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Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clin Mol Hepatol 2025; 31:S255-S284. [PMID: 39604328 PMCID: PMC11925447 DOI: 10.3350/cmh.2024.0541] [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: 07/10/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.
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Affiliation(s)
- Jaeho Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Vatche G Agopian
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica S Liu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Ekaterina K Koltsova
- Smidt Heart Institute, Department of Medicine, Department of Biomedical Sciences, 8700 Beverly Blvd, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Solhi R, Pourhamzeh M, Zarrabi A, Hassan M, Mirzaei H, Vosough M. Novel biomarkers for monitoring and management of hepatocellular carcinoma. Cancer Cell Int 2024; 24:428. [PMID: 39719624 DOI: 10.1186/s12935-024-03600-1] [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: 01/28/2024] [Accepted: 12/05/2024] [Indexed: 12/26/2024] Open
Abstract
Due to current challenges in the early detection, less than 40% of individuals diagnosed with hepatocellular carcinoma (HCC) are viable candidates for surgical intervention. Therefore, validating and launching of a novel precise diagnostic approach is essential for early diagnosis. Based on developing evidence using circulating tumor cells and their derivatives, circulating miRNAs, and extracellular vesicles (EVs), liquid biopsy may offer a reliable platform for the HCC's early diagnosis. Each liquid biopsy analyte may provide significant areas for diagnosis, prognostic assessment, and treatment monitoring of HCC patients depending on its kind, sensitivity, and specificity. The current review addresses potential clinical applications, current research, and future developments for liquid biopsy in HCC management.
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Affiliation(s)
- Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Pourhamzeh
- Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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3
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Kumar S, Poria R, Kala D, Nagraik R, Dhir Y, Dhir S, Singh B, Kaushik NK, Noorani MS, Kumar D, Gupta S, Kaushal A. Recent advances in ctDNA detection using electrochemical biosensor for cancer. Discov Oncol 2024; 15:517. [PMID: 39356360 PMCID: PMC11448507 DOI: 10.1007/s12672-024-01365-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/18/2024] [Indexed: 10/03/2024] Open
Abstract
In the quest for early cancer diagnosis, early identification and treatment are paramount. Recently, ctDNA detection has emerged as a viable avenue for early screening of cancer. The examination of ctDNA in fluid biopsies has gained substantial attention in tumor diagnosis and therapy. Both the scientific community and industry are actively exploring this field. However, developing cost-effective, portable, and real-time ctDNA measurement methods using conventional gene detection equipment poses a significant challenge. This challenge has led to the exploration of alternative approaches. Electrochemical biosensors, distinguished by their heightened sensitivity, remarkable specificity, affordability, and excellent portability, have emerged as a promising avenue for ctDNA detection. This review is dedicated to the specific focus on ctDNA detection, highlighting recent advancements in this evolving detection technology. We aimed to reference previous studies related to ctDNA-targeted cancer detection using electrochemical biosensors to advocate the utilization of electrochemical biosensors in healthcare diagnostics. Further research is imperative for the effective integration of ctDNA analysis into point-of-care cancer testing. Innovative approaches utilizing multiple markers need to be explored to advance this technology and make substantial contributions to societal well-being.
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Affiliation(s)
- Sahil Kumar
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India
| | - Renu Poria
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India
| | - Deepak Kala
- NL-11 Centera Tetrahertz Laboratory, Institute of High Pressure Physics, Polish Academy of Sciences, 29/37 Sokolowska Street, Warsaw, 01142, Poland
| | - Rupak Nagraik
- School of Bioengineering and Food Technology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh, India
| | - Yashika Dhir
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India
| | - Sunny Dhir
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India
| | - Bharat Singh
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India
| | - Naveen Kumar Kaushik
- Department of Industrial Biotechnology, College of Biotechnology, Chaudhary Charan Singh Haryana Agricultural University, Hisar, Haryana, India
| | - Md Salik Noorani
- Department of Botany, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, 173229, Himachal Pradesh, India.
| | - Shagun Gupta
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India.
| | - Ankur Kaushal
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be) University, Mullana, 133203, Ambala, India.
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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Hu L, Ji YY, Zhu P, Lu RQ. Mutation-Selected Amplification droplet digital PCR: A new single nucleotide variant detection assay for TP53 R249S mutant in tumor and plasma samples. Anal Chim Acta 2024; 1318:342929. [PMID: 39067934 DOI: 10.1016/j.aca.2024.342929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/21/2024] [Accepted: 06/30/2024] [Indexed: 07/30/2024]
Abstract
The early detection of gene mutations in physiological and pathological processes is a powerful approach to guide decisions in precision medicine. However, detecting low-copy mutant DNA from clinical samples poses a challenge due to the enrichment of wild-type DNA backgrounds. In this study, we devised a novel strategy, named Mutation-Selected Amplification droplet digital PCR (MSA-ddPCR), to quantitatively analyze single nucleotide variants (SNVs) at low variant allele frequencies (VAFs). Using TP53R249S (a hotspot mutation associated with hepatocellular carcinoma) as a model, we optimized the concentration ratio of primers, the annealing temperature and nucleic acid amplification modifiers. Subsequently, we evaluated the linear range and precision of MSA-ddPCR by detecting TP53R249S and TP53wild-type (TP53WT) plasmid DNA, respectively. MSA-ddPCR demonstrated superior ability to discriminate between mutant DNA and wild-type DNA compared to traditional TaqMan-MGB PCR. We further applied MSA-ddPCR to analyze the TP53R249S mutation in 20 plasma samples and 15 formalin-fixed paraffin-embedded (FFPE) tissue samples, and assessed the agreement rates between MSA-ddPCR and amplicon high-throughput sequencing. The results showed that the limit of blanks of MSA-ddPCR are 0.449 copies μL-1 in the FAM channel and 0.452 copies μL-1 in the VIC channel. MSA-ddPCR could accurately quantify VAFs as low as 0.01 %, surpassing existing PCR and next-generation sequencing (NGS) methods. In the detection of clinical samples, a high correlation was found between MSA-ddPCR and amplicon high-throughput sequencing. Additionally, MSA-ddPCR outperformed sequencing methods in terms of detection time and simplicity of data analysis. MSA-ddPCR can be easily implemented into clinical practice and serve as a robust tool for detecting mutant genes due to its high sensitivity and accuracy.
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Affiliation(s)
- Ling Hu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 20032, China
| | - Yuan-Ye Ji
- Department of Medical Laboratory, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Peng Zhu
- Department of Medical Laboratory, Ningbo No.2 Hospital, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China.
| | - Ren-Quan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 20032, China.
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Tsuruoka M, Ninomiya M, Inoue J, Iwata T, Sano A, Sato K, Onuki M, Sawahashi S, Masamune A. Changes in Mutations of Cell-Free DNA and Liver Tumor Tissue in Patients with Advanced Hepatocellular Carcinoma before and after Introduction of Lenvatinib. Oncology 2024; 102:1072-1083. [PMID: 39047713 PMCID: PMC11614310 DOI: 10.1159/000540438] [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: 03/10/2024] [Accepted: 07/07/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. METHODS We analyzed cfDNA before and 6-8 weeks after the start of treatment in 20 advanced HCC patients who started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, -124C>T and -146C>T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. Computerized tomography evaluation was performed at 6-8 weeks and 3-4 months to assess the efficacy. RESULTS Frequencies of TERT promoter, CTNNB1, and TP53 mutations in pretreatment cfDNA were 45%, 65%, and 65%, but 53%, 41%, and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. CONCLUSION This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs.
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Affiliation(s)
- Mio Tsuruoka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan,
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kosuke Sato
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masazumi Onuki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Satoko Sawahashi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Peruhova M, Banova-Chakarova S, Miteva DG, Velikova T. Genetic screening of liver cancer: State of the art. World J Hepatol 2024; 16:716-730. [PMID: 38818292 PMCID: PMC11135278 DOI: 10.4254/wjh.v16.i5.716] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria
| | - Sonya Banova-Chakarova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria.
| | - Dimitrina Georgieva Miteva
- Department of Genetics, Faculty of Biology, Sofia University" St. Kliment Ohridski, Sofia 1164, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Han JE, Cho HJ. Exploring the prognostic value of ultra-low-pass whole-genome sequencing of circulating tumor DNA in hepatocellular carcinoma. Clin Mol Hepatol 2024; 30:160-163. [PMID: 38414374 PMCID: PMC11016494 DOI: 10.3350/cmh.2024.0141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 02/24/2024] [Indexed: 02/29/2024] Open
Affiliation(s)
- Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Du S, Cao K, Yan Y, Wang Y, Wang Z, Lin D. Developments and current status of cell-free DNA in the early detection and management of hepatocellular carcinoma. J Gastroenterol Hepatol 2024; 39:231-244. [PMID: 37990622 DOI: 10.1111/jgh.16416] [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: 07/25/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/23/2023]
Abstract
Nowadays, hepatocellular carcinoma (HCC) is still a major threat to human health globally, with a disappointing prognosis. Regular monitoring of patients at high risk, utilizing abdominal ultrasonography combined with alpha-fetoprotein (AFP) serum analysis, enables the early detection of potentially treatable tumors. However, the approach has limitations due to its lack of sensitivity. Meanwhile, the current standard procedure for obtaining a tumor biopsy in cases of HCC is invasive and lacks the ability to assess the dynamic progression of cancer or account for tumor heterogeneity. Hence, there is a pressing need to develop non-invasive, highly sensitive biomarkers for HCC which can improve the accuracy of early diagnosis, assess treatment response and accurately predict the prognosis. In contrast to the conventional method of tissue biopsy, liquid biopsy offers a non-invasive approach that can be readily repeated. As a liquid biopsy approach, the analysis of cell-free DNA (cfDNA) offers real-time insights that can accurately portray the tumor burden and provide a comprehensive depiction of the genetic profile associated with HCC. In this review, we present a comprehensive summary of the recent research findings pertaining to the significance and potential practicality of cfDNA analysis in the early detection and effective management of HCC.
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Affiliation(s)
- Sihao Du
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Ke Cao
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yadong Yan
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yupeng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhenshun Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Dongdong Lin
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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Beaufrère A, Paisley S, Ba I, Laouirem S, Priori V, Cazier H, Favre L, Cauchy F, Lesurtel M, Calderaro J, Kannengiesser C, Paradis V. Differential diagnosis of small hepatocellular nodules in cirrhosis: surrogate histological criteria of TERT promoter mutations. Histopathology 2024; 84:473-481. [PMID: 37903649 DOI: 10.1111/his.15086] [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: 06/28/2023] [Revised: 09/25/2023] [Accepted: 10/14/2023] [Indexed: 11/01/2023]
Abstract
AIMS The differential diagnosis of small hepatocellular nodules in cirrhosis between dysplastic nodules and hepatocellular carcinoma (HCC) remains challenging on biopsy. As TERT promoter (pTERT) mutations may indicate the nodules already engaged in the malignant process, the aim of this study was to identify histological criteria associated with pTERT mutations by detecting these mutations by ddPCR in small formalin-fixed paraffin-embedded (FFPE) hepatocellular nodules arising in cirrhosis. METHODS AND RESULTS We built a bicentric cohort data set of 339 hepatocellular nodules < 2 cm from cirrhotic samples, divided into a test cohort of 299 resected samples and a validation cohort of 40 biopsies. Pathological review, based on the evaluation of 14 histological criteria, classified all nodules. pTERT mutations were identified by ddPCR in FFPE samples. Among the 339 nodules, ddPCR revealed pTERT mutations in 105 cases (31%), including 90 and 15 cases in the test and validation cohorts, respectively. On multivariate analysis, three histological criteria were associated with pTERT mutations in the test cohort: increased cell density (P = 0.003), stromal invasion (P = 0.036) and plate-thickening anomalies (P < 0.001). With the combination of at least two of these major criteria, the AUC for predicting pTERT mutations was 0.84 in the test cohort (sensitivity: 86%, specificity: 83%) and 0.81 in the validation cohort (sensitivity: 87%, specificity: 76%). CONCLUSIONS We identified three histological criteria as surrogate markers of pTERT mutations that may be used in routine biopsy to more clearly classify small hepatocellular nodules arising in cirrhosis.
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Affiliation(s)
- Aurélie Beaufrère
- Université Paris Cité, Paris, France
- AP-HP.Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Sarah Paisley
- AP-HP.Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Ibrahima Ba
- AP-HP.Nord, Department of Molecular Genetics, Bichat Hospital, Paris, France
| | - Samira Laouirem
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Victoria Priori
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Hélène Cazier
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Loëtitia Favre
- AP-HP, Department of Pathology, Henri Mondor Hospital, Créteil, France
| | - François Cauchy
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Mickael Lesurtel
- Université Paris Cité, Paris, France
- AP-HP.Nord, Department of HPB Surgery an d Liver Transplantation, Beaujon Hospital, Clichy, France
| | - Julien Calderaro
- AP-HP, Department of Pathology, Henri Mondor Hospital, Créteil, France
| | | | - Valérie Paradis
- Université Paris Cité, Paris, France
- AP-HP.Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
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Huang A, Guo DZ, Zhang X, Sun Y, Zhang SY, Zhang X, Fu XT, Wang YP, Yang GH, Sun QM, He YF, Song K, Huang XW, Yang XR, Liu WR, Ding ZB, Shi YH, Fan J, Zhou J. Serial circulating tumor DNA profiling predicts tumor recurrence after liver transplantation for liver cancer. Hepatol Int 2024; 18:254-264. [PMID: 37980313 DOI: 10.1007/s12072-023-10594-x] [Citation(s) in RCA: 2] [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: 04/26/2023] [Accepted: 09/04/2023] [Indexed: 11/20/2023]
Abstract
BACKGROUND Minimal residual disease (MRD) is proposed to be responsible for tumor recurrence. The role of circulating tumor DNA (ctDNA) to detect MRD, monitor recurrence, and predict prognosis in liver cancer patients undergoing liver transplantation (LT) remains unrevealed. METHODS Serial blood samples were collected to profile ctDNA mutational changes. Baseline ctDNA mutational profiles were compared with those of matched tumor tissues. Correlations between ctDNA status and recurrence rate (RR) and recurrence-free survival (RFS) were analyzed, respectively. Dynamic change of ctDNA was monitored to predict tumor recurrence. RESULTS Baseline mutational profiles of ctDNA were highly concordant with those of tumor tissues (median, 89.85%; range 46.2-100%) in the 74 patients. Before LT, positive ctDNA status was associated with higher RR (31.7% vs 11.5%; p = 0.001) and shorter RFS than negative ctDNA status (17.8 vs 19.4 months; p = 0.019). After LT, the percentage of ctDNA positivity decreased (17.6% vs 47.0%; p < 0.001) and patients with positive ctDNA status had higher RR (46.2% vs 21.3%; p < 0.001) and shorter RFS (17.2 vs 19.2 months; p = 0.010). Serial ctDNA profiling demonstrated patients with decreased or constant negative ctDNA status had lower RR (33.3% vs 50.0%; p = 0.015) and favorable RFS (18.2 vs 15.0 months, p = 0.003) than those with increased or constant positive ctDNA status. Serial ctDNA profiling predicted recurrence months ahead of imaging evidence and serum tumor biomarkers. CONCLUSIONS ctDNA could effectively detect MRD and predict tumor recurrence in liver cancer patients undergone LT.
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Affiliation(s)
- Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - De-Zhen Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xuan Zhang
- Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, 310030, China
- GenomiCare Biotechnology (Shanghai) Co., Ltd., 5th Floor, Building #2, No. 111 Xiangke Road, Shanghai, 201210, China
| | - Ying Sun
- GenomiCare Biotechnology (Shanghai) Co., Ltd., 5th Floor, Building #2, No. 111 Xiangke Road, Shanghai, 201210, China
| | - Shi-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiu-Tao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yu-Peng Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Guo-Huan Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qi-Man Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yi-Feng He
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kang Song
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiao-Wu Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei-Ren Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhen-Bin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China
| | - Ying-Hong Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200031, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
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12
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Manea I, Iacob R, Iacob S, Cerban R, Dima S, Oniscu G, Popescu I, Gheorghe L. Liquid biopsy for early detection of hepatocellular carcinoma. Front Med (Lausanne) 2023; 10:1218705. [PMID: 37809326 PMCID: PMC10556479 DOI: 10.3389/fmed.2023.1218705] [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: 05/08/2023] [Accepted: 08/30/2023] [Indexed: 10/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly prevalent and lethal cancer globally. Over 90% of HCC cases arise in the context of liver cirrhosis, and the severity of the underlying liver disease or advanced tumor stage at diagnosis significantly limits treatment options. Early diagnosis is crucial, and all guidelines stress the importance of screening protocols for HCC early detection as a public health objective. As serum biomarkers are not optimal for early diagnosis, liquid biopsy has emerged as a promising tool for diagnosis, prognostication, and patients' stratification for personalized therapy in various solid tumors, including HCC. While circulating tumor cells (CTCs) are better suited for personalized therapy and prognosis, cell-free DNA (cfDNA) and extracellular vesicle-based technologies show potential for early diagnosis, HCC screening, and surveillance protocols. Evaluating the added value of liquid biopsy genetic and epigenetic biomarkers for HCC screening is a key goal in translational research. Somatic mutations commonly found in HCC can be investigated in cfDNA and plasma exosomes as genetic biomarkers. Unique methylation patterns in cfDNA or cfDNA fragmentome features have been suggested as innovative tools for early HCC detection. Likewise, extracellular vesicle cargo biomarkers such as miRNAs and long non-coding RNAs may serve as potential biomarkers for early HCC detection. This review will explore recent findings on the utility of liquid biopsy for early HCC diagnosis. Combining liquid biopsy methods with traditional serological biomarkers could improve the overall diagnostic accuracy for early HCC detection.
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Affiliation(s)
- Ioana Manea
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Iacob
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Speranta Iacob
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Cerban
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Simona Dima
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Gabriel Oniscu
- Transplant Division, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - Irinel Popescu
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Liliana Gheorghe
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
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Biglari N, Soltani-Zangbar MS, Mohammadian J, Mehdizadeh A, Abbasi K. ctDNA as a novel and promising approach for cancer diagnosis: a focus on hepatocellular carcinoma. EXCLI JOURNAL 2023; 22:752-780. [PMID: 37720239 PMCID: PMC10502204 DOI: 10.17179/excli2023-6277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 07/26/2023] [Indexed: 09/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer worldwide. Therefore, it is essential to diagnose and treat HCC patients promptly. As a novel discovery, circulating tumor DNA (ctDNA) can be used to analyze the tumor type and the cancer location. Additionally, ctDNA assists the cancer stage determination, which enables medical professionals to provide patients with the most appropriate treatment. This review will discuss the HCC-related mutated genes diagnosed by ctDNA. In addition, we will introduce the different and the most appropriate ctDNA diagnosis approaches based on the facilities.
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Affiliation(s)
- Negin Biglari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamal Mohammadian
- School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khadijeh Abbasi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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Kumar S, Nadda N, Quadri A, Kumar R, Paul S, Tanwar P, Gamanagatti S, Dash NR, Saraya A, Shalimar, Nayak B. Assessments of TP53 and CTNNB1 gene hotspot mutations in circulating tumour DNA of hepatitis B virus-induced hepatocellular carcinoma. Front Genet 2023; 14:1235260. [PMID: 37593116 PMCID: PMC10429180 DOI: 10.3389/fgene.2023.1235260] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
Background: Hepatitis B virus (HBV) infection is one of the major causes of chronic liver disease, which progresses from chronic hepatitis B (CHB) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Early detection and laboratory-based screening of hepatocellular carcinoma are still major challenges. This study was undertaken to determine whether the cancer hallmark gene signatures that are released into circulation as circulating tumour DNA (ctDNA) can be used as a liquid biopsy marker for screening, early detection, and prognosis of HCC. Methods: A total of 130 subjects, including HBV-HCC (n = 80), HBV-cirrhotic and non-cirrhotic (n = 35), and healthy (n = 15) controls, were evaluated for TP53 and beta-catenin (CTNNB1) gene hotspot mutations in ctDNA by Sanger-based cycle sequencing and droplet digital PCR (ddPCR) assays. Mutation detection frequency, percentage mutant fractions, and their association with tumour stage, mortality, and smoking habits were determined. Results: Sanger-based cycle sequencing was carried out for 32 HCC patients. Predict SNP Tools analysis indicated several pathogenic driver mutations in the ctDNA sequence, which include p.D228N, p.C229R, p.H233R, p.Y234D, p.S240T, p.G245S, and p.R249M for TP53 gene exon 7 and p.S33T for CTNNB1 gene exon 3. The TP53 c.746G>T (p.R249M) mutation was detected predominately (25% cases) by sequencing, but there was no dominant mutation at position c.747G>T (p.R249S) that was reported for HBV-HCC patients. A dual-probe ddPCR assay was developed to determine mutant and wild-type copy numbers of TP53 (p.R249M and p.R249S) and CTNNB1 (p.S45P) and their percentage mutant fraction in all 130 subjects. The TP53 R249M and CTNNB1 S45P mutations were detected in 31.25% and 26.25% of HCC patients, respectively, with a high mutant-to-wild-type fraction percentage (1.81% and 1.73%), which is significant as compared to cirrhotic and non-cirrhotic patients. Poor survival was observed in HCC patients with combined TP53 and CTNNB1 gene driver mutations. The TP53 R249M mutation was also significantly (p < 0.0001) associated with smoking habits (OR, 11.77; 95% CI, 3.219-36.20), but not the same for the TP53 R249S mutation. Conclusion: Screening of ctDNA TP53 and CTNNB1 gene mutations by ddPCR may be helpful for early detection and identifying the risk of HCC progression.
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Affiliation(s)
- Sonu Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Neeti Nadda
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Afnan Quadri
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Rahul Kumar
- Laboratory Oncology Unit (BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | - Shashi Paul
- Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Pranay Tanwar
- Laboratory Oncology Unit (BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | | | - Nihar Ranjan Dash
- Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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15
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Kopystecka A, Patryn R, Leśniewska M, Budzyńska J, Kozioł I. The Use of ctDNA in the Diagnosis and Monitoring of Hepatocellular Carcinoma-Literature Review. Int J Mol Sci 2023; 24:ijms24119342. [PMID: 37298294 DOI: 10.3390/ijms24119342] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/18/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important limitations, especially in very small nodules and those which show atypical imaging features. In recent years, liquid biopsy and molecular analysis of tumor breakdown products have become an attractive source of new biomarkers. Patients with liver and biliary malignancies, including hepatocellular carcinoma (HCC), may greatly benefit from ctDNA testing. These patients are often diagnosed at an advanced stage of the disease, and relapses are common. Molecular analysis may indicate the best cancer treatment tailored to particular patients with specific tumor DNA mutations. Liquid biopsy is a minimally invasive technique that facilitates the early detection of cancer. This review summarizes the knowledge of ctDNA in liquid biopsy as an indicator for early diagnosis and monitoring of hepatocellular cancer.
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Affiliation(s)
- Agnieszka Kopystecka
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Rafał Patryn
- Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Magdalena Leśniewska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Julia Budzyńska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ilona Kozioł
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
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16
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Mutated genes on ctDNA detecting postoperative recurrence presented reduced neoantigens in primary tumors in colorectal cancer cases. Sci Rep 2023; 13:1366. [PMID: 36693917 PMCID: PMC9873919 DOI: 10.1038/s41598-023-28575-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 01/20/2023] [Indexed: 01/25/2023] Open
Abstract
The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.
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17
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Zhou Z, Xu X, Liu Y, Liu Q, Zhang W, Wang K, Wang J, Yin Y. Liquid Biopsy in Hepatocellular Carcinoma. Methods Mol Biol 2023; 2695:213-225. [PMID: 37450121 DOI: 10.1007/978-1-0716-3346-5_14] [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] [Indexed: 07/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly neoplasms with a poor prognosis. Due to the significant tumor heterogeneity of HCC, alpha-fetoprotein (AFP) or liver biopsy has not yet met the clinical needs in terms of early diagnosis or determining prognosis. In recent years, liquid biopsy techniques that analyze tumor by-products released into the circulation have shown great potential. Its ability to monitor tumors in real time and respond to their global characteristics is expected to improve the management of HCC patients clinically. This review discusses some of the findings of a liquid biopsy in terms of diagnosis and prognosis of HCC.
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Affiliation(s)
- Zheyu Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoliang Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qiaoyu Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Kun Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jincheng Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yin Yin
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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18
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Ding J, Zhao W. The Application of Liquid Biopsy Techniques in High-Risk Population for Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:2735-2748. [PMID: 36133739 PMCID: PMC9484767 DOI: 10.2147/cmar.s373165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/27/2022] [Indexed: 12/01/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.
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Affiliation(s)
- Jingnuo Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People's Republic of China
| | - Weifeng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People's Republic of China
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Kirchweger P, Wundsam HV, Rumpold H. Circulating tumor DNA for diagnosis, prognosis and treatment of gastrointestinal malignancies. World J Clin Oncol 2022; 13:473-484. [PMID: 35949436 PMCID: PMC9244970 DOI: 10.5306/wjco.v13.i6.473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/06/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Minimally invasive detection of circulating tumor DNA (ctDNA) in peripheral blood or other body fluids of patients with gastrointestinal malignancies via liquid biopsy has emerged as a promising biomarker. This is urgently needed, as conventional imaging and plasma protein-derived biomarkers lack sensitivity and specificity in prognosis, early detection of relapse or treatment monitoring. This review summarizes the potential role of liquid biopsy in diagnosis, prognosis and treatment monitoring of gastrointestinal malignancies, including upper gastrointestinal, liver, bile duct, pancreatic and colorectal cancer. CtDNA can now be part of the clinical routine as a promising, highly sensitive and specific biomarker with a broad range of applicability. Liquid-biopsy based postoperative relapse prediction could lead to improved survival by intensification of adjuvant treatment in patients identified to be at risk of early recurrence. Moreover, ctDNA allows monitoring of antineoplastic treatment success, with identification of potentially developed resistance or therapeutic targets during the course of treatment. It may also assist in early change of chemotherapy in metastatic gastrointestinal malignancies prior to imaging findings of relapse. Nevertheless, clinical utility is dependent on the tumor’s entity and burden.
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Affiliation(s)
- Patrick Kirchweger
- Department of Surgery, Ordensklinikum Linz, Linz 4010, Austria
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz 4010, Austria
- Medical Faculty, JKU University Linz, Linz 4040, Austria
| | | | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz 4010, Austria
- Medical Faculty, JKU University Linz, Linz 4040, Austria
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20
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Li CL, Yeh SH, Chen PJ. Circulating Virus–Host Chimera DNAs in the Clinical Monitoring of Virus-Related Cancers. Cancers (Basel) 2022; 14:cancers14102531. [PMID: 35626135 PMCID: PMC9139492 DOI: 10.3390/cancers14102531] [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: 03/18/2022] [Revised: 05/18/2022] [Accepted: 05/18/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Cell-free tumor DNA (ctDNA), the DNA released into circulation from tumors, is a promising tumor marker with versatile applications. The associations of the amount, somatic mutation frequency, and epigenetic modifications of ctDNA with the tumor burden, tumor behavior, and prognosis have been widely investigated in different types of tumors. However, there are still some challenging issues to be resolved before ctDNA can complement or even replace current serum tumor markers. We propose employing exogenous viral DNA integration that produces unique virus–host chimera DNA (vh-DNA) at junction sites. Cell-free vh-DNA may become a new biomarker because it overcomes background interference detection problems, takes advantage of virus tropism to localize the tumor, and acts as a universal marker for monitoring clonal expansion or tumor loads in tumors related to oncogenic viruses. Abstract The idea of using tumor-specific cell-free DNA (ctDNA) as a tumor biomarker has been widely tested and validated in various types of human cancers and different clinical settings. ctDNA can reflect the presence or size of tumors in a real-time manner and can enable longitudinal monitoring with minimal invasiveness, allowing it to be applied in treatment response assessment and recurrence monitoring for cancer therapies. However, tumor detection by ctDNA remains a great challenge due to the difficulty in enriching ctDNA from a large amount of homologous non-tumor cell-free DNA (cfDNA). Only ctDNA with nonhuman sequences (or rearrangements) can be selected from the background of cfDNA from nontumor DNAs. This is possible for several virus-related cancers, such as hepatitis B virus (HBV)-related HCC or human papillomavirus (HPV)-related cervical or head and neck cancers, which frequently harbor randomly integrated viral DNA. The junction fragments of the integrations, namely virus–host chimera DNA (vh-DNA), can represent the signatures of individual tumors and are released into the blood. Such ctDNA can be enriched by capture with virus-specific probes and therefore exploited as a circulating biomarker to track virus-related cancers in clinical settings. Here, we review virus integrations in virus-related cancers to evaluate the feasibility of vh-DNA as a cell-free tumor marker and update studies on the development of detection and applications. vh-DNA may be a solution to the development of specific markers to manage virus-related cancers in the future.
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Affiliation(s)
- Chiao-Ling Li
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
| | - Shiou-Hwei Yeh
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Correspondence: (S.-H.Y.); (P.-J.C.)
| | - Pei-Jer Chen
- Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
- Correspondence: (S.-H.Y.); (P.-J.C.)
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21
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Yang JC, Hu JJ, Li YX, Luo W, Liu JZ, Ye DW. Clinical Applications of Liquid Biopsy in Hepatocellular Carcinoma. Front Oncol 2022; 12:781820. [PMID: 35211399 PMCID: PMC8860830 DOI: 10.3389/fonc.2022.781820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognosis in the world. The low rate of early diagnosis, as well as the high risk of postoperative metastasis and recurrence, led to the poor clinical prognosis of HCC patients. Currently, it mainly depends on serum markers, imaging examination, and tissue biopsy to diagnose and determine the recurrence and metastasis of HCC after treatments. Nevertheless, the accuracy and sensitivity of serum markers and imaging for early HCC diagnosis are suboptimal. Tissue biopsy, containing limited tissue samples, is insufficient to reveal comprehensive tumor biology information and is inappropriate to monitor dynamic tumor progression due to its invasiveness. Thus, low invasive diagnostic methods and novel biomarkers with high sensitivity and reliability must be found to improve HCC detection and prediction. As a non-invasive, dynamic, and repeatable detection method, “liquid biopsy”, has attracted much attention to early diagnosis and monitoring of treatment response, which promotes the progress of precision medicine. This review summarizes the clinical applications of liquid biopsy in HCC, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosome in early diagnosis, prognostic evaluation, disease monitoring, and guiding personalized treatment.
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Affiliation(s)
- Jin-Cui Yang
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun-Jie Hu
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Xin Li
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Luo
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin-Zhou Liu
- Department of Pain Management, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Da-Wei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Pancreatic-Biliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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22
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Lyu X, Tsui YM, Ho DWH, Ng IOL. Liquid Biopsy Using Cell-Free or Circulating Tumor DNA in the Management of Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2022; 13:1611-1624. [PMID: 35183803 PMCID: PMC9048068 DOI: 10.1016/j.jcmgh.2022.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/18/2022]
Abstract
Liver cancer (hepatocellular carcinoma [HCC]) is a fatal cancer worldwide and often is detected at an advanced stage when treatment options are very limited. This drives the development of techniques and platforms for early detection of HCC. In recent years, liquid biopsy has provided a means of noninvasive detection of cancers. By detecting plasma circulating tumor DNA (ctDNA) released from dying cancer cells, the presence of HCC can be detected in a noninvasive manner. In this review, we discuss the molecular characteristics of ctDNA and its various molecular landscapes in HCC. These include the mutational landscape, single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The consistency between the plasma ctDNA and the tumor tissue genomic DNA mutational profile is pivotal for the clinical utility of ctDNA in the clinical management of HCC. With strategic use of genetic information provided from plasma ctDNA profiling and procedure standardization to facilitate implementation in clinical practice, better clinical management would become permissible through more efficient detection and diagnosis of HCC, better prognostication, precision-matched treatment guidance, and more reliable disease monitoring.
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Affiliation(s)
| | | | - Daniel Wai-Hung Ho
- Correspondence Address correspondence to: Daniel Wai-Hung Ho, PhD, Department of Pathology, L704, Laboratory Block, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. fax: (852) 2819-5375.
| | - Irene Oi-Lin Ng
- Irene Oi-Lin Ng, MD, PhD, Department of Pathology, Room 7-13, Block T, Queen Mary Hospital, Pokfulam, Hong Kong. fax: 852-28872-5197.
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23
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Xin Z, Li J, Zhang H, Zhou Y, Song J, Chen P, Bai L, Chen H, Zhou J, Chen J, Ying B. Cancer Genomic Alterations Can Be Potential Biomarkers Predicting Microvascular Invasion and Early Recurrence of Hepatocellular Carcinoma. Front Oncol 2022; 12:783109. [PMID: 35155229 PMCID: PMC8828586 DOI: 10.3389/fonc.2022.783109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/03/2022] [Indexed: 02/05/2023] Open
Abstract
Background High recurrence incidence and poor survival after hepatectomy are enormous threats to hepatocellular carcinoma (HCC) patients, which can be caused by microvascular invasion (MVI). However, it is difficult to predict preoperative MVI status. In this study, we focus on cancer genomic alterations to comprehensively explore potential MVI and early recurrence biomarkers and provide clues to the mechanisms of HCC invasion and metastasis. Methods Forty-one patients with initially suspected HCC who were undergoing hepatectomy were finally enrolled. High-throughput targeted sequencing was performed on genomic alterations in their preoperative plasma and surgical fresh tumor tissues utilizing the 1,021-gene panel. Results HCC patients without MVI had longer RFS than MVI ones (p < 0.0001). The mutant incidence of genes like KEAP1, TP53, HIST1H3D, NFKBIA, PIK3CB, and WRN was higher in both MVI and early-recurrence patients than their counterparts. Besides, the alteration rates of Rap1 and Ras signaling pathways were significantly higher in MVI patients than NMVI ones (p < 0.05), and a similar trend of differences was also found in early-recurrence/non-recurrence comparison. The maximal variant allele frequency (VAF) of circulating tumor DNA (ctDNA) was statistically higher in MVI patients than NMVI ones (0.038 vs. 0.012, p = 0.0048). With the cutoff value of 0.018, ctDNA maximal VAF could potentially predict the presence of MVI with an AUC of 0.85 (95% CI 0.693–0.998, p = 0.0062). Conclusion The integration of a panel containing specific mutated genes and ctDNA maximal VAF for predicting MVI and early recurrence of HCC may achieve better performance.
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Affiliation(s)
- Zhaodan Xin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China.,West China School of Medicine, Sichuan University, Chengdu, China
| | - Jin Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Haili Zhang
- West China School of Medicine, Sichuan University, Chengdu, China.,Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Jiajia Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Piaopiao Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Ling Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Hao Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.,Med+ Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
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24
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Chen F, Wang J, Wu Y, Gao Q, Zhang S. Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy. Front Oncol 2022; 12:822449. [PMID: 35186756 PMCID: PMC8851237 DOI: 10.3389/fonc.2022.822449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
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Affiliation(s)
- Fanghua Chen
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Junming Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yingcheng Wu
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Shu Zhang,
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25
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Abouali H, Hosseini SA, Purcell E, Nagrath S, Poudineh M. Recent Advances in Device Engineering and Computational Analysis for Characterization of Cell-Released Cancer Biomarkers. Cancers (Basel) 2022; 14:288. [PMID: 35053452 PMCID: PMC8774172 DOI: 10.3390/cancers14020288] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 01/04/2022] [Indexed: 02/04/2023] Open
Abstract
During cancer progression, tumors shed different biomarkers into the bloodstream, including circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA). The analysis of these biomarkers in the blood, known as 'liquid biopsy' (LB), is a promising approach for early cancer detection and treatment monitoring, and more recently, as a means for cancer therapy. Previous reviews have discussed the role of CTCs and ctDNA in cancer progression; however, ctDNA and EVs are rapidly evolving with technological advancements and computational analysis and are the subject of enormous recent studies in cancer biomarkers. In this review, first, we introduce these cell-released cancer biomarkers and briefly discuss their clinical significance in cancer diagnosis and treatment monitoring. Second, we present conventional and novel approaches for the isolation, profiling, and characterization of these markers. We then investigate the mathematical and in silico models that are developed to investigate the function of ctDNA and EVs in cancer progression. We convey our views on what is needed to pave the way to translate the emerging technologies and models into the clinic and make the case that optimized next-generation techniques and models are needed to precisely evaluate the clinical relevance of these LB markers.
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Affiliation(s)
- Hesam Abouali
- Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada; (H.A.); (S.A.H.)
| | - Seied Ali Hosseini
- Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada; (H.A.); (S.A.H.)
| | - Emma Purcell
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109-2800, USA; (E.P.); (S.N.)
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109-2800, USA; (E.P.); (S.N.)
| | - Mahla Poudineh
- Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada; (H.A.); (S.A.H.)
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26
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Khatib SA, Wang XW. Causes and functional intricacies of inter- and intratumor heterogeneity of primary liver cancers. Adv Cancer Res 2022; 156:75-102. [DOI: 10.1016/bs.acr.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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27
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Kalasekar SM, VanSant-Webb CH, Evason KJ. Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities. Cancers (Basel) 2021; 13:5524. [PMID: 34771685 PMCID: PMC8582820 DOI: 10.3390/cancers13215524] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: β-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions.
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Affiliation(s)
| | | | - Kimberley J. Evason
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (S.M.K.); (C.H.V.-W.)
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28
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Zhang Y, Liu Z, Ji K, Li X, Wang C, Ren Z, Liu Y, Chen X, Han X, Meng L, Li L, Li Z. Clinical Application Value of Circulating Cell-free DNA in Hepatocellular Carcinoma. Front Mol Biosci 2021; 8:736330. [PMID: 34660697 PMCID: PMC8511426 DOI: 10.3389/fmolb.2021.736330] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/14/2021] [Indexed: 01/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Due to late diagnosis, early intrahepatic metastasis and nonresponse to systemic treatments, surgical resection and/or biopsy specimens remain the gold standard for disease staging, grading and clinical decision-making. Since only a small amount of tissue was obtained in a needle biopsy, the conventional tissue biopsy is unable to represent tumor heterogeneity in HCC. For this reason, it is imperative to find a new non-invasive and easily available diagnostic tool to detect HCC at an early stage and to monitor HCC recurrence. The past decade has witnessed considerable evolution in the development of liquid biopsy technologies with the emergence of next-generation sequencing. As a liquid biopsy approach, molecular analysis of cell-free DNA (cfDNA), characterized by noninvasiveness and real-time analysis, may accurately represent the tumor burden and comprehensively reflect genetic profile of HCC. Therefore, cfDNA may be used clinically as a predictive biomarker in early diagnosis, outcome assessment, and even molecular typing. In this review, we provide an update on the recent advances made in clinical applications of cfDNA in HCC.
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Affiliation(s)
- Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Kun Ji
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Xin Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Caihong Wang
- Department of Magnetic Resonance, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infections Disease, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Yang Liu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinju Chen
- First Ward of Spleen, Stomach, Liver and Gall, The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Lingfang Meng
- Department of Ultrasound, Zhengzhou Sixth People's Hospital, Henan Infectious Disease Hospital, Zhengzhou, China
| | - Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhen Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
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29
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Sefrioui D, Verdier V, Savoye-Collet C, Beaussire L, Ghomadi S, Gangloff A, Goria O, Riachi G, Montialoux H, Schwarz L, Tuech JJ, Frebourg T, Michel P, Sarafan-Vasseur N, Di Fiore F. Circulating DNA changes are predictive of disease progression after transarterial chemoembolization. Int J Cancer 2021; 150:532-541. [PMID: 34622951 DOI: 10.1002/ijc.33829] [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: 12/13/2020] [Revised: 04/25/2021] [Accepted: 05/12/2021] [Indexed: 11/09/2022]
Abstract
Transarterial chemoembolization (TACE) is used to treat patients with unresectable hepatocellular carcinoma (HCC). We evaluated the clinical impact of a-fetoprotein (AFP) and circulating cell-free and tumor DNA (cfDNA and ctDNA) changes around the TACE procedure. Our prospective monocentric study enrolled consecutive patients treated with TACE, with samples collected at baseline (D - 1), Day 2 (D + 2) and 1 month (M + 1) after TACE. cfDNA was quantified by the fluorometric method, and ctDNA was quantified by digital polymerase chain reaction designed for two hotspot TERT mutations. Computerized tomography scans or magnetic resonance imaging were performed at M + 1 every 3 months following TACE and independently reviewed. The objective was to identify thresholds of cfDNA, ctDNA and AFP changes associated with progressive disease (PD) using receiver operating characteristic curves. Thirty-eight patients were included from March 2018 to March 2019. All markers significantly increased from D - 1 to D + 2 (P < .005), and cfDNA and ctDNA significantly decreased from D + 2 to M + 1 (P < .0001). The analysis of changes from D - 1 to M + 1 identified thresholds at +31.4% for cfDNA and 0% for ctDNA that were significantly associated with PD at M + 1 (44.4% [>+31.4%] vs 3.8% [≤+31.4%] and 50.0% [>0%] vs 5.0% [≤0%], respectively). No significant threshold was identified for AFP. Using a score combining cfDNA and ctDNA, the patients were classified into high- or low-risk PD groups at M + 1, with PD rates of 80.0% vs 4.3% (P = .001) and median progression-free survival times of 1.3 vs 10.3 months (P = .002). Our study suggests that cfDNA and ctDNA increases around the TACE procedure and are associated with therapeutic failure.
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Affiliation(s)
- David Sefrioui
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Vincent Verdier
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Céline Savoye-Collet
- UNIROUEN, Quantif-LITIS EA 4108, Normandie Univ, Rouen, France.,Department of Radiology, Rouen University Hospital, Rouen, France
| | | | - Slim Ghomadi
- Department of Radiology, Rouen University Hospital, Rouen, France.,UNIROUEN, Normandie Univ, Rouen, France
| | - Alice Gangloff
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Odile Goria
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Ghassan Riachi
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Hélène Montialoux
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | - Lilian Schwarz
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Digestive Surgery Department, Rouen University Hospital, Rouen, France
| | - Jean-Jacques Tuech
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Digestive Surgery Department, Rouen University Hospital, Rouen, France
| | - Thierry Frebourg
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Genetics, Rouen University Hospital, Rouen, France
| | - Pierre Michel
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
| | | | - Frédéric Di Fiore
- UNIROUEN, Inserm 1245, IRON group, Normandie Univ, Rouen, France.,Department of Hepatogastroenterology, Rouen University Hospital, Rouen, France
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30
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Moati E, Taly V, Garinet S, Didelot A, Taieb J, Laurent-Puig P, Zaanan A. Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives. Cancers (Basel) 2021; 13:4743. [PMID: 34638228 PMCID: PMC8507552 DOI: 10.3390/cancers13194743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.
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Affiliation(s)
- Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
| | - Valerie Taly
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
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Maravelia P, Silva DN, Rovesti G, Chrobok M, Stål P, Lu YC, Pasetto A. Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy. Cancers (Basel) 2021; 13:4334. [PMID: 34503144 PMCID: PMC8431414 DOI: 10.3390/cancers13174334] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/21/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.
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Affiliation(s)
- Panagiota Maravelia
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Daniela Nascimento Silva
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Giulia Rovesti
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Michael Chrobok
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Per Stål
- Unit of Gastroenterology and Hepatology, Department of Medicine/Huddinge, Karolinska Institutet, Department of Upper GI Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden;
| | - Yong-Chen Lu
- Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Anna Pasetto
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
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Lin SY, Chang TT, Steffen JD, Chen S, Jain S, Song W, Lin YJ, Su YH. Detection of CTNNB1 Hotspot Mutations in Cell-Free DNA from the Urine of Hepatocellular Carcinoma Patients. Diagnostics (Basel) 2021; 11:1475. [PMID: 34441409 PMCID: PMC8393790 DOI: 10.3390/diagnostics11081475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/30/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32-37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection.
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Affiliation(s)
- Selena Y. Lin
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
| | - Jamin D. Steffen
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Sitong Chen
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Wei Song
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan 701, Taiwan
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA
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Tran NH, Kisiel J, Roberts LR. Using cell-free DNA for HCC surveillance and prognosis. JHEP Rep 2021; 3:100304. [PMID: 34136776 PMCID: PMC8182265 DOI: 10.1016/j.jhepr.2021.100304] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/22/2021] [Accepted: 04/24/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Its incidence is rising faster than any other cancer in the United States and it remains one of the leading causes of cancer-related deaths worldwide. While advances in massive parallel sequencing and integration of 'omics information have transformed the field of oncology, tissue access is often limited in HCC and a single biopsy is poorly representative of the known genetic heterogeneity of tumours. Liquid biopsy has emerged as a promising strategy for analysing circulating tumour components including circulating tumour DNA. Cell-free DNA and tumour DNA are derived from necrotic, apoptotic and living eukaryotic cells. The profiling of genetic and epigenetic alterations in circulating cell-free DNA has potential clinical applications including early disease detection, prediction of treatment response and prognostication in real time. Novel biomarker candidates for disease detection and monitoring are under study. Of these, methylation analyses of circulating tumour DNA have shown promising performance for early HCC detection in at-risk patients. Assessments of assay performance in longitudinal validation cohorts are ongoing. Implementation of liquid biopsy for HCC will likely improve upon the current surveillance strategy. This review summarises the most recent developments on the role and utility of circulating cell-free DNA in the detection and management of HCC.
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Affiliation(s)
- Nguyen H Tran
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States
| | - John Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
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Lin LH, Cheng HW, Liu CJ. Droplet digital polymerase chain reaction for detection and quantification of cell-free DNA TP53 target somatic mutations in oral cancer. Cancer Biomark 2021; 33:29-41. [PMID: 34366328 PMCID: PMC8925125 DOI: 10.3233/cbm-210275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND: TP53 mutation is a driver mutation of oral carcinogenesis. This study investigated cancerous and cell-free DNA (cfDNA) in patients with oral squamous cell carcinoma (OSCC) to detect the target hotspot somatic mutation of TP53. OBJECTIVE: TP53 target hotspot mutations were determined in surgically resected primary tumor samples from 107 OSCC patients. METHODS: Cancerous and cfDNA samples were examined for mutations through droplet digital polymerase chain reaction (ddPCR) by using mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data. RESULTS: In total, 23 cases had target TP53 mutations in varying degrees. We found that OSCC had relatively low cfDNA shedding, and mutations were at low allele frequencies. Of these 23 cases, 13 had target TP53 mutations in their corresponding cfDNA. Target somatic mutations in cancerous DNA and cfDNA are related to cervical lymph node metastasis. The cfDNA concentration is related to primary tumor size, lymph node metastasis, and OSCC stage. CONCLUSIONS: Our results show that the detection of TP53 target somatic mutations in OSCC patients by using ddPCR is technically feasible. Low levels of cfDNA may produce different results between cancerous tissue and cfDNA analyses. Future research on cfDNA may quantify diagnostic biomarkers in the surveillance of OSCC patients.
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Affiliation(s)
- Li-Han Lin
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Hui-Wen Cheng
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chung-Ji Liu
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Oral and Maxillofacial Surgery, Taipei MacKay Memorial Hospital, Taipei, Taiwan
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Fujii Y, Ono A, Hayes CN, Aikata H, Yamauchi M, Uchikawa S, Kodama K, Teraoka Y, Fujino H, Nakahara T, Murakami E, Miki D, Okamoto W, Kawaoka T, Tsuge M, Imamura M, Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:215. [PMID: 34174931 PMCID: PMC8235843 DOI: 10.1186/s13046-021-02016-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02016-3.
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Affiliation(s)
- Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Wataru Okamoto
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, 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, Hiroshima University, Hiroshima, Japan. .,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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Pelizzaro F, Cardin R, Penzo B, Pinto E, Vitale A, Cillo U, Russo FP, Farinati F. Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now? Cancers (Basel) 2021; 13:2274. [PMID: 34068786 PMCID: PMC8126224 DOI: 10.3390/cancers13092274] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Romilda Cardin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Barbara Penzo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Elisa Pinto
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
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Li Y, Zheng Y, Wu L, Li J, Ji J, Yu Q, Dai W, Feng J, Wu J, Guo C. Current status of ctDNA in precision oncology for hepatocellular carcinoma. J Exp Clin Cancer Res 2021; 40:140. [PMID: 33902698 PMCID: PMC8074474 DOI: 10.1186/s13046-021-01940-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/06/2021] [Indexed: 01/12/2023] Open
Abstract
The conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China.
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China.
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Ge Z, Helmijr JCA, Jansen MPHM, Boor PPC, Noordam L, Peppelenbosch M, Kwekkeboom J, Kraan J, Sprengers D. Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma. Transl Oncol 2021; 14:101073. [PMID: 33915518 PMCID: PMC8100622 DOI: 10.1016/j.tranon.2021.101073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/17/2021] [Accepted: 03/08/2021] [Indexed: 12/24/2022] Open
Abstract
In paired analysis CTCs were detected in 27% and ctDNA in 77% of HCC patients. The TERT promoter mutation C228T was present in all patients with one or more ctDNA mutations, or detectable CTCs. CtDNA (or TERT C228T) positivity was associated with macrovascular invasion and poor survival of advanced HCC patients. Background and aims Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients. Methods Twenty-six mostly advanced HCC patients were enrolled. 30 mL peripheral blood from each patient was obtained. CellSearch system was used for CTC detection. A sequencing panel covering 14 cancer-relevant genes was used to identify oncogenic mutations. TERT promoter C228T and C250T mutations were determined by droplet digital PCR. Results CTCs were detected in 27% (7/26) of subjects but at low numbers (median: 2 cells, range: 1–15 cells) and ctDNA in 77% (20/26) of patients. Mutations in ctDNA were identified in several genes: TERT promoter C228T (77%, 20/26), TP53 (23%, 6/26), CTNNB1 (12%, 3/26), PIK3CA (12%, 3/26) and NRAS (4%, 1/26). The TERT C228T mutation was present in all patients with one or more ctDNA mutations, or detectable CTCs. The TERT C228T and TP53 mutations detected in ctDNA were present at higher levels in matched primary HCC tumor tissue. The maximal variant allele frequency (VAF) of ctDNA was linearly correlated with largest tumor size and AFP level (Log10). CtDNA (or TERT C228T) positivity was associated with macrovascular invasion, and positivity of ctDNA (or TERT C228T) or CTCs (≥ 2) correlated with poor patient survival. Conclusions Oncogenic mutations could be detected in ctDNA from advanced HCC patients. CtDNA analysis may serve as a promising liquid biopsy to identify druggable mutations.
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Affiliation(s)
- Zhouhong Ge
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jean C A Helmijr
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maurice P H M Jansen
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Patrick P C Boor
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Lisanne Noordam
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Maikel Peppelenbosch
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaap Kwekkeboom
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaco Kraan
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Dave Sprengers
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
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Strub T, Martel A, Nahon-Esteve S, Baillif S, Ballotti R, Bertolotto C. Translation of single-cell transcriptomic analysis of uveal melanomas to clinical oncology. Prog Retin Eye Res 2021; 85:100968. [PMID: 33852963 DOI: 10.1016/j.preteyeres.2021.100968] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022]
Abstract
Uveal melanoma (UM) is an aggressive and deadly neoplasm. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes in UM, enabling the identification of key cellular processes and signalling pathways. Still, there is no effective treatment for the metastatic disease. Intratumoural heterogeneity (ITH) is thought to be one of the leading determinants of metastasis, therapeutic resistance and recurrence. Crucially, tumours are complex ecosystems, where cancer cells, and diverse cell types from their microenvironment engage in dynamic spatiotemporal crosstalk that allows cancer progression, adaptation and evolution. This highlights the urgent need to gain insight into ITH in UM and its intersection with the microenvironment to overcome treatment failure. Here we provide an overview of the studies and technologies to study ITH in human UMs and tumour micro-environmental composition. We discuss how to incorporate ITH into clinical consideration for the purpose of advocating for new clinical management. We focus on the application of single-cell transcriptomic analysis and propose that understanding the driving forces and functional consequences of the observed tumour heterogeneity holds promise for changing the treatment paradigm of metastatic UMs, surmounting resistance and improving patient prognosis.
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Affiliation(s)
- Thomas Strub
- University Côte d'Azur, France; Inserm, Biology and Pathologies of Melanocytes, Team1, Equipe Labellisée Ligue 2020 and Equipe Labellisée ARC 2019, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Arnaud Martel
- University Côte d'Azur, France; Centre Hospitalier Universitaire de Nice, Department of Ophthalmology, Nice, France
| | - Sacha Nahon-Esteve
- University Côte d'Azur, France; Centre Hospitalier Universitaire de Nice, Department of Ophthalmology, Nice, France
| | - Stéphanie Baillif
- University Côte d'Azur, France; Centre Hospitalier Universitaire de Nice, Department of Ophthalmology, Nice, France
| | - Robert Ballotti
- University Côte d'Azur, France; Inserm, Biology and Pathologies of Melanocytes, Team1, Equipe Labellisée Ligue 2020 and Equipe Labellisée ARC 2019, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Corine Bertolotto
- University Côte d'Azur, France; Inserm, Biology and Pathologies of Melanocytes, Team1, Equipe Labellisée Ligue 2020 and Equipe Labellisée ARC 2019, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
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Jian W, Huanqiu C, Chao Y. Utilizing circulating free DNA in diagnosing early gastric cancer in a patient with situs inversus totalis: A case report and literature review. PRECISION MEDICAL SCIENCES 2021. [DOI: 10.1002/prm2.12037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Wang Jian
- Department of General Surgery Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing China
| | - Chen Huanqiu
- Department of General Surgery Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing China
| | - Yue Chao
- Department of General Surgery Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing China
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Camus V, Jardin F. Cell-Free DNA for the Management of Classical Hodgkin Lymphoma. Pharmaceuticals (Basel) 2021; 14:ph14030207. [PMID: 33801462 PMCID: PMC7998645 DOI: 10.3390/ph14030207] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cell-free DNA (cfDNA) testing, is an emerging “liquid biopsy” tool for noninvasive lymphoma detection, and an increased amount of data are now available to use this technique with accuracy, especially in classical Hodgkin lymphoma (cHL). The advantages of cfDNA include simplicity of repeated blood sample acquisition over time; dynamic, noninvasive, and quantitative analysis; fast turnover time; reasonable cost; and established consistency with results from tumor genomic DNA. cfDNA analysis offers an easy method for genotyping the overall molecular landscape of pediatric and adult cHL and may help in cases of diagnostic difficulties between cHL and other lymphomas. cfDNA levels are correlated with clinical, prognostic, and metabolic features, and may serve as a therapeutic response evaluation tool and as a minimal residual disease (MRD) biomarker in complement to positron emission tomography (PET). Indeed, cfDNA real-time monitoring by fast high-throughput techniques enables the prompt detection of refractory disease or may help to address PET residual hypermetabolic situations during or at the end of treatment. The major recent works presented and described here demonstrated the clinically meaningful applicability of cfDNA testing in diagnostic and theranostic settings, but also in disease risk assessment, therapeutic molecular response, and monitoring of cHL treatments.
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Affiliation(s)
- Vincent Camus
- Correspondence: ; Tel.: +33(0)-2-32-08-29-47; Fax: +33-(0)-2-32-08-22-83
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Chan LK, Tsui YM, Ho DWH, Ng IOL. Cellular heterogeneity and plasticity in liver cancer. Semin Cancer Biol 2021; 82:134-149. [PMID: 33647386 DOI: 10.1016/j.semcancer.2021.02.015] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/22/2021] [Indexed: 02/07/2023]
Abstract
Hepatocarcinogenesis involves complex genetic and cellular dysregulations which drive the formation of hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, with extensive heterogeneity. In contrast to the broad spectrum of molecularly driven therapies available for defined patient groups in certain cancer types, unfortunately the treatment options for HCC are highly limited. The lack of representative molecular and cellular signatures in the heterogeneous HCC tumors that can effectively guide the choice of the most appropriate treatment among the patients unavoidably limits the treatment outcome. Advancement and wide availability of the next-generation sequencing technologies have empowered us to examine and capture not only the detailed genetic alterations of the HCC cells but also the precise composition of different cell types within the tumor microenvironment and their interactions with the HCC cells at an unprecedented level. The information generated has provided new insight and better defined the inter-patient intertumoral heterogeneity, intra-patient intratumoral heterogeneity as well as the plasticity of HCC cells. These collectively provide a robust scientific basis in guiding the development and use of targeted therapy and immunotherapy. To complement, liquid biopsy coupled with high-sensitivity sequencing could potentially be adopted as a more practical and safer approach to detect and reflect the tumor heterogeneity in HCC patients in guiding the choice of treatment and monitoring disease progression.
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Affiliation(s)
- Lo-Kong Chan
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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Dhanasekaran R. Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)-Multi-Omic and Singulomic Approaches. Semin Liver Dis 2021; 41:9-18. [PMID: 33764481 PMCID: PMC8136683 DOI: 10.1055/s-0040-1722261] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Tumor heterogeneity, a key hallmark of hepatocellular carcinomas (HCCs), poses a significant challenge to developing effective therapies or predicting clinical outcomes in HCC. Recent advances in next-generation sequencing-based multi-omic and single cell analysis technologies have enabled us to develop high-resolution atlases of tumors and pull back the curtain on tumor heterogeneity. By combining multiregion targeting sampling strategies with deep sequencing of the genome, transcriptome, epigenome, and proteome, several studies have revealed novel mechanistic insights into tumor initiation and progression in HCC. Advances in multiparametric immune cell profiling have facilitated a deeper dive into the biological complexity of HCC, which is crucial in this era of immunotherapy. Moreover, studies using liquid biopsy have demonstrated their potential to circumvent the need for tissue sampling to investigate heterogeneity. In this review, we discuss how multi-omic and single-cell sequencing technologies have advanced our understanding of tumor heterogeneity in HCC.
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Affiliation(s)
- Renumathy Dhanasekaran
- Department of Medicine, Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
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Li CL, Ho MC, Lin YY, Tzeng ST, Chen YJ, Pai HY, Wang YC, Chen CL, Lee YH, Chen DS, Yeh SH, Chen PJ. Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer. Hepatology 2020; 72:2063-2076. [PMID: 32171027 DOI: 10.1002/hep.31230] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/21/2020] [Accepted: 02/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
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Affiliation(s)
- Chiao-Ling Li
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Yun-Ju Chen
- TCM Biotech International Corp., Taipei, Taiwan
| | | | | | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Hsin Lee
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Kim SS, Eun JW, Choi JH, Woo HG, Cho HJ, Ahn HR, Suh CW, Baek GO, Cho SW, Cheong JY. MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma. Sci Rep 2020; 10:17862. [PMID: 33082400 PMCID: PMC7576198 DOI: 10.1038/s41598-020-74494-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023] Open
Abstract
Liquid biopsy can provide a strong basis for precision medicine. We aimed to identify novel single-nucleotide variants (SNVs) in circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC). Deep sequencing of plasma-derived ctDNA from 59 patients with HCC was performed using a panel of 2924 SNVs in 69 genes. In 55.9% of the patients, at least one somatic mutation was detected. Among 25 SNVs in 12 genes, four frequently observed SNVs, MLH1 (13%), STK11 (13%), PTEN (9%), and CTNNB1 (4%), were validated using droplet digital polymerase chain reaction with ctDNA from 62 patients with HCC. Three candidate SNVs were detected in 35.5% of the patients, with a frequency of 19% for MLH1 chr3:37025749T>A, 11% for STK11 chr19:1223126C>G, and 8% for PTEN chr10:87864461C>G. The MLH1 and STK11 SNVs were also confirmed in HCC tissues. The presence of the MLH1 SNV, in combination with an increased ctDNA level, predicted poor overall survival among 107 patients. MLH1 chr3:37025749T>A SNV detection in ctDNA is feasible, and thus, ctDNA can be used to detect somatic mutations in HCC. Furthermore, the presence or absence of the MLH1 SNV in ctDNA, combined with the ctDNA level, can predict the prognosis of patients with HCC.
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Affiliation(s)
- Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ji-Hye Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hye Ri Ahn
- Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Chul Won Suh
- Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Geum Ok Baek
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.
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Mota A, S Oltra S, Moreno-Bueno G. Insight updating of the molecular hallmarks in ovarian carcinoma. EJC Suppl 2020; 15:16-26. [PMID: 33240439 PMCID: PMC7573468 DOI: 10.1016/j.ejcsup.2019.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 10/17/2019] [Accepted: 11/16/2019] [Indexed: 12/31/2022] Open
Abstract
Background and purpose Ovarian cancer (OC) is the deadliest gynaecologic cancer characterised by a high heterogeneity not only at the clinical point of view but also at the molecular level. This review focuses on the new insights about the OC molecular classification. Materials and methods We performed a bibliographic search for different indexed articles focused on the new molecular classification of OC. All of them have been published in PubMed and included information about the most frequent molecular alterations in OC confirmed by omics approaches. In addition, we have extracted information about the role of liquid biopsy in the OC diagnosis and prognosis. Results New molecular insights into OC have allowed novel clinical entities to be defined. Among OC, high-grade serous ovarian carcinoma (HGSOC) which is the most common OC is characterised by omics approaches, mutations in TP53 and in other genes involved in the homologous recombination repair, especially BRCA1/2. Recent studies in HGSOC have allowed a new molecular classification in subgroups according to their mutational, transcriptional, methylation and copy number variation signatures with a real impact in the characterisation of new therapeutic targets for OC to be defined. Furthermore, despite the intrinsic intra-tumour heterogeneity, the advances in next generation sequencing (NGS) analyses of ascetic liquid from OC have opened new ways for its characterisation and treatment. Conclusions The advances in genomic approaches have been used for the identification of new molecular profiling techniques which define OC subgroups and has supposed advances in the diagnosis and in the personalised treatment of OC.
Classification of ovarian cancer regarding to widespread genetic and genomic data. Highlighted role of p53 and BRCA1/2 in ovarian cancer for diagnosis and treatment. Intra-tumour genetic heterogeneity in ovarian cancer. Useful of liquid biopsy study in ovarian cancer diagnosis.
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Affiliation(s)
- Alba Mota
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, MD Anderson International Foundation Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Sara S Oltra
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, MD Anderson International Foundation Madrid, Spain
| | - Gema Moreno-Bueno
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, MD Anderson International Foundation Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
- Corresponding author: Departamento de Bioquímica, Facultad de Medicina (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Arzobispo Morcillo 4, Madrid, 28029, Spain. Fax: +34 91-5854401.
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Shintani D, Hihara T, Ogasawara A, Sato S, Yabuno A, Tai K, Fujiwara K, Watanabe K, Hasegawa K. Tumor-related mutations in cell-free DNA in pre-operative plasma as a prognostic indicator of recurrence in endometrial cancer. Int J Gynecol Cancer 2020; 30:1340-1346. [PMID: 32699017 DOI: 10.1136/ijgc-2019-001053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVES Circulating tumor DNA (ctDNA) has potential as a basis for understanding the molecular features of a tumor non-invasively and for use as a diagnostic, prognostic, and disease-monitoring marker. The aim of this study was to evaluate the clinical roles of ctDNA in patients with endometrial cancer. METHODS Since PIK3CA and KRAS are among the most common mutated genes in endometrial cancer, somatic mutations of these genes were investigated in tumor specimens and plasma collected before surgery, using droplet digital polymerase chain reaction (ddPCR). ctDNA was defined as positive when the corresponding mutation between somatic and plasma was also detected in plasma cell-free DNA (cfDNA). Relationships of the presence of ctDNA with clinicopathological features were examined. RESULTS Somatic PIK3CA and/or KRAS mutations were found in 68 (34%) of 199 patients with endometrial cancer. Ten (14.7%) of 68 patients had similar mutations in cfDNA. ctDNA detected in pre-operative plasma was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.008), histology (p=0.028), and lymphovascular space invasion (p=0.002), and with shorter recurrence-free and overall survival (p=0.004 and p=0.010, respectively, by log-rank test). CONCLUSION Tumor-related ctDNA detected in plasma before surgery was associated with poorer oncologic outcome on univariate analysis in patients with endometrial cancer harboring PIK3CA or KRAS mutations.
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Affiliation(s)
- Daisuke Shintani
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Taro Hihara
- Tsukuba Research Laboratories, Eisai Inc. Ltd, Tsukuba, Ibaraki, Japan
| | - Aiko Ogasawara
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Sho Sato
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Akira Yabuno
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Kenji Tai
- Tsukuba Research Laboratories, Eisai Inc. Ltd, Tsukuba, Ibaraki, Japan
| | - Keiichi Fujiwara
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Keisuke Watanabe
- Tsukuba Research Laboratories, Eisai Inc. Ltd, Tsukuba, Ibaraki, Japan
| | - Kosei Hasegawa
- Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
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Zhang Q, Lou Y, Bai XL, Liang TB. Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies. World J Gastroenterol 2020; 26:3720-3736. [PMID: 32774053 PMCID: PMC7383842 DOI: 10.3748/wjg.v26.i26.3720] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by high heterogeneity in both intratumoral and interpatient manners. While interpatient heterogeneity is related to personalized therapy, intratumoral heterogeneity (ITH) largely influences the efficacy of therapies in individuals. ITH contributes to tumor growth, metastasis, recurrence, and drug resistance and consequently limits the prognosis of patients with HCC. There is an urgent need to understand the causes, characteristics, and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival. Here, we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity. In parallel, evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem. We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions, combined with population-based clinical trials, will help to clarify the clinical implications of ITH, develop novel intervention strategies, and improve patient prognosis.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Xue-Li Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Ting-Bo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
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Mocan T, Simão AL, Castro RE, Rodrigues CMP, Słomka A, Wang B, Strassburg C, Wöhler A, Willms AG, Kornek M. Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning? J Clin Med 2020; 9:jcm9051541. [PMID: 32443747 PMCID: PMC7291267 DOI: 10.3390/jcm9051541] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/18/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and the third most common cause of cancer-related death. One of the major problems faced by researchers and clinicians in this area is the lack of reliable disease biomarkers, which would allow for an earlier diagnosis, follow-up or prediction of treatment response, among others. In this regard, the “HCC circulome”, defined as the pool of circulating molecules in the bloodstream derived from the primary tumor, represents an appealing target, the so called liquid biopsy. Such molecules encompass circulating tumor proteins, circulating tumor cells (CTCs), extracellular vesicles (EVs), tumor-educated platelets (TEPs), and circulating tumor nucleic acids, namely circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). In this article, we summarize recent findings highlighting the promising role of liquid biopsies as novel potential biomarkers in HCC, emphasizing on its clinical performance.
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Affiliation(s)
- Tudor Mocan
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu, University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
| | - André L. Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum, 85-094 Bydgoszcz, Poland;
| | - Bingduo Wang
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
| | - Christian Strassburg
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
| | - Aliona Wöhler
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital Koblenz, 56072 Koblenz, Germany; (A.W.); (A.G.W.)
| | - Arnulf G. Willms
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital Koblenz, 56072 Koblenz, Germany; (A.W.); (A.G.W.)
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
- Correspondence:
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50
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Ogasawara A, Hihara T, Shintani D, Yabuno A, Ikeda Y, Tai K, Fujiwara K, Watanabe K, Hasegawa K. Evaluation of Circulating Tumor DNA in Patients with Ovarian Cancer Harboring Somatic PIK3CA or KRAS Mutations. Cancer Res Treat 2020; 52:1219-1228. [PMID: 32599986 PMCID: PMC7577815 DOI: 10.4143/crt.2019.688] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 05/01/2020] [Indexed: 01/08/2023] Open
Abstract
Purpose Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA. Methods We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the corresponding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma. Results The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis. Conclusion The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.
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Affiliation(s)
- Aiko Ogasawara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Taro Hihara
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Daisuke Shintani
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Akira Yabuno
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Yuji Ikeda
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Kenji Tai
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | | | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
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