) of 0.789 and a significant log-rank test (p = 7.6E-18). We also performed unsupervised classification to identify HCC subgroups from image features. The optimal two subgroups discovered using Inception model image features showed significant differences in both overall (C-index = 0.628 and p = 7.39E-07) and DFS (C-index = 0.558 and p = 0.012). Our work demonstrates the utility of extracting image features using pre-trained models by using them to build accurate prognostic models of HCC as well as highlight significant correlations between these features, clinical survival, and relevant biological pathways. Image features extracted from HCC histopathological images using the pre-trained CNN models VGG 16, Inception V3 and ResNet 50 can accurately distinguish normal and cancer samples. Furthermore, these image features are significantly correlated with survival and relevant biological pathways.
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Affiliation(s)
- Liangqun Lu
- Departments of Biological Sciences and Computer Science, The University of Memphis, Memphis, TN, USA
| | - Bernie J. Daigle
- Departments of Biological Sciences and Computer Science, The University of Memphis, Memphis, TN, USA
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31
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McEvoy CR, Fox SB, Prall OWJ. Emerging entities in NUTM1-rearranged neoplasms. Genes Chromosomes Cancer 2020; 59:375-385. [PMID: 32060986 DOI: 10.1002/gcc.22838] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 12/11/2022] Open
Abstract
Structural alterations of NUTM1 were originally thought to be restricted to poorly differentiated carcinomas with variable squamous differentiation originating in the midline organs of children and adolescents. Termed NUT carcinomas (NCs), they were defined by a t(15;19) chromosomal rearrangement that was found to result in a BRD4-NUTM1 gene fusion. However, the use of DNA and RNA-based next-generation sequencing has recently revealed a multitude of new NUTM1 fusion partners in a diverse array of neoplasms including sarcoma-like tumors, poromas, and acute lymphoblastic leukemias (ALLs) that we propose to call NUTM1-rearranged neoplasms (NRNs). Intriguingly, the nosology of NRNs often correlates with the functional classification of the fusion partner, suggesting different oncogenic mechanisms within each NRN division. Indeed, whereas NCs are characterized by their aggressiveness and intransigence to standard therapeutic measures, the more positive clinical outcomes seen in some sarcoma and ALL NRNs may reflect these mechanistic differences. Here we provide a broad overview of the molecular, nosological, and clinical features in these newly discovered neoplastic entities. We describe how aberrant expression of NUTM1 due to fusion with an N-terminal DNA/chromatin-binding protein can generate a potentially powerful chromatin modifier that can give rise to oncogenic transformation in numerous cellular contexts. We also conclude that classification, clinical behavior, and therapeutic options may be best defined by the NUTM1 fusion partner rather than by tumor morphology or immunohistochemical profile.
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Affiliation(s)
- Christopher R McEvoy
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Stephen B Fox
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Owen W J Prall
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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32
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DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma. Oncogene 2020; 39:3229-3244. [PMID: 32071398 DOI: 10.1038/s41388-020-1215-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 01/04/2023]
Abstract
Liver hepatocellular carcinoma (LIHC) is the second leading cause of cancer mortality worldwide. Although cancer driver genes identified so far have been considered to be saturated or nearly saturated, challenges remain in discovering novel genes underlying carcinogenesis due to significant tumor heterogeneity. Here, in a small cohort of hepatitis B virus (HBV)-associated LIHC, we investigated the transcriptional patterns of tumor-mutated alleles using both whole-exome and RNA sequencing data. A graph clustering of the transcribed tumor-mutated alleles characterized overlapped functional clusters, and thus prioritized potentially novel oncogenes. We validated the function of the potentially novel oncogenes in vitro and in vivo. We showed that a component of the retromer complex-the vacuolar protein sorting-associated protein 35 (VPS35)-promoted the proliferation of hepatoma cell through the PI3K/AKT signaling pathway. In VPS35-knockout hepatoma cells, a significantly reduced distribution of membrane fibroblast growth factor receptor 3 (FGFR3) demonstrated the effects of VPS35 on sorting and trafficking of transmembrane receptor. This study provides insight into the roles of the retromer complex on carcinogenesis and has important implications for the development of personalized therapeutic strategies for LIHC.
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33
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Huang FY, Wong DKH, Tsui VWM, Seto WK, Mak LY, Cheung TT, Lai KKY, Yuen MF. Targeted genomic profiling identifies frequent deleterious mutations in FAT4 and TP53 genes in HBV-associated hepatocellular carcinoma. BMC Cancer 2019; 19:789. [PMID: 31395065 PMCID: PMC6686555 DOI: 10.1186/s12885-019-6002-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/31/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV-associated HCC pathogenesis is still unclear. Genetic alterations in cancer-related genes have been linked to many human cancers. Here, we aimed to explore genetic alterations in selected cancer-related genes in patients with HBV-associated HCC. METHODS Targeted sequencing was used to analyze six cancer-related genes (PIK3CA, TP53, FAT4, IRF2, HNF4α and ARID1A) in eight pairs of HBV-associated HCC tumors and their adjacent non-tumor tissues. Sanger sequencing, quantitative PCR, Western-blotting and RNAi-mediated gene knockdown were used to further validate findings. RESULTS Targeted sequencing revealed thirteen non-synonymous mutations, of which 9 (69%) were found in FAT4 and 4 (31%) were found in TP53 genes. Non-synonymous mutations were not found in PIK3CA, IRF2, HNF4α and ARID1A. Among these 13 non-synonymous mutations, 12 (8 in FAT4 and 4 in TP53) were predicted to have deleterious effect on protein function by in silico analysis. For TP53, Y220S, R249S and P250R non-synonymous mutations were solely identified in tumor tissues. Further expression profiling of FAT4 and TP53 on twenty-eight pairs of HCC tumor and non-tumor tissues confirmed significant downregulation of both genes in HCC tumors compared with their non-tumor counterparts (P < 0.001 and P < 0.01, respectively). Functional analysis using RNAi-mediated knockdown of FAT4 revealed an increased cancer cell growth and proliferation, suggesting the putative tumor suppressor role of FAT4 in HCC. CONCLUSIONS This study highlights the importance of FAT4 and TP53 in HCC pathogenesis and identifies new genetic variants that may have potentials for development of precise therapy for HCC.
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Affiliation(s)
- Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Vivien Wai-Man Tsui
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong
| | - Keane K-Y Lai
- Depatment of Pathology, City of Hope National Medical Center, Duarte, CA, USA.,Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.,City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, Hong Kong. .,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, Hong Kong.
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34
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Ji H, Zhou Y, Zhuang X, Zhu Y, Wu Z, Lu Y, Li S, Zeng Y, Lu QR, Huo Y, Shi Y, Bu H. HDAC3 Deficiency Promotes Liver Cancer through a Defect in H3K9ac/H3K9me3 Transition. Cancer Res 2019; 79:3676-3688. [PMID: 31097476 PMCID: PMC6679938 DOI: 10.1158/0008-5472.can-18-3767] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/10/2019] [Accepted: 05/09/2019] [Indexed: 02/05/2023]
Abstract
DNA damage triggers diverse cancers, particularly hepatocellular carcinoma (HCC), but the intrinsic link between DNA damage and tumorigenesis remains unclear. Because of its role as an epigenetic and transcriptional regulator, histone deacetylase 3 (HDAC3) is essential for DNA damage control and is often aberrantly expressed in human HCC. In this study, we used individual class I HDAC member-deficient mice to demonstrate that K9 in histone H3 (H3K9), which is the critical site for the assembly of DNA damage response complexes, is exclusively targeted by HDAC3. Ablation of HDAC3 disrupted the deacetylation and consequent trimethylation of H3K9 (H3K9me3), the first step in double-strand break repair, and led to the accumulation of damaged DNA. Simultaneously, hyperacetylated H3K9 (H3K9ac) served as a transcriptional activator and enhanced multiple signaling pathways to promote tumorigenesis. Together, these results show that HDAC3 targets the H3K9ac/H3K9me3 transition to serve as a critical regulator that controls both DNA damage repair and the transcription of many tumor-related genes. Moreover, these findings provide novel insights into the link between DNA damage and transcriptional reprogramming in tumorigenesis. SIGNIFICANCE: These findings show that HDAC3 exclusively regulates H3K9ac in response to DNA damage, and loss of HDAC3 activity shifts the balance from DNA damage control to protumorigenic transcriptional activity.
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Affiliation(s)
- Hongjie Ji
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
- School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Yongjie Zhou
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Zhuang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongjie Zhu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenru Wu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Yannrong Lu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Shengfu Li
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Qing R Lu
- Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Yanying Huo
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Yujun Shi
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Bu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
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35
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Kim SK, Takeda H, Takai A, Matsumoto T, Kakiuchi N, Yokoyama A, Yoshida K, Kaido T, Uemoto S, Minamiguchi S, Haga H, Shiraishi Y, Miyano S, Seno H, Ogawa S, Marusawa H. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J Gastroenterol 2019; 54:628-640. [PMID: 30756187 DOI: 10.1007/s00535-019-01555-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 01/30/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing. METHODS We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs. RESULTS Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression. CONCLUSION Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.
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Affiliation(s)
- Soo Ki Kim
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Kobe Asahi Hospital, Kobe, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Omics-Based Medicine, Center for Preventive Medicine, Chiba University, Chiba, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Tomonori Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akira Yokoyama
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenichi Yoshida
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Yuichi Shiraishi
- Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoru Miyano
- Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. .,Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
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36
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Chan LK, Ng IOL. Proteomic profiling in liver cancer: another new page. Transl Gastroenterol Hepatol 2019; 4:47. [PMID: 31304424 DOI: 10.21037/tgh.2019.06.03] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 06/03/2019] [Indexed: 12/14/2022] Open
Affiliation(s)
- Lo-Kong Chan
- Department of Pathology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
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37
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Cho W, Jin X, Pang J, Wang Y, Mivechi NF, Moskophidis D. The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways. Mol Cell Biol 2019; 39:e00391-18. [PMID: 30745413 PMCID: PMC6469921 DOI: 10.1128/mcb.00391-18] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/21/2018] [Accepted: 02/04/2019] [Indexed: 02/06/2023] Open
Abstract
Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC but also for the development of diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several cochaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, the HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of the carcinogen-induced DNA damage response, at the tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and this may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently, activation of a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) negative feedback pathway diminishes oncogenic signals, thereby attenuating premalignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.
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Affiliation(s)
- Wonkyoung Cho
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Xiongjie Jin
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Junfeng Pang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Yan Wang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Nahid F Mivechi
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Radiology and Imaging, Augusta University, Augusta, Georgia, USA
| | - Demetrius Moskophidis
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Medicine, Augusta University, Augusta, Georgia, USA
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38
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Udden SN, Kwak YT, Godfrey V, Khan MAW, Khan S, Loof N, Peng L, Zhu H, Zaki H. NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife 2019; 8:40396. [PMID: 30990169 PMCID: PMC6483596 DOI: 10.7554/elife.40396] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 03/25/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
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Affiliation(s)
- Sm Nashir Udden
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Youn-Tae Kwak
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States.,Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
| | - Victoria Godfrey
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Md Abdul Wadud Khan
- Department of Surgical Oncology, MD Anderson Cancer Center, Houston, United States
| | - Shahanshah Khan
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Nicolas Loof
- Children's Research Institute, UT Southwestern Medical Center, Dallas, United States
| | - Lan Peng
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Hao Zhu
- Children's Research Institute, UT Southwestern Medical Center, Dallas, United States.,Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States.,Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, United States.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
| | - Hasan Zaki
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
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Shukla A, Girisha KM, Somashekar PH, Nampoothiri S, McClellan R, Vernon HJ. Variants in the transcriptional corepressor BCORL1 are associated with an X-linked disorder of intellectual disability, dysmorphic features, and behavioral abnormalities. Am J Med Genet A 2019; 179:870-874. [PMID: 30941876 DOI: 10.1002/ajmg.a.61118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 02/08/2019] [Accepted: 02/25/2019] [Indexed: 11/05/2022]
Abstract
BCORL1, a transcriptional corepressor, is involved in negative gene regulation through associations with several protein complexes including Class II histone deacetylases (HDACs). Acquired somatic mutations in BCORL1 have been implicated in the pathogenesis of several malignancies, but germline mutations of BCORL1 have not been associated with a specific genetic syndrome. We report five individuals from three pedigrees with phenotypes including intellectual disability, behavioral difficulties, and dysmorphic features who were found via whole exome sequencing to have variants in BCORL1. In silico analysis of these variants strongly suggests pathogenicity. We propose that hemizygous pathogenic variants in BCORL1 underlie a newly identified X-linked epigenetic syndrome.
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Affiliation(s)
- Anju Shukla
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Puneeth H Somashekar
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sheela Nampoothiri
- Department of Paediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India
| | - Rebecca McClellan
- Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland
| | - Hilary J Vernon
- Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
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Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities. Mol Cell 2019; 74:421-435.e10. [PMID: 30926243 DOI: 10.1016/j.molcel.2019.02.029] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 12/13/2018] [Accepted: 02/20/2019] [Indexed: 12/12/2022]
Abstract
Deubiquitinases have emerged as promising drug targets for cancer therapy. The two DUBs USP25 and USP28 share high similarity but vary in their cellular functions. USP28 is known for its tumor-promoting role, whereas USP25 is a regulator of the innate immune system and, recently, a role in tumorigenesis was proposed. We solved the structures of the catalytic domains of both proteins and established substantial differences in their activities. While USP28 is a constitutively active dimer, USP25 presents an auto-inhibited tetramer. Our data indicate that the activation of USP25 is not achieved through substrate or ubiquitin binding. USP25 cancer-associated mutations lead to activation in vitro and in vivo, thereby providing a functional link between auto-inhibition and the cancer-promoting role of the enzyme. Our work led to the identification of significant differences between USP25 and USP28 and provided the molecular basis for the development of new and highly specific anti-cancer drugs.
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Latysheva NS, Babu MM. Molecular Signatures of Fusion Proteins in Cancer. ACS Pharmacol Transl Sci 2019; 2:122-133. [PMID: 32219217 PMCID: PMC7088938 DOI: 10.1021/acsptsci.9b00019] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Indexed: 01/07/2023]
Abstract
![]()
Although gene fusions
are recognized as driver mutations in a wide
variety of cancers, the general molecular mechanisms underlying oncogenic
fusion proteins are insufficiently understood. Here, we employ large-scale
data integration and machine learning and (1) identify three functionally
distinct subgroups of gene fusions and their molecular signatures;
(2) characterize the cellular pathways rewired by fusion events across
different cancers; and (3) analyze the relative importance of over
100 structural, functional, and regulatory features of ∼2200
gene fusions. We report subgroups of fusions that likely act as driver
mutations and find that gene fusions disproportionately affect pathways
regulating cellular shape and movement. Although fusion proteins are
similar across different cancer types, they affect cancer type-specific
pathways. Key indicators of fusion-forming proteins include high and
nontissue specific expression, numerous splice sites, and higher centrality
in protein-interaction networks. Together, these findings provide
unifying and cancer type-specific trends across diverse oncogenic
fusion proteins.
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Affiliation(s)
- Natasha S Latysheva
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom
| | - M Madan Babu
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom
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NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. Am J Surg Pathol 2019; 42:636-645. [PMID: 29356724 DOI: 10.1097/pas.0000000000001021] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
NUT midline carcinoma is an aggressive tumor that occurs mainly in the head and neck and, less frequently, the mediastinum and lung. Following identification of an index case of a NUTM1 fusion positive undifferentiated soft tissue tumor, we interrogated additional cases of primary undifferentiated soft tissue and visceral tumors for NUTM1 abnormalities. Targeted next-generation sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue, and results validated by fluorescence in situ hybridization using custom bacterial artificial chromosome probes. Six patients were identified: mean age of 42 years (range, 3 to 71 y); equal sex distribution; and, tumors involved the extremity soft tissues (N=2), kidney (N=2), stomach, and brain. On systemic work-up at presentation all patients lacked a distant primary tumor. Morphologically, the tumors were heterogenous, with undifferentiated round-epithelioid-rhabdoid cells arranged in solid sheets, nests, and cords. Mitotic activity was generally brisk. Four cases expressed pancytokeratin, but in only 2 cases was this diffuse. Next-generation sequencing demonstrated the following fusions: BRD4-NUTM1 (3 cases), BRD3-NUTM1, MXD1-NUTM1, and BCORL1-NUTM1. Independent testing by fluorescence in situ hybridization confirmed the presence of NUTM1 and partner gene rearrangement. This study establishes that NUT-associated tumors transgress the midline and account for a subset of primitive neoplasms occurring in soft tissue and viscera. Tumors harboring NUTM1 gene fusions are presumably underrecognized, and the extent to which they account for undifferentiated mesenchymal, neuroendocrine, and/or epithelial neoplasms is unclear. Moreover, the relationship, if any, between NUT-associated tumors in soft tissue and/or viscera, and conventional NUT carcinoma, remains to be elucidated.
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Chaudhary K, Poirion OB, Lu L, Huang S, Ching T, Garmire LX. Multimodal Meta-Analysis of 1,494 Hepatocellular Carcinoma Samples Reveals Significant Impact of Consensus Driver Genes on Phenotypes. Clin Cancer Res 2019; 25:463-472. [PMID: 30242023 PMCID: PMC6542354 DOI: 10.1158/1078-0432.ccr-18-0088] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 05/28/2018] [Accepted: 09/17/2018] [Indexed: 01/04/2023]
Abstract
Although driver genes in hepatocellular carcinoma (HCC) have been investigated in various previous genetic studies, prevalence of key driver genes among heterogeneous populations is unknown. Moreover, the phenotypic associations of these driver genes are poorly understood. This report aims to reveal the phenotypic impacts of a group of consensus driver genes in HCC. We used MutSigCV and OncodriveFM modules implemented in the IntOGen pipeline to identify consensus driver genes across six HCC cohorts comprising 1,494 samples in total. To access their global impacts, we used The Cancer Genome Atlas (TCGA) mutations and copy-number variations to predict the transcriptomics data, under generalized linear models. We further investigated the associations of the consensus driver genes to patient survival, age, gender, race, and risk factors. We identify 10 consensus driver genes across six HCC cohorts in total. Integrative analysis of driver mutations, copy-number variations, and transcriptomic data reveals that these consensus driver mutations and their copy-number variations are associated with a majority (62.5%) of the mRNA transcriptome but only a small fraction (8.9%) of miRNAs. Genes associated with TP53, CTNNB1, and ARID1A mutations contribute to the tripod of most densely connected pathway clusters. These driver genes are significantly associated with patients' overall survival. Some driver genes are significantly linked to HCC gender (CTNNB1, ALB, TP53, and AXIN1), race (TP53 and CDKN2A), and age (RB1) disparities. This study prioritizes a group of consensus drivers in HCC, which collectively show vast impacts on the phenotypes. These driver genes may warrant as valuable therapeutic targets of HCC.
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Affiliation(s)
| | - Olivier B Poirion
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
| | - Liangqun Lu
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
- Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, Hawaii
| | - Sijia Huang
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
- Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, Hawaii
| | - Travers Ching
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
- Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, Hawaii
| | - Lana X Garmire
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
- Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, Hawaii
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44
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Popa ML, Albulescu R, Neagu M, Hinescu ME, Tanase C. Multiplex assay for multiomics advances in personalized-precision medicine. J Immunoassay Immunochem 2019; 40:3-25. [PMID: 30632882 DOI: 10.1080/15321819.2018.1562940] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Building the future of precision medicine is the main focus in cancer domain. Clinical trials are moving toward an array of studies that are more adapted to precision medicine. In this domain, there is an enhanced need for biomarkers, monitoring devices, and data-analysis methods. Omics profiling using whole genome, epigenome, transcriptome, proteome, and metabolome can offer detailed information of the human body in an integrative manner. Omes profiles reflect more accurately real-time physiological status. Personalized omics analyses both disease as a whole and the main disease processes, for a better understanding of the individualized health. Through this, multi-omic approaches for health monitoring, preventative medicine, and personalized treatment can be targeted simultaneously and can lead clinicians to have a comprehensive view on the diseasome.
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Affiliation(s)
- Maria-Linda Popa
- a Biochemistry-Proteomics Department , Victor Babes National Institute of Pathology , Bucharest , Romania
- b Cellular and Molecular Biology and Histology Department , "Carol Davila" University of Medicine and Pharmacy , Bucharest , Romania
| | - Radu Albulescu
- a Biochemistry-Proteomics Department , Victor Babes National Institute of Pathology , Bucharest , Romania
- c Pharmaceutical Biotechnology Department , National Institute for Chemical-Pharmaceutical R&D , Bucharest , Romania
| | - Monica Neagu
- a Biochemistry-Proteomics Department , Victor Babes National Institute of Pathology , Bucharest , Romania
- d Faculty of Biology , University of Bucharest , Bucharest , Romania
| | - Mihail Eugen Hinescu
- a Biochemistry-Proteomics Department , Victor Babes National Institute of Pathology , Bucharest , Romania
- b Cellular and Molecular Biology and Histology Department , "Carol Davila" University of Medicine and Pharmacy , Bucharest , Romania
| | - Cristiana Tanase
- a Biochemistry-Proteomics Department , Victor Babes National Institute of Pathology , Bucharest , Romania
- e Cajal Institute , Titu Maiorescu University , Bucharest , Romania
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45
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Hung MH, Wang XW. Molecular Alterations and Heterogeneity in Hepatocellular Carcinoma. MOLECULAR AND TRANSLATIONAL MEDICINE 2019. [DOI: 10.1007/978-3-030-21540-8_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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46
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Okrah K, Tarighat S, Liu B, Koeppen H, Wagle MC, Cheng G, Sun C, Dey A, Chang MT, Sumiyoshi T, Mounir Z, Cummings C, Hampton G, Amler L, Fridlyand J, Hegde PS, Turley SJ, Lackner MR, Huang SM. Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of disease progression and tumor immune biology. NPJ Precis Oncol 2018; 2:25. [PMID: 30456308 PMCID: PMC6237857 DOI: 10.1038/s41698-018-0068-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) develops in the context of chronic inflammatory liver disease and has an extremely poor prognosis. An immunosuppressive tumor microenvironment may contribute to therapeutic failure in metastatic HCC. Here, we identified unique molecular signatures pertaining to HCC disease progression and tumor immunity by analyzing genome-wide RNA-Seq data derived from HCC patient tumors and non-tumor cirrhotic tissues. Unsupervised clustering of gene expression data revealed a gradual suppression of local tumor immunity that coincided with disease progression, indicating an increasingly immunosuppressive tumor environment during HCC disease advancement. IHC examination of the spatial distribution of CD8+ T cells in tumors revealed distinct intra- and peri-tumoral subsets. Differential gene expression analysis revealed an 85-gene signature that was significantly upregulated in the peri-tumoral CD8+ T cell-excluded tumors. Notably, this signature was highly enriched with components of underlying extracellular matrix, fibrosis, and epithelial-mesenchymal transition (EMT). Further analysis condensed this signature to a core set of 23 genes that are associated with CD8+ T cell localization, and were prospectively validated in an independent cohort of HCC specimens. These findings suggest a potential association between elevated fibrosis, possibly modulated by TGF-β, PDGFR, SHH or Notch pathway, and the T cell-excluded immune phenotype. Indeed, targeting fibrosis using a TGF-β neutralizing antibody in the STAM™ model of murine HCC, we found that ameliorating the fibrotic environment could facilitate redistribution of CD8+ lymphocytes into tumors. Our results provide a strong rationale for utilizing immunotherapies in HCC earlier during treatment, potentially in combination with anti-fibrotic therapies.
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Affiliation(s)
- K. Okrah
- Department of Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. Tarighat
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - B. Liu
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - H. Koeppen
- Department of Research Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. C. Wagle
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - G. Cheng
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - C. Sun
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - A. Dey
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. T. Chang
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - T. Sumiyoshi
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - Z. Mounir
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - C. Cummings
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - G. Hampton
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - L. Amler
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - J. Fridlyand
- Department of Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - P. S. Hegde
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. J. Turley
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. R. Lackner
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. M. Huang
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
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Lee G, Jeong YS, Kim DW, Kwak MJ, Koh J, Joo EW, Lee JS, Kah S, Sim YE, Yim SY. Clinical significance of APOB inactivation in hepatocellular carcinoma. Exp Mol Med 2018; 50:1-12. [PMID: 30429453 PMCID: PMC6235894 DOI: 10.1038/s12276-018-0174-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 07/03/2018] [Accepted: 07/18/2018] [Indexed: 12/19/2022] Open
Abstract
Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.
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Affiliation(s)
- Gena Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Seong Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Do Won Kim
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Min Jun Kwak
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Wook Joo
- Department of Gynecology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Susie Kah
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Yeong-Eun Sim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Sun Young Yim
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,Department of Internal Medicine, Korea University, College of Medicine, Seoul, Korea.
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48
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Huang W, Skanderup AJ, Lee CG. Advances in genomic hepatocellular carcinoma research. Gigascience 2018; 7:5232228. [PMID: 30521023 PMCID: PMC6335342 DOI: 10.1093/gigascience/giy135] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the cancer with the second highest mortality in the world due to its late presentation and limited treatment options. As such, there is an urgent need to identify novel biomarkers for early diagnosis and to develop novel therapies. The availability of next-generation sequencing (NGS) data from tumors of liver cancer patients has provided us with invaluable resources to better understand HCC through the integration of data from different sources to facilitate the identification of promising biomarkers or therapeutic targets. Findings Here, we review key insights gleaned from more than 20 NGS studies of HCC tumor samples, comprising approximately 582 whole genomes and 1,211 whole exomes mainly from the East Asian population. Through consolidation of reported somatic mutations from multiple studies, we identified genes with different types of somatic mutations, including single nucleotide variations, insertion/deletions, structural variations, and copy number alterations as well as genes with multiple frequent viral integration. Pathway analysis showed that this curated list of somatic mutations is critically involved in cancer-related pathways, viral carcinogenesis, and signaling pathways. Lastly, we addressed the future directions of HCC research as more NGS datasets become available. Conclusions Our review is a comprehensive resource for the current NGS research in HCC, consolidating published articles, potential gene candidates, and their related biological pathways.
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Affiliation(s)
- Weitai Huang
- Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Graduate School of Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 117456, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Anders Jacobsen Skanderup
- Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
| | - Caroline G Lee
- Graduate School of Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 117456, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Singapore 169610, Singapore.,Duke-NUS Graduate Medical School Singapore, Singapore 169547, Singapore
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Petrizzo A, Tagliamonte M, Mauriello A, Costa V, Aprile M, Esposito R, Caporale A, Luciano A, Arra C, Tornesello ML, Buonaguro FM, Buonaguro L. Unique true predicted neoantigens (TPNAs) correlates with anti-tumor immune control in HCC patients. J Transl Med 2018; 16:286. [PMID: 30340600 PMCID: PMC6194606 DOI: 10.1186/s12967-018-1662-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/09/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND A novel prediction algorithm is needed for the identification of effective tumor associated mutated neoantigens. Only those with no homology to self wild type antigens are true predicted neoantigens (TPNAs) and can elicit an antitumor T cell response, not attenuated by central tolerance. To this aim, the mutational landscape was evaluated in HCV-associated hepatocellular carcinoma. METHODS Liver tumor biopsies and adjacent non-tumor liver tissues were obtained from 9 HCV-chronically infected subjects and subjected to RNA-Seq analysis. Mutant peptides were derived from single nucleotide variations and TPNAs were predicted using two prediction servers (e.g. NetTepi and NetMHCstabpan) by comparison with corresponding wild-type sequences, non-related self and pathogen-related antigens. Immunological confirmation was obtained in preclinical as well as clinical setting. RESULTS The development of such an improved algorithm resulted in a handful of TPNAs despite the large number of predicted neoantigens. Furthermore, TPNAs may share homology to pathogen's antigens and be targeted by a pre-existing T cell immunity. Cross-reactivity between such antigens was confirmed in an experimental pre-clinical setting. Finally, TPNAs homologous to pathogen's antigens were found in the only HCC long-term survival patient, suggesting a correlation between the pre-existing T cell immunity specific for these TPNAs and the favourable clinical outcome. CONCLUSIONS The new algorithm allowed the identification of the very few TPNAs in cancer cells, and those targeted by a pre-existing immunity strongly correlated with long-term survival. Only such TPNAs represent the optimal candidates for immunotherapy strategies.
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Affiliation(s)
- Annacarmen Petrizzo
- Laboratory of Cancer Immunoregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, Via Mariano Semmola, 1, 80131 Naples, Italy
| | - Maria Tagliamonte
- Laboratory of Cancer Immunoregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, Via Mariano Semmola, 1, 80131 Naples, Italy
| | - Angela Mauriello
- Laboratory of Cancer Immunoregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, Via Mariano Semmola, 1, 80131 Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), National Research Council, 80131 Naples, Italy
| | - Marianna Aprile
- Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), National Research Council, 80131 Naples, Italy
| | - Roberta Esposito
- Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), National Research Council, 80131 Naples, Italy
| | - Andrea Caporale
- Institute of Biostructures and Biomaging (IBB), National Research Council, 80134 Naples, Italy
| | - Antonio Luciano
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, 80131 Naples, Italy
| | - Claudio Arra
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, 80131 Naples, Italy
| | - Maria Lina Tornesello
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, 80131 Naples, Italy
| | - Franco M. Buonaguro
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, 80131 Naples, Italy
| | - Luigi Buonaguro
- Laboratory of Cancer Immunoregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione Pascale”-IRCCS, Via Mariano Semmola, 1, 80131 Naples, Italy
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Comprehensive assessment for miRNA polymorphisms in hepatocellular cancer risk: a systematic review and meta-analysis. Biosci Rep 2018; 38:BSR20180712. [PMID: 29976775 PMCID: PMC6153371 DOI: 10.1042/bsr20180712] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 06/23/2018] [Accepted: 07/04/2018] [Indexed: 02/07/2023] Open
Abstract
MiRNA polymorphisms had potential to be biomarkers for hepatocellular cancer (HCC) susceptibility. Recently, miRNA single nucleotide polymorphisms (SNPs) were reported to be associated with HCC risk, but the results were inconsistent. We performed a systematic review with a meta-analysis for the association of miRNA SNPs with HCC risk. Thirty-seven studies were included with a total of 11821 HCC patients and 15359 controls in this meta-analysis. We found hsa-mir-146a rs2910164 was associated with a decreased HCC risk in the recessive model (P=0.017, OR = 0.90, 95% confidence interval (CI) = 0.83–0.98). While hsa-mir-34b/c rs4938723 was related with an increased HCC risk in the co-dominant model (P=0.016, odds ratio (OR) = 1.19, 95%CI = 1.03–1.37). When analyzing the Hepatitis B virus (HBV)-related HCC risk, hsa-mir-196a-2 rs11614913 was associated with a decreased HBV-related HCC risk in the co-dominant and allelic models. And hsa-mir-149 rs2292832 was found to be associated with a decreased HBV-related HCC risk in the dominant and recessive models. In conclusion, hsa-mir-146a rs2910164 and hsa-mir-34b/c rs4938723 could be biomarkers for the HCC risk while hsa-mir-196a-2 rs11614913 and hsa-mir-149 rs2292832 had potential to be biomarkers for HBV-related HCC risk.
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