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Akabane M, Imaoka Y, Kawashima J, Pawlik TM. Advancing precision medicine in hepatocellular carcinoma: current challenges and future directions in liquid biopsy, immune microenvironment, single nucleotide polymorphisms, and conversion therapy. Hepat Oncol 2025; 12:2493457. [PMID: 40260687 PMCID: PMC12026093 DOI: 10.1080/20450923.2025.2493457] [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: 01/31/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, CA, USA
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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MAEZAWA M, KIKUZAWA M, TAKIGUCHI A, SAITO R, CHAMBERS JK, UCHIDA K, INOKUMA H. A clinical case of enzootic bovine leukosis in a Holstein cow with minor clonality of B-cell in the peripheral blood. J Vet Med Sci 2024; 86:1289-1293. [PMID: 39496454 PMCID: PMC11612243 DOI: 10.1292/jvms.24-0298] [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: 07/27/2024] [Accepted: 10/25/2024] [Indexed: 11/06/2024] Open
Abstract
A 4-year 9-month-old Holstein-Friesian dairy cow presented with anorexia. On physical examination, swelling of superficial lymph nodes, pelvic masses, and prolonged urination posture after urinating a small amount were noted. Hematological examination revealed no lymphocytosis. The bovine leukemia virus proviral load was relatively high. At necropsy, enlarged lymph nodes, a large mass in the pelvic cavity, and mass lesions in several organs were observed. Histopathological examination revealed the proliferation of neoplastic lymphocytes, which were immune-positive for CD79α and negative for CD3. B-cell clonality test indicated the presence of monoclonality in the urine, masses, and lymph nodes and minor clonality in the peripheral blood. These findings led to a diagnosis of EBL with minor clonality of B-cell in the peripheral blood.
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Affiliation(s)
- Masaki MAEZAWA
- Laboratory of OSG Veterinary Science for Global Disease
Management, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
Tokyo, Japan
| | - Misato KIKUZAWA
- Laboratory of Theriogenology, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Asahi TAKIGUCHI
- Veterinary Clinic of Hinode Dairy Cooperative Association,
Ibaraki, Japan
| | - Ryo SAITO
- Laboratory of Veterinary Pathology, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - James K CHAMBERS
- Laboratory of Veterinary Pathology, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazuyuki UCHIDA
- Laboratory of Veterinary Pathology, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hisashi INOKUMA
- Laboratory of OSG Veterinary Science for Global Disease
Management, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
Tokyo, Japan
- Laboratory of Theriogenology, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Boukovala M, Westphalen CB, Probst V. Liquid biopsy into the clinics: Current evidence and future perspectives. THE JOURNAL OF LIQUID BIOPSY 2024; 4:100146. [PMID: 40027149 PMCID: PMC11863819 DOI: 10.1016/j.jlb.2024.100146] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 03/05/2025]
Abstract
As precision oncology has become a major part of the treatment landscape in oncology, liquid biopsies have developed as a particularly powerful tool as it surmounts several limitations of traditional tissue biopsies. These biopsies involve most commonly the isolation of circulating extracellular nucleic acids, including cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA), as well as circulating tumor cells (CTCs), typically from blood. The clinical applications of liquid biopsies are diverse, encompassing the initial diagnosis and cancer detection, the application as a tool for prognostication in early and advanced tumor settings, the identification of potentially actionable alterations, the monitoring of response and resistance under systemic therapy and the detection of resistance mechanisms, the differentiation of distinct immune checkpoint blockade response patterns through serial samples, the prediction of immune checkpoint blockade responses based on initial liquid biopsy characteristics and the assessment of tumor heterogeneity. Moreover, molecular relapse monitoring in early-stage cancers and the personalization of adjuvant or additive therapy via MRD have become a major field of research in recent years. Compared to tissue biopsies, liquid biopsies are less invasive and can be collected serially, offering real-time molecular insights. Furthermore, liquid biopsies may allow for a more holistic evaluation of a patient's disease, as they assess material from all tumor sites and can theoretically reflect tumor heterogeneity. Furthermore, quicker turnaround-time also constitutes an advantage of liquid biopsies. Disadvantages or hurdles include the challenge of detecting low amounts of tumor deposits in peripheral blood or other fluids and the potential of different amounts tumor-shedding from different metastatic sites, as well as potentially false-positive from clonal hematopoietic mutations of indeterminate potential (CHIP) mutations. The clinical utility of liquid biopsies still must be validated in most settings and further research has to be done. Clinal trials including alternate bodily fluids and leveraging AI-technology are expected to revolutionize the field of liquid biopsies.
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Lin S, Wang S, Xu B. Fragmentation patterns of cell-free DNA and somatic mutations in the urine of metastatic breast cancer patients. J Cancer Res Ther 2024; 20:563-569. [PMID: 38454812 DOI: 10.4103/jcrt.jcrt_1359_23] [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: 06/14/2023] [Accepted: 11/08/2023] [Indexed: 03/09/2024]
Abstract
BACKGROUND Urinary cell-free deoxyribonucleic acid (DNA) (ucfDNA) holds promise as a biomarker; however, its potential remains largely unexplored. We examined the fragmentation pattern of ucfDNA and identified somatic mutations within urine samples from metastatic breast cancer (MBC) patients. METHODS Urine and blood specimens were collected before treatment from 45 MBC patients and posttreatment urine samples from 16 of the 45 patients at the China National Cancer Center. Somatic mutations and tumor mutational burden (TMB) in the urine and plasma of 10 patients were analyzed by next-generation sequencing (NGS). Fragmentation patterns of cfDNA were displayed using electropherograms. Differences in the extracted amount of cfDNA, length of cfDNA fragments, and TMB between urine and plasma were compared using a Wilcoxon test. RESULTS The fragmentation patterns of ucfDNA were categorized as follows: (1) profile A (n = 26) containing a short peak (100-200 bp) and a long peak (>1500 bp); (2) profile B (n = 8) containing only a long peak; and (3) profile C (n = 11) containing flat pattern. For profile A patients, the short-peaked ucfDNA circulating in the bloodstream was much shorter compared with plasma cfDNA (149 vs. 171 bp, Wilcoxon test, P = 0.023). The fragmentation patterns in lung metastasis patients exhibited a higher propensity toward profile C ( P = 0.002). After treatment, 87.5% of the patients exhibited consistent fragmentation patterns. The concordance rate for somatic mutations in the plasma and urine was 30%, and the median TMB of urine and plasma was not significantly different. CONCLUSIONS This study established a fragmentation pattern for ucfDNA and detected somatic mutations in the urine of MBC patients. These results suggest the potential application of ucfDNA as a biomarker for MBC.
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Affiliation(s)
- Shaoyan Lin
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Shusen Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
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5
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Wever BMM, Steenbergen RDM. Unlocking the potential of tumor-derived DNA in urine for cancer detection: methodological challenges and opportunities. Mol Oncol 2024. [PMID: 38462745 DOI: 10.1002/1878-0261.13628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/20/2023] [Accepted: 01/27/2024] [Indexed: 03/12/2024] Open
Abstract
High cancer mortality rates and the rising cancer burden worldwide drive the development of innovative methods in order to advance cancer diagnostics. Urine contains a viable source of tumor material and allows for self-collection from home. Biomarker testing in this liquid biopsy represents a novel approach that is convenient for patients and can be effective in detecting cancer at a curable stage. Here, we set out to provide a detailed overview of the rationale behind urine-based cancer detection, with a focus on non-urological cancers, and its potential for cancer diagnostics. Moreover, evolving methodological challenges and untapped opportunities for urine biomarker testing are discussed, particularly emphasizing DNA methylation of tumor-derived cell-free DNA. We also provide future recommendations for technical advancements in urine-based cancer detection and elaborate on potential mechanisms involved in the transrenal transport of cell-free DNA.
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Affiliation(s)
- Birgit M M Wever
- Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam, The Netherlands
- Imaging and Biomarkers, Cancer Center Amsterdam, The Netherlands
| | - Renske D M Steenbergen
- Department of Pathology, Amsterdam UMC, location Vrije Universiteit Amsterdam, The Netherlands
- Imaging and Biomarkers, Cancer Center Amsterdam, The Netherlands
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Bhambhani C, Kang Q, Hovelson DH, Sandford E, Olesnavich M, Dermody SM, Wolfgang J, Tuck KL, Brummel C, Bhangale AD, He K, Gutierrez MG, Lindstrom RH, Liu CJ, Tuck M, Kandarpa M, Mierzwa M, Casper K, Prince ME, Krauss JC, Talpaz M, Henry NL, Giraldez MD, Ramnath N, Tomlins SA, Swiecicki PL, Brenner JC, Tewari M. ctDNA transiting into urine is ultrashort and facilitates noninvasive liquid biopsy of HPV+ oropharyngeal cancer. JCI Insight 2024; 9:e177759. [PMID: 38516891 PMCID: PMC11018327 DOI: 10.1172/jci.insight.177759] [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: 11/20/2023] [Accepted: 02/02/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUNDTransrenal cell-free tumor DNA (TR-ctDNA), which transits from the bloodstream into urine, has the potential to enable noninvasive cancer detection for a wide variety of nonurologic cancer types.MethodsUsing whole-genome sequencing, we discovered that urine TR-ctDNA fragments across multiple cancer types are predominantly ultrashort (<50 bp) and, therefore, likely to be missed by conventional ctDNA assays. We developed an ultrashort droplet digital PCR assay to detect TR-ctDNA originating from HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) and confirmed that assaying ultrashort DNA is critical for sensitive cancer detection from urine samples.ResultsTR-ctDNA was concordant with plasma ctDNA for cancer detection in patients with HPV+ OPSCC. As proof of concept for using urine TR-ctDNA for posttreatment surveillance, in a small longitudinal case series, TR-ctDNA showed promise for noninvasive detection of recurrence of HPV+ OPSCC.ConclusionOur data indicate that focusing on ultrashort fragments of TR-ctDNA will be important for realizing the full potential of urine-based cancer diagnostics. This has implications for urine-based detection of a wide variety of cancer types and for facilitating access to care through at-home specimen collections.FundingNIH grants R33 CA229023, R21 CA225493; NIH/National Cancer Institute grants U01 CA183848, R01 CA184153, and P30CA046592; American Cancer Society RSG-18-062-01-TBG; American Cancer Society Mission Boost grant MBGI-22-056-01-MBG; and the A. Alfred Taubman Medical Research Institute.
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Affiliation(s)
| | - Qing Kang
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Daniel H. Hovelson
- Michigan Center for Translational Pathology
- Department of Computational Medicine & Bioinformatics
| | - Erin Sandford
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Mary Olesnavich
- Department of Internal Medicine, Division of Hematology/Oncology
| | | | - Jenny Wolfgang
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Kirsten L. Tuck
- Department of Internal Medicine, Division of Hematology/Oncology
| | | | | | - Kuang He
- Department of Internal Medicine, Division of Hematology/Oncology
| | | | | | - Chia-Jen Liu
- Michigan Center for Translational Pathology
- Department of Pathology
| | - Melissa Tuck
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Malathi Kandarpa
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Michelle Mierzwa
- Department of Radiation Oncology, and
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Keith Casper
- Department of Otolaryngology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark E. Prince
- Department of Otolaryngology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - John C. Krauss
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Moshe Talpaz
- Department of Internal Medicine, Division of Hematology/Oncology
| | - N. Lynn Henry
- Department of Internal Medicine, Division of Hematology/Oncology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Maria D. Giraldez
- Department of Internal Medicine, Division of Hematology/Oncology
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain
| | - Nithya Ramnath
- Department of Internal Medicine, Division of Hematology/Oncology
| | - Scott A. Tomlins
- Michigan Center for Translational Pathology
- Department of Pathology
- Department of Urology
| | - Paul L. Swiecicki
- Department of Internal Medicine, Division of Hematology/Oncology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - J. Chad Brenner
- Department of Otolaryngology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pharmacology
| | - Muneesh Tewari
- Department of Internal Medicine, Division of Hematology/Oncology
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
- Department of Biomedical Engineering, and
- Center for Computational Biology and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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Kim AK, Lin SY, Wang Z, Luu H, Hamilton JP, Song W, Su YH. Impact of Cell-Debris and Room-Temperature Storage on Urine Circulating Tumor DNA from Hepatocellular Carcinoma. J Mol Diagn 2023; 25:913-920. [PMID: 37813297 PMCID: PMC10734279 DOI: 10.1016/j.jmoldx.2023.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/01/2023] [Accepted: 08/25/2023] [Indexed: 10/11/2023] Open
Abstract
This study evaluated the impact of cell debris and 7-day room temperature storage on the quality and yield of transrenal DNA. Archived urine specimens collected from five hepatocellular carcinoma (HCC) patients and two pregnant women carrying male fetuses were used to assess the impact of cell debris on urine cell-free DNA (ucfDNA) isolation as measured by quantitative PCR for Y-chromosome DNA, or HCC-associated mutation and methylation markers, and by capillary electrophoresis. Prospectively collected urine from 21 HCC patients was aliquoted after collection for paired immediate freezing versus 7-day room temperature storage followed by freezing for further analysis. Cell debris contained more Y-chromosome DNA than supernatant in three of the six urine specimens tested from pregnant women, suggesting that cell debris can be associated with 20.6% to 84.9% of transrenal ucfDNA. Ninety-five percent (20 of 21) of frozen and room temperature urine pairs had overlapping DNA size distribution. ucfDNA quantity determined by quantitative PCR for TP53, CTNNB1, TERT, and HCC-associated urine circulating tumor DNA markers were statistically similar between room temperature and frozen samples. This suggests no significant difference in DNA degradation between the groups. The association of transrenal ucfDNA with cell debris and HCC circulating DNA stability at room temperature is significant to further the understanding of transrenal circulating tumor DNA pre-analytical handling for HCC screening.
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Affiliation(s)
- Amy K Kim
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Zhili Wang
- JBS Science, Inc., Doylestown, Pennsylvania
| | - Harry Luu
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - James P Hamilton
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Wei Song
- JBS Science, Inc., Doylestown, Pennsylvania
| | - Ying-Hsiu Su
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania.
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Deng K, Xing J, Xu G, Jin B, Wan X, Zheng Y, Du S, Sang X. Urinary biomarkers for hepatocellular carcinoma: current knowledge for clinicians. Cancer Cell Int 2023; 23:239. [PMID: 37833757 PMCID: PMC10571477 DOI: 10.1186/s12935-023-03092-5] [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: 05/29/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer, causing many illnesses and deaths worldwide. The insidious clinical presentation, difficulty in early diagnosis, and the highly malignant nature make the prognosis of HCC extremely poor. The complex and heterogeneous pathogenesis of HCC poses significant challenges to developing therapies. Urine-based biomarkers for HCC, including diagnostic, prognostic, and monitoring markers, may be valuable supplements to current tools such as serum α-fetoprotein (AFP) and seem promising for progress in precision medicine. Herein, we reviewed the major urinary biomarkers for HCC and assessed their potential for clinical application. Molecular types, testing platforms, and methods for building multimolecule models in the included studies have shown great diversity, thus providing abundant novel tools for future clinical transformation and applications.
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Affiliation(s)
- Kaige Deng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Jiali Xing
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Gang Xu
- Department of Liver Surgery and Liver Transplant Center, West China Hospital of Sichuan University, Chengdu, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Yongchang Zheng
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Spârchez Z, Crăciun R, Nenu I, Mocan LP, Spârchez M, Mocan T. Refining Liver Biopsy in Hepatocellular Carcinoma: An In-Depth Exploration of Shifting Diagnostic and Therapeutic Applications. Biomedicines 2023; 11:2324. [PMID: 37626820 PMCID: PMC10452389 DOI: 10.3390/biomedicines11082324] [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: 07/26/2023] [Revised: 08/17/2023] [Accepted: 08/19/2023] [Indexed: 08/27/2023] Open
Abstract
The field of hepatocellular carcinoma (HCC) has faced significant change on multiple levels in the past few years. The increasing emphasis on the various HCC phenotypes and the emergence of novel, specific therapies have slowly paved the way for a personalized approach to primary liver cancer. In this light, the role of percutaneous liver biopsy of focal lesions has shifted from a purely confirmatory method to a technique capable of providing an in-depth characterization of any nodule. Cancer subtype, gene expression, the mutational profile, and tissue biomarkers might soon become widely available through biopsy. However, indications, expectations, and techniques might suffer changes as the aim of the biopsy evolves from providing minimal proof of the disease to high-quality specimens for extensive analysis. Consequently, a revamped position of tissue biopsy is expected in HCC, following the reign of non-invasive imaging-only diagnosis. Moreover, given the advances in techniques that have recently reached the spotlight, such as liquid biopsy, concomitant use of all the available methods might gather just enough data to improve therapy selection and, ultimately, outcomes. The current review aims to discuss the changing role of liver biopsy and provide an evidence-based rationale for its use in the era of precision medicine in HCC.
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Affiliation(s)
- Zeno Spârchez
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Rareș Crăciun
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Iuliana Nenu
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Lavinia Patricia Mocan
- Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Mihaela Spârchez
- 2nd Pediatric Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400124 Cluj-Napoca, Romania;
| | - Tudor Mocan
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- UBBMed Department, Babeș-Bolyai University, 400349 Cluj-Napoca, Romania
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10
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Raszeja-Wyszomirska J, Macech M, Kolanowska M, Krawczyk M, Nazarewski S, Wójcicka A, Małyszko J. Free-Circulating Nucleic Acids as Biomarkers in Patients After Solid Organ Transplantation. Ann Transplant 2023; 28:e939750. [PMID: 37580899 PMCID: PMC10439677 DOI: 10.12659/aot.939750] [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: 02/07/2023] [Accepted: 05/17/2023] [Indexed: 08/16/2023] Open
Abstract
A number types of extracellular DNA (eg, cell-free, cfDNA) circulate in human blood, including mitochondrial, transcriptome, and regulatory DNA, usually at low concentrations. Larger amounts of cfDNA appear in any inflammatory condition, including organ damage due to a variety of reasons. The role of cfDNA in solid organ transplantation is discussed in this review as a valuable additional tool in the standard of care of transplant patients. Post-transplant monitoring requires the use of high-quality biomarkers for early detection of graft damage or rejection to be able to apply early therapeutic intervention. CfDNA complements the traditional monitoring strategies, being a risk stratification tool and an important prognostic marker. However, improving the sensitivity and specificity of cfDNA detection is necessary to facilitate personalized patient management, warranting further research in terms of measurement, test standardization, and storage, processing, and shipping. A diagnostic test (Allosure, CareDx, Inc., Brisbane, CA) for kidney, heart and lung transplant patients is now commercially available, and validation for other organs (eg, liver) is pending. To date, donor-derived cfDNA in combination with other biomarkers appears to be a promising tool in graft rejection as it is minimally invasive, time-sensitive, and cost-effective. However, improvement of sensitivity and specificity is required to facilitate personalized patient management. Whether it could be an alternate to graft biopsy remains unclear.
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Affiliation(s)
- Joanna Raszeja-Wyszomirska
- Department of Hepatology, Transplantology, and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michał Macech
- Department of General, Vascular, and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland
| | | | - Marek Krawczyk
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Sławomir Nazarewski
- Department of General, Vascular, and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland
| | | | - Jolanta Małyszko
- Department of Nephrology, Dialysis, and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
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11
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Santini D, Botticelli A, Galvano A, Iuliani M, Incorvaia L, Gristina V, Taffon C, Foderaro S, Paccagnella E, Simonetti S, Fazio F, Scagnoli S, Pomati G, Pantano F, Perrone G, De Falco E, Russo A, Spinelli GP. Network approach in liquidomics landscape. J Exp Clin Cancer Res 2023; 42:193. [PMID: 37542343 PMCID: PMC10401883 DOI: 10.1186/s13046-023-02743-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/27/2023] [Indexed: 08/06/2023] Open
Abstract
Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.
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Affiliation(s)
- Daniele Santini
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | - Andrea Botticelli
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | - Antonio Galvano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Michele Iuliani
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Lorena Incorvaia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Valerio Gristina
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Chiara Taffon
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico Di Roma, Rome, Italy
| | - Simone Foderaro
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Elisa Paccagnella
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.So Della Repubblica 79, 04100, Latina, Italy
| | - Sonia Simonetti
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Federico Fazio
- UOC Oncologia Territoriale, Polo Pontino, La Sapienza Università Di Roma, Latina, Italy.
| | - Simone Scagnoli
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | | | - Francesco Pantano
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Giuseppe Perrone
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico Di Roma, Rome, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.So Della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, 80122, Naples, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Gian Paolo Spinelli
- UOC Oncologia Territoriale, Polo Pontino, La Sapienza Università Di Roma, Latina, Italy
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12
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Assi T, Khoury R, Ibrahim R, Baz M, Ibrahim T, LE Cesne A. Overview of the role of liquid biopsy in cancer management. Transl Oncol 2023; 34:101702. [PMID: 37267803 DOI: 10.1016/j.tranon.2023.101702] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 06/04/2023] Open
Abstract
With the emergence of novel targeted therapeutic options in early-stage and advanced-stage malignancies, researchers have shifted their focus on developing personalized treatment plans through molecular profiling. Circulating tumor DNA (ctDNA) is a cell-free DNA (ctDNA) fragment, originating from tumor cells, and circulating in the bloodstream as well as biological fluids. Over the past decade, many techniques were developed for liquid biopsies through next-generation sequencing. This alternative non-invasive biopsy offers several advantages in various types of tumors over traditional tissue biopsy. The process of liquid biopsy is considered minimally invasive and therefore easily repeatable when needed, providing a more dynamic analysis of the tumor cells. Moreover, it has an advantage in patients with tumors that are not candidates for tissue sampling. Besides, it offers a deeper understanding of tumor burden as well as treatment response, thereby enhancing the detection of minimal residual disease and therapeutic guidance for personalized medicine. Despite its many advantages, ctDNA and liquid biopsy do have some limitations. This paper discusses the basis of ctDNA and the current data available on the subject, as well as its clinical utility. We also reflect on the limitations of using ctDNA in addition to its future perspectives in clinical oncology and precision medicine.
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Affiliation(s)
- Tarek Assi
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France.
| | - Rita Khoury
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Rebecca Ibrahim
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Maria Baz
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Tony Ibrahim
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Axel LE Cesne
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
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13
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Jordaens S, Zwaenepoel K, Tjalma W, Deben C, Beyers K, Vankerckhoven V, Pauwels P, Vorsters A. Urine biomarkers in cancer detection: A systematic review of preanalytical parameters and applied methods. Int J Cancer 2023; 152:2186-2205. [PMID: 36647333 DOI: 10.1002/ijc.34434] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/25/2022] [Accepted: 12/29/2022] [Indexed: 01/18/2023]
Abstract
The aim of this review was to explore the status of urine sampling as a liquid biopsy for noninvasive cancer research by reviewing used preanalytical parameters and protocols. We searched two main health sciences databases, PubMed and Web of Science. From all eligible publications (2010-2022), information was extracted regarding: (a) study population characteristics, (b) cancer type, (c) urine preanalytics, (d) analyte class, (e) isolation method, (f) detection method, (g) comparator used, (h) biomarker type, (i) conclusion and (j) sensitivity and specificity. The search query identified 7835 records, of which 924 unique publications remained after screening the title, abstract and full text. Our analysis demonstrated that many publications did not report information about the preanalytical parameters of their urine samples, even though several other studies have shown the importance of standardization of sample handling. Interestingly, it was noted that urine is used for many cancer types and not just cancers originating from the urogenital tract. Many different types of relevant analytes have been shown to be found in urine. Additionally, future considerations and recommendations are discussed: (a) the heterogeneous nature of urine, (b) the need for standardized practice protocols and (c) the road toward the clinic. Urine is an emerging liquid biopsy with broad applicability in different analytes and several cancer types. However, standard practice protocols for sample handling and processing would help to elaborate the clinical utility of urine in cancer research, detection and disease monitoring.
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Affiliation(s)
- Stephanie Jordaens
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Novosanis NV, Wijnegem, Belgium
| | - Karen Zwaenepoel
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Wiebren Tjalma
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Multidisciplinary Breast Clinic, Gynecological Oncology Unit, Department of Obstetrics and Gynecology, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Christophe Deben
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
| | | | - Vanessa Vankerckhoven
- Novosanis NV, Wijnegem, Belgium.,Center for Evaluation of Vaccination (CEV), Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.,Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Alex Vorsters
- Center for Evaluation of Vaccination (CEV), Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
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14
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Lin SY, Halegoua-DeMarzio D, Block P, Kao YL, Civan J, Shieh FS, Song W, Hann HW, Su YH. Persistently Elevated HBV Viral-Host Junction DNA in Urine as a Biomarker for Hepatocellular Carcinoma Minimum Residual Disease and Recurrence: A Pilot Study. Diagnostics (Basel) 2023; 13:1537. [PMID: 37174929 PMCID: PMC10177231 DOI: 10.3390/diagnostics13091537] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 05/15/2023] Open
Abstract
Hepatitis B virus (HBV)-host junction sequences (HBV-JSs) has been detected in the urine of patients with HBV infection. This study evaluated HBV-JSs as a marker of minimum residual disease (MRD) and tumor recurrence after treatment in HBV-hepatocellular carcinoma (HCC) patients. Archived serial urine DNA from two HBV-HCC with recurrence as confirmed by MRI and four HBV-related cirrhosis (LC) patients were used. Urinary HBV-JSs were identified by an HBV-targeted NGS assay. Quantitative junction-specific PCR assays were developed to investigate dynamic changes of the most abundant urinary HBV-JS. Abundant urinary HBV-JSs were identified in two cases of tumor recurrence. In case 1, a 78-year-old female with HBV- HCC underwent a follow-up MRI following microwave ablation. While MRI results were variable, the unique HBV-JS DNA, HBV-Chr17, steadily increased from initial diagnosis to HCC recurrence. In case 2, a 74-year-old male with HBV-HCC contained two HBV-JS DNA, HBV-Chr11 and HBV-TERT, that steadily increased after initial HCC diagnosis till recurrence. One LC examined had HBV-TERT DNA detected, but transiently in 3.5 years during HCC surveillance. HBV-JS DNA was persistently elevated prior to the diagnosis of recurrent HCC, suggesting the potential of urinary HBV-JS DNA to detect MRD and HCC recurrence after treatment.
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Affiliation(s)
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Peter Block
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yu-Lan Kao
- Department of Translational Science, Baruch S. Blumberg Institute, Doylestown, PA 18901, USA
| | - Jesse Civan
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | | | - Wei Song
- JBS Science Inc., Doylestown, PA 18901, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Ying-Hsiu Su
- Department of Translational Science, Baruch S. Blumberg Institute, Doylestown, PA 18901, USA
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15
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Pilotto Heming C, Niemeyer Filho P, Moura-Neto V, Aran V. Recent advances in the use of liquid biopsy to fight central nervous system tumors. Cancer Treat Res Commun 2023; 35:100709. [PMID: 37088042 DOI: 10.1016/j.ctarc.2023.100709] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/25/2023]
Abstract
Brain tumors are considered one of the deadliest types of cancer, being challenging to treat, especially due to the blood-brain barrier, which has been linked to treatment resistance. The genomic classification of brain tumors has been helping in the diagnostic precision, however tumor heterogeneity in addition to the difficulties to obtain tissue biopsies, represent a challenge. The biopsies are usually obtained either via neurosurgical removal or stereotactic tissue biopsy, which can be risky procedures for the patient. To overcome these challenges, liquid biopsy has become an interesting option by constituting a safer procedure than conventional biopsy, which may offer valuable cellular and molecular information representative of the whole organism. Besides, it is relatively easy to obtain such as in the case of blood (venipuncture) and urine sample collection. In the present comprehensive review, we discuss the newest information regarding liquid biopsy in the brain tumors' field, methods employed, the different sources of bio-fluids and their potential circulating targets.
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Affiliation(s)
- Carlos Pilotto Heming
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), R. do Rezende, 156 - Centro, Rio de Janeiro, 20231-092, Brazil
| | - Paulo Niemeyer Filho
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), R. do Rezende, 156 - Centro, Rio de Janeiro, 20231-092, Brazil
| | - Vivaldo Moura-Neto
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), R. do Rezende, 156 - Centro, Rio de Janeiro, 20231-092, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), R. do Rezende, 156 - Centro, Rio de Janeiro, 20231-092, Brazil.
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16
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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17
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Ibrahim J, Peeters M, Van Camp G, Op de Beeck K. Methylation biomarkers for early cancer detection and diagnosis: Current and future perspectives. Eur J Cancer 2023; 178:91-113. [PMID: 36427394 DOI: 10.1016/j.ejca.2022.10.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/11/2022] [Accepted: 10/17/2022] [Indexed: 11/25/2022]
Abstract
The increase in recent scientific studies on cancer biomarkers has brought great new insights into the field. Moreover, novel technological breakthroughs such as long read sequencing and microarrays have enabled high throughput profiling of many biomarkers, while advances in bioinformatic tools have made the possibility of developing highly reliable and accurate biomarkers a reality. These changes triggered renewed interest in biomarker research and provided tremendous opportunities for enhancing cancer management and improving early disease detection. DNA methylation alterations are known to accompany and contribute to carcinogenesis, making them promising biomarkers for cancer, namely due to their stability, frequency and accessibility in bodily fluids. The advent of newer minimally invasive experimental methods such as liquid biopsies provide the perfect setting for methylation-based biomarker development and application. Despite their huge potential, accurate and robust biomarkers for the conclusive diagnosis of most cancer types are still not routinely used, hence a strong need for sustained research in this field is still needed. This review provides a brief exposition of current methylation biomarkers for cancer diagnosis and early detection, including markers already in clinical use as well as various upcoming ones. It also outlines how recent big data and novel technologies will revolutionise the next generation of cancer tests in supplementing or replacing currently existing invasive techniques.
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Affiliation(s)
- Joe Ibrahim
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Marc Peeters
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
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18
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Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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19
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Tivey A, Church M, Rothwell D, Dive C, Cook N. Circulating tumour DNA - looking beyond the blood. Nat Rev Clin Oncol 2022; 19:600-612. [PMID: 35915225 PMCID: PMC9341152 DOI: 10.1038/s41571-022-00660-y] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2022] [Indexed: 02/06/2023]
Abstract
Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.
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Affiliation(s)
- Ann Tivey
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- The Christie NHS Foundation Trust, Manchester, UK
| | - Matt Church
- The Christie NHS Foundation Trust, Manchester, UK
| | - Dominic Rothwell
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Manchester, UK
| | - Caroline Dive
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, The University of Manchester, Manchester, UK
| | - Natalie Cook
- Division of Cancer Sciences, The University of Manchester, Manchester, UK.
- The Christie NHS Foundation Trust, Manchester, UK.
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20
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Kim AK, Hamilton JP, Lin SY, Chang TT, Hann HW, Hu CT, Lou Y, Lin YJ, Gade TP, Park G, Luu H, Lee TJ, Wang J, Chen D, Goggins MG, Jain S, Song W, Su YH. Urine DNA biomarkers for hepatocellular carcinoma screening. Br J Cancer 2022; 126:1432-1438. [PMID: 35046521 PMCID: PMC9091244 DOI: 10.1038/s41416-022-01706-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/20/2021] [Accepted: 01/07/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test. METHODS Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test. RESULTS Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A). CONCLUSION Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.
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Affiliation(s)
- Amy K Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James P Hamilton
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hie-Won Hann
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Chi-Tan Hu
- Division of Gastroenterology, Department of Internal Medicine, Hualien Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Yue Lou
- The Baruch S. Blumberg Institute, Doylestown, PA, USA
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan, Republic of China
| | - Terence P Gade
- Department of Radiology, University of Pennsylvania College of Medicine, Philadelphia, PA, USA
| | - Grace Park
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Harry Luu
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tai-Jung Lee
- The Baruch S. Blumberg Institute, Doylestown, PA, USA
| | | | - Dion Chen
- ClinPharma Consulting, Inc, Phoenixville, PA, USA
| | - Michael G Goggins
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA
| | | | - Wei Song
- JBS Science, Inc., Doylestown, PA, USA
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Institute, Doylestown, PA, USA.
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21
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Dermody SM, Bhambhani C, Swiecicki PL, Brenner JC, Tewari M. Trans-Renal Cell-Free Tumor DNA for Urine-Based Liquid Biopsy of Cancer. Front Genet 2022; 13:879108. [PMID: 35571046 PMCID: PMC9091346 DOI: 10.3389/fgene.2022.879108] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer biomarkers are a promising tool for cancer detection, personalization of therapy, and monitoring of treatment response or recurrence. “Liquid biopsy” commonly refers to minimally invasive or non-invasive sampling of a bodily fluid (i.e., blood, urine, saliva) for detection of cancer biomarkers such as circulating tumor cells or cell-free tumor DNA (ctDNA). These methods offer a means to collect frequent tumor assessments without needing surgical biopsies. Despite much progress with blood-based liquid biopsy approaches, there are limitations—including the limited amount of blood that can be drawn from a person and challenges with collecting blood samples at frequent intervals to capture ctDNA biomarker kinetics. These limitations are important because ctDNA is present at extremely low levels in plasma and there is evidence that measuring ctDNA biomarker kinetics over time can be useful for clinical prediction. Additionally, blood-based assays require access to trained phlebotomists and often a trip to a healthcare facility. In contrast, urine is a body fluid that can be self-collected from a patient’s home, at frequent intervals, and mailed to a laboratory for analysis. Multiple reports indicate that fragments of ctDNA pass from the bloodstream through the kidney’s glomerular filtration system into the urine, where they are known as trans-renal ctDNA (TR-ctDNA). Accumulating studies indicate that the limitations of blood based ctDNA approaches for cancer can be overcome by measuring TR-ctDNA. Here, we review current knowledge about TR-ctDNA in urine as a cancer biomarker approach, and discuss its clinical potential and open questions in this research field.
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Affiliation(s)
- Sarah M. Dermody
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI, United States
| | - Chandan Bhambhani
- Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Paul L. Swiecicki
- Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, United States
- Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
| | - J. Chad Brenner
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI, United States
| | - Muneesh Tewari
- Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, United States
- Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- Center for Computational Biology and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Muneesh Tewari,
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22
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Lone SN, Nisar S, Masoodi T, Singh M, Rizwan A, Hashem S, El-Rifai W, Bedognetti D, Batra SK, Haris M, Bhat AA, Macha MA. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer 2022; 21:79. [PMID: 35303879 PMCID: PMC8932066 DOI: 10.1186/s12943-022-01543-7] [Citation(s) in RCA: 379] [Impact Index Per Article: 126.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 02/07/2023] Open
Abstract
Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly evolved over the past few years as described in the review, thus providing greater details about tumor characteristics such as tumor progression, tumor staging, heterogeneity, gene mutations, and clonal evolution, etc. Liquid biopsies from cancer patients have opened up newer avenues in detection and continuous monitoring, treatment based on precision medicine, and screening of markers for therapeutic resistance. Though the technology of liquid biopsies is still evolving, its non-invasive nature promises to open new eras in clinical oncology. The purpose of this review is to provide an overview of the current methodologies involved in liquid biopsies and their application in isolating tumor markers for detection, prognosis, and monitoring cancer treatment outcomes.
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Affiliation(s)
- Saife N Lone
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Arshi Rizwan
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Sheema Hashem
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
| | - Davide Bedognetti
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar
- Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE 68198, Omaha, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center , Omaha, NE 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, University of Nebraska Medical Center, NE 68198, Omaha, USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
- Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Ajaz A Bhat
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, (IUST), 192122, Awantipora, Jammu & Kashmir, India.
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23
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Reddy T, Esmail A, Chang JC, Ghobrial RM, Abdelrahim M. Utility of Cell-Free DNA Detection in Transplant Oncology. Cancers (Basel) 2022; 14:cancers14030743. [PMID: 35159010 PMCID: PMC8833373 DOI: 10.3390/cancers14030743] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/20/2022] [Accepted: 01/29/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. This review aims to provide a comprehensive overview of the history and emergence of cfDNA technology, its applications to specifically monitor tumor burden at pre-and post-liver transplant stages, and evaluate transplant rejection. The use of ctDNA to evaluate transplant rejection has been extensively studied in non-hepatocellular carcinoma (HCC) diseases. Emerging studies have also investigated the use of ctDNA detection in evaluating HCC tumor burden pre-and post-surgery as well as transplant rejection. However, extensive studies still need to be conducted to evaluate the role of ctDNA detection in the medical management of transplant oncology patients. Abstract Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care is efficient monitoring of tumor burden pre-and post-transplant and transplant rejection. Cell-free DNA (cfDNA) detection has emerged as a vital tool in revolutionizing the management of cancer patients who undergo organ transplantation. The advances in cfDNA technology have provided options to perform a pre-transplant evaluation of minimal residual disease (MRD) and post-transplant evaluation of cancer recurrence and transplant rejection. This review aims to provide a comprehensive overview of the history and emergence of cfDNA technology, its applications to specifically monitor tumor burden at pre-and post-transplant stages, and evaluate transplant rejection.
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Affiliation(s)
- Tejaswini Reddy
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (T.R.); (A.E.)
- Texas A&M Health Science Center, College of Medicine, Bryan, TX 77807, USA
- Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (T.R.); (A.E.)
- Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Jenny C. Chang
- Houston Methodist Research Institute, Houston, TX 77030, USA;
- Section of Breast, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Rafik Mark Ghobrial
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA;
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Center for Transplantation, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (T.R.); (A.E.)
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA;
- Cockrell Center of Advanced Therapeutics Phase I program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Correspondence:
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Nath LR, Murali M, Nair B. Critical biomarkers of hepatocellular carcinoma in body fluids and gut microbiota. World J Gastrointest Oncol 2021; 13:2219-2222. [PMID: 35070054 PMCID: PMC8713307 DOI: 10.4251/wjgo.v13.i12.2219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/15/2021] [Accepted: 11/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and one of the major causes of cancer-related death. The development of specific non-invasive or diagnostic markers from blood, urine and feces may represent a valuable tool for detecting HCC at an early stage. Biomarkers are considered novel potential targets for therapeutic intervention. It helps in the prediction of prognosis or recurrence of HCC, and also assist in the selection of appropriate treatment modality. We summarize the most relevant existing data about various biomarkers that play a key role in the progression of HCC.
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Affiliation(s)
- Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Maneesha Murali
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Bhagyalakshmi Nair
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
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25
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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26
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Lin SY, Su Y, Trauger ER, Song BP, Thompson EG, Hoffman MC, Chang T, Lin Y, Kao Y, Cui Y, Hann H, Park G, Shieh F, Song W, Su Y. Detection of Hepatitis B Virus-Host Junction Sequences in Urine of Infected Patients. Hepatol Commun 2021; 5:1649-1659. [PMID: 34558837 PMCID: PMC8485884 DOI: 10.1002/hep4.1783] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/24/2021] [Accepted: 06/20/2021] [Indexed: 01/25/2023] Open
Abstract
Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral-host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy.
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Affiliation(s)
| | - Yih‐Ping Su
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | | | | | | | | | - Ting‐Tsung Chang
- Department of Internal MedicineNational Cheng Kung University Hospital, College of MedicineTainanTaiwan, Republic of China
| | - Yih‐Jyh Lin
- Department of SurgeryNational Cheng Kung University Hospital, College of MedicineTainanTaiwan, Republic of China
| | - Yu‐Lan Kao
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | - Yixiao Cui
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
| | - Hie‐Won Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologyThomas Jefferson University HospitalPhiladelphiaPAUSA
| | - Grace Park
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologyThomas Jefferson University HospitalPhiladelphiaPAUSA
| | | | - Wei Song
- JBS Science, Inc.DoylestownPAUSA
| | - Ying‐Hsiu Su
- The Baruch S. Blumberg Research InstituteDoylestownPAUSA
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Transplant Oncology: An Evolving Field in Cancer Care. Cancers (Basel) 2021; 13:cancers13194911. [PMID: 34638395 PMCID: PMC8508383 DOI: 10.3390/cancers13194911] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The application of oncology, transplant medicine, and surgery to improve patients' survival and quality of life is the core of transplant oncology. Hepatobiliary malignancies have been treated by liver transplantation (LT) with significant improved outcome. In addition, as the liver is the most common site of metastasis for colorectal cancer (CRC), patients with CRC who have stable unresectable liver metastases are good candidates for LT, and initial studies have shown improved survival compared to palliative systemic therapy. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years in a stepwise manner; however, they have only been shown to improve patient survival in the setting of limited systemic therapy options. This review illustrates the concept and history of transplant oncology as an evolving field for the management of hepatocellular carcinoma, intrahepatic biliary cancer, and liver-only metastasis of non-hepatobiliary carcinoma. The utility of immunotherapy in the transplant setting is discussed as well as the feasibility of using circulating tumor DNA for surveillance post-transplantation.
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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: 6] [Impact Index Per Article: 1.5] [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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29
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Cimmino I, Bravaccini S, Cerchione C. Urinary Biomarkers in Tumors: An Overview. Methods Mol Biol 2021; 2292:3-15. [PMID: 33651347 DOI: 10.1007/978-1-0716-1354-2_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] [Indexed: 02/16/2023]
Abstract
Recent reports suggest that urine is a useful noninvasive tool for the identification of urogenital tumors, including bladder, prostate, kidney, and other nonurological cancers. As a liquid biopsy, urine represents an important source for the improvement of new promising biomarkers, a suitable tool to identify indolent cancer and avoid overtreatment. Urine is enriched with DNAs, RNAs, proteins, circulating tumor cells, exosomes, and other small molecules which can be detected with several diagnostic methodologies.We provide an overview of the ongoing state of urinary biomarkers underlying both their potential utilities to improve cancer prognosis, diagnosis, and therapeutic strategy and their limitations.
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Affiliation(s)
- Ilaria Cimmino
- Department of Translational Medicine, University of Naples "Federico II", Naples, Italy
| | - Sara Bravaccini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Claudio Cerchione
- Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
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30
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Lin SY, Luo Y, Marshall MM, Johnson BJ, Park SR, Wang Z, Su YH. A New Method for Improving Extraction Efficiency and Purity of Urine and Plasma Cell-Free DNA. Diagnostics (Basel) 2021; 11:diagnostics11040650. [PMID: 33916811 PMCID: PMC8067265 DOI: 10.3390/diagnostics11040650] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/26/2021] [Accepted: 03/31/2021] [Indexed: 12/17/2022] Open
Abstract
This study assessed three commercially available cell-free DNA (cfDNA) extraction kits and the impact of a PEG-based DNA cleanup procedure (DNApure) on cfDNA quality and yield. Six normal donor urine and plasma samples and specimens from four pregnant (PG) women carrying male fetuses underwent extractions with the JBS cfDNA extraction kit (kit J), MagMAX Cell-Free DNA Extraction kit (kit M), and QIAamp Circulating Nucleic Acid Kit (kit Q). Recovery of a PCR product spike-in, endogenous TP53, and Y-chromosome DNA was used to assess kit performance. Nucleosomal-sized DNA profiles varied among the kits, with prominent multi-nucleosomal-sized peaks present in urine and plasma DNA isolated by kits J and M only. Kit J recovered significantly more spike-in DNA than did kits M or Q (p < 0.001) from urine, and similar amounts from plasma (p = 0.12). Applying DNApure to kit M- and Q-isolated DNA significantly improved the amplification efficiency of spike-in DNA from urine (p < 0.001) and plasma (p ≤ 0.013). Furthermore, kit J isolated significantly more Y-chromosome DNA from PG urine compared to kit Q (p = 0.05). We demonstrate that DNApure can provide an efficient means of improving the yield and purity of cfDNA and minimize the effects of pre-analytical biospecimen variability on liquid biopsy assay performance.
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Affiliation(s)
- Selena Y. Lin
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (M.M.M.); (B.J.J.); (Z.W.)
| | - Yue Luo
- The Baruch S Blumberg Institute, Doylestown, PA 18902, USA; (Y.L.); (S.R.P.)
| | - Matthew M. Marshall
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (M.M.M.); (B.J.J.); (Z.W.)
| | - Barbara J. Johnson
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (M.M.M.); (B.J.J.); (Z.W.)
| | - Sung R. Park
- The Baruch S Blumberg Institute, Doylestown, PA 18902, USA; (Y.L.); (S.R.P.)
| | - Zhili Wang
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (M.M.M.); (B.J.J.); (Z.W.)
| | - Ying-Hsiu Su
- The Baruch S Blumberg Institute, Doylestown, PA 18902, USA; (Y.L.); (S.R.P.)
- Correspondence: ; Tel.: +(1)-215-489-4907
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Arechederra M, Recalde M, Gárate-Rascón M, Fernández-Barrena MG, Ávila MA, Berasain C. Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease. Cancers (Basel) 2021; 13:1265. [PMID: 33809263 PMCID: PMC7998165 DOI: 10.3390/cancers13061265] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.
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Affiliation(s)
- María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
| | - María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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Labgaa I, Villanueva A, Dormond O, Demartines N, Melloul E. The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication. Cancers (Basel) 2021; 13:cancers13040659. [PMID: 33562173 PMCID: PMC7914891 DOI: 10.3390/cancers13040659] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest cancer. Clinical guidelines for the management of HCC endorse algorithms deriving from clinical variables whose performances to prognosticate HCC is limited. Liquid biopsy is the molecular analysis of tumor by-products released into the bloodstream. It offers minimally-invasive access to circulating analytes like DNA, RNA, exosomes and cells. This technology demonstrated promising results for various applications in cancers, including prognostication. This review aimed to provide a comprehensive overview of the contribution of liquid biopsy in HCC prognostication. The results suggested that liquid biopsy may be a polyvalent and valuable tool to prognosticate HCC. Abstract Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication.
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Affiliation(s)
- Ismail Labgaa
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Olivier Dormond
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
- Correspondence:
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
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Zhang W, Zhang XJ, Chao SY, Chen SJ, Zhang ZJ, Zhao J, Lv YN, Yao JJ, Bai YY. Update on urine as a biomarker in cancer: a necessary review of an old story. Expert Rev Mol Diagn 2020; 20:477-488. [PMID: 32212972 DOI: 10.1080/14737159.2020.1743687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Cancer causes thousands of deaths worldwide each year. Therefore, monitoring of health status and the early diagnosis of cancer using noninvasive assays, such as the analysis of molecular biomarkers in urine, is essential. However, effective biomarkers for early diagnosis of cancer have not been established in many types of cancer.Areas covered: In this review, we discuss recent findings with regard to the use of urine composition as a biomarker in eleven types of cancer. We also highlight the use of urine biomarkers for improving early diagnosis.Expert opinion: Urinary biomarkers have been applied for clinical application of early diagnosis. The main limitation is a lack of integrated approaches for identification of new biomarkers in most cancer. The utilization of urinary biomarker detection will be promoted by improved detection methods and new data from different types of cancers. With the development of precision medicine, urinary biomarkers will play an increasingly important clinical role. Future early diagnosis would benefit from changes in the utilization of urinary biomarkers.
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Affiliation(s)
- Wei Zhang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Xiao Jian Zhang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Shen Yan Chao
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Su Juan Chen
- Synthetic Biology Engineering Lab of Henan Province, School of Sciences and Technology, Xinxiang Medical University, Henan, China
| | - Zi Jing Zhang
- Institute of Animal Husbandry and Veterinary Science, Henan Academy of Agricultural Sciences, Zhengzhou, Henan, PR China
| | - Jian Zhao
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Ya Nan Lv
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Jing Jie Yao
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, China
| | - Yue Yu Bai
- Animal Health Supervision in Henan Province, Zhengzhou, Henan, PR China
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with high mortality. The currently used methods for diagnosing HCC, including imaging modalities and liver biopsy, detect tumors at a relatively advanced stage or are invasive. Non-invasive biomarkers are urgently needed to facilitate screening and early diagnosis of HCC, as well as treatment monitoring and detection of tumor recurrence. Liquid biopsy, the analysis of blood or other body fluids to obtain genetic and epigenetic information, has historically been applied to other types of cancer including breast and prostate cancer. Over the past few decades, liquid biopsy analysis has shed significant insights on genetic and epigenetic aberrations in HCC detectable in peripheral blood. Aberrations in nucleic acids found circulating freely in body fluids or contained within extracellular vesicles such as exosomes or microvesicles show potential clinical utility as non-invasive biomarkers. In this review, we present available literature on cell-free nucleic acids in the diagnosis of HCC.
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Affiliation(s)
- Bubu A Banini
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
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Jain S, Lin SY, Song W, Su YH. Urine-Based Liquid Biopsy for Nonurological Cancers. Genet Test Mol Biomarkers 2019; 23:277-283. [PMID: 30986103 DOI: 10.1089/gtmb.2018.0189] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIMS The use of circulating cell-free DNA for detection of cancer genetics has been studied extensively. Liquid biopsy often refers to the use of blood as a minimally invasive source of body fluid for detecting circulating tumor DNA (ctDNA). However, urine collection, which is completely noninvasive, has been shown to also have great promise to serve as an alternate body fluid source for ctDNA. In this review article, we focus on the clinical utility of urine for genetic liquid biopsy of nonurological cancers. CONCLUSION Although still in early stages as compared with blood-based liquid biopsy, recent studies have demonstrated the value of urine-based liquid biopsies for: nonurological cancer screening; early detection; monitoring for recurrence and metastasis; and therapeutic efficacy. Overall, the completely noninvasive and patient-friendly nature of the urine-based biopsy warrants further development and offers a promising alternative to blood-based biopsies.
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Affiliation(s)
- Surbhi Jain
- 1 JBS Science, Inc., Doylestown, Pennsylvania
| | | | - Wei Song
- 1 JBS Science, Inc., Doylestown, Pennsylvania
| | - Ying-Hsiu Su
- 2 Department of Translational Medical Science, The Baruch S. Blumberg Institute, Doylestown, Pennsylvania
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36
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Wang S, Gribskov M. Transcriptome analysis identifies metallothionein as biomarkers to predict recurrence in hepatocellular cacinoma. Mol Genet Genomic Med 2019; 7:e693. [PMID: 31056863 PMCID: PMC6565558 DOI: 10.1002/mgg3.693] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 02/17/2019] [Accepted: 03/14/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Liver cancer is the fifth most common cancer, and hepatocellular carcinoma (HCC) is the major liver tumor type seen in adults. HCC is usually caused by chronic liver disease such as hepatitis B virus or hepatitis C virus infection. One of the promising treatments for HCC is liver transplantation, in which a diseased liver is replaced with a healthy liver from another person. However, recurrence of HCC after surgery is a significant problem. Therefore, it is important to discover reliable cellular biomarkers that can predict recurrence in HCC. METHODS We analyzed previously published HCC RNA-Seq data that includes 21 paired tumor and normal samples, in which nine tumors were recurrent after orthotopic liver transplantation and 12 were nonrecurrent tumors with their paired normal samples. We used both the reference genome and de novo transcriptome assembly based analyses to identify differentially expressed genes (DEG) and used RandomForest to discover biomarkers. RESULTS We obtained 398 DEG using the Reference approach and 412 DEG using de novo assembly approach. Among these DEG, 258 genes were identified by both approaches. We further identified 30 biomarkers that could predict the recurrence. We used another independent HCC study that includes 50 patients normal and tumor samples. By using these 30 biomarkers, the prediction accuracy was 100% for normal condition and 98% for tumor condition. A group of Metallothionein was specifically discovered as biomarkers in both reference and de novo assembly approaches. CONCLUSION We identified a group of Metallothionein genes as biomarkers to predict recurrence. The metallothionein genes were all down-regulated in tumor samples, suggesting that low metallothionein expression may be a promoter of tumor growth. In addition, using de novo assembly identified some unique biomarkers, further confirmed the necessity of conducting a de novo assembly in human cancer study.
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Affiliation(s)
- Sufang Wang
- School of Life SciencesNorthwestern Polytechnical UniversityXi'anShaanxiChina
- Center of Special Environmental Biomechanics & Biomedical EngineeringNorthwestern Polytechnical UniversityXi'anShaanxiChina
| | - Michael Gribskov
- Department of Biological SciencesPurdue UniversityWest LafayetteIndianaUSA
- Department of Computer SciencesPurdue UniversityWest LafayetteIndianaUSA
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37
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Abstract
Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.
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38
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Koessler T, Addeo A, Nouspikel T. Implementing circulating tumor DNA analysis in a clinical laboratory: A user manual. Adv Clin Chem 2019; 89:131-188. [PMID: 30797468 DOI: 10.1016/bs.acc.2018.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Liquid biopsy, the analysis of cell-free circulating tumor DNA (ctDNA), is becoming one of the most promising tools in oncology. It has already shown its usefulness in selecting and modulating therapy via remote analysis of the tumor genome and holds important promises in cancer therapy and management, such as assessing the success of key therapeutic steps, monitoring residual disease, early detection of relapses, and establishing prognosis. Yet, ctDNA analysis is technically challenging and its implementation in the laboratory raises multiple strategic and practical issues. As for oncology clinics, integration of this novel test in well-established therapeutic protocols can also pose numerous questions. The current review is intended as a field guide for (1) diagnostic laboratories wishing to implement, validate and possibly accredit ctDNA testing and (2) clinical oncologists interested in integrating the various applications of liquid biopsies in their daily practice. We provide advice and practical recommendations based on our own experience with the technical validations of these methods and on a review of the current literature, with a focus toward gastro-intestinal, lung and breast cancers.
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Affiliation(s)
- Thibaud Koessler
- Department of Oncology, Geneva University Hospital, Geneva, Switzerland
| | - Alfredo Addeo
- Department of Oncology, Geneva University Hospital, Geneva, Switzerland
| | - Thierry Nouspikel
- Service of Medical Genetics, Diagnostics Department, Geneva University Hospital, Geneva, Switzerland.
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Mann J, Reeves HL, Feldstein AE. Liquid biopsy for liver diseases. Gut 2018; 67:2204-2212. [PMID: 30177542 DOI: 10.1136/gutjnl-2017-315846] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
With the growing number of novel therapeutic approaches for liver diseases, significant research efforts have been devoted to the development of liquid biopsy tools for precision medicine. This can be defined as non-invasive reliable biomarkers that can supplement and eventually replace the invasive liver biopsy for diagnosis, disease stratification and monitoring of response to therapeutic interventions. Similarly, detection of liver cancer at an earlier stage of the disease, potentially susceptible to curative resection, can be critical to improve patient survival. Circulating extracellular vesicles, nucleic acids (DNA and RNA) and tumour cells have emerged as attractive liquid biopsy candidates because they fulfil many of the key characteristics of an ideal biomarker. In this review, we summarise the currently available information regarding these promising and potential transformative tools, as well as the issues still needed to be addressed for adopting various liquid biopsy approaches into clinical practice. These studies may pave the way to the development of a new generation of reliable, mechanism-based disease biomarkers.
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Affiliation(s)
- Jelena Mann
- Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, California, USA
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40
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Su YH, Kim AK, Jain S. Liquid biopsies for hepatocellular carcinoma. Transl Res 2018; 201:84-97. [PMID: 30056068 PMCID: PMC6483086 DOI: 10.1016/j.trsl.2018.07.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/18/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the world's second leading cause of cancer death; 82.4% of patients die within 5 years. This grim prognosis is the consequence of a lack of effective early detection tools, limited treatment options, and the high frequency of HCC recurrence. Advances in the field of liquid biopsy hold great promise in improving early detection of HCC, advancing patient prognosis, and ultimately increasing the survival rate. In an effort to address the current challenges of HCC screening and management, several studies have identified and evaluated liver-cancer-associated molecular signatures such as genetic alterations, methylation, and noncoding RNA expression in the form of circulating biomarkers in body fluids and circulating tumor cells of HCC patients. In this review, we summarize the recent progress in HCC liquid biopsy, organized by the intended clinical application of the reported study.
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Affiliation(s)
- Ying-Hsiu Su
- The Baruch S. Blumberg Institute, Doylestown, Pennsylvania.
| | - Amy K Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore Maryland.
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, Pennsylvania.
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41
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Li Q, Deng C, Zhang T, Li X. Association of GSTP1 and P16 promoter methylation with the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Onco Targets Ther 2018; 11:5789-5796. [PMID: 30254471 PMCID: PMC6140744 DOI: 10.2147/ott.s168444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Study on the relationship between glutathione-S-transferase Pi 1 (GSTP1) and P16 promoter region methylation and the risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) has produced inconsistent results. Objectives To assess the correlation between GSTP1 and P16 promoter methylation frequency and HBV-related HCC susceptibility. Methods All relevant studies were identified by searching PubMed, Embase, Web of Science, and China National Knowledge Infrastructure literature databases before December, 2017. The OR and the corresponding 95% CI were calculated to investigate the risk of GSTP1 and P16 promoter methylation rate and HBV-related HCC. Sensitivity analysis was performed and publication bias was estimated using the Begg’s and Egger’s test. Results Our meta-analysis identified the relationships of GSTP1 (six studies including 213 HBV-related HCC tumor tissues) and P16 (nine studies with 287 HBV-related HCC tumor tissue) promoter methylation with HCC risk. Compared with normal liver tissue and cirrhosis, the pooled ORs of GSTP1 promoter region methylation in HBV-related HCC cancer tissues were 6.05 (95% CI =1.20–30.52) and 5.21 (95% CI =2.19–12.41), respectively. Compared with paracancerous tissue, normal liver tissue, cirrhosis, and chronic hepatitis B as controls, the pooled ORs of P16 promoter region methylation in HBV-related HCC cancer tissues were 7.18 (95% CI =2.31–22.33), 24.89 (95% CI =3.38–183.03), 5.92 (95% CI =1.78–19.68), and 12.12 (95% CI =0.75–196.50). Conclusion In summary, our meta-analysis found strong associations between GSTP1 and P16 gene promoter methylation and an increased HBV-related HCC susceptibility. Moreover, GSTP1 and P16 methylation in promoter region could obviously increase the risk of HBV-related HCC in patients with cirrhosis, indicating that these would be promising biomarkers for early clinical diagnosis of HBV-related HCC.
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Affiliation(s)
- Qin Li
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Ting Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Xiang Li
- School of Pharmacy, The Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China,
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42
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Black AP, Mehta AS. The search for biomarkers of hepatocellular carcinoma and the impact on patient outcome. Curr Opin Pharmacol 2018; 41:74-78. [PMID: 29772420 DOI: 10.1016/j.coph.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/14/2018] [Accepted: 04/03/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the 5th most common cancer, but the 3rd leading cause of cancer death globally with approximately 700,000 fatalities annually. The severity of this cancer arises from its difficulty to detect and treat. The major etiologies of HCC are liver fibrosis or cirrhosis from chronic viral infections, as well as metabolic conditions. Since most cases arise from prior pathologies, biomarker surveillance in high-risk individuals is an essential approach for early detection and improved patient outcome. While many molecular biomarkers have been associated with HCC, there are few that have made clinical impact for this disease. Here we review some major approaches used for HCC biomarker discovery-proteomics and glycomics-and describe new methodologies being tested for biomarker development.
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Affiliation(s)
- Alyson P Black
- Medical University of South Carolina, Charleston, SC 29425, United States
| | - Anand S Mehta
- Medical University of South Carolina, Charleston, SC 29425, United States.
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43
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Ng CKY, Di Costanzo GG, Terracciano LM, Piscuoglio S. Circulating Cell-Free DNA in Hepatocellular Carcinoma: Current Insights and Outlook. Front Med (Lausanne) 2018; 5:78. [PMID: 29632864 PMCID: PMC5880118 DOI: 10.3389/fmed.2018.00078] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 03/08/2018] [Indexed: 12/25/2022] Open
Abstract
Over the past decade, the advancements in massively parallel sequencing have provided a new paradigm in biomedical research to uncover the genetic basis of human diseases. Integration of ‘omics information has begun transforming clinical management of cancer patients in terms of diagnostics and treatment options, giving rise to the era of precision medicine. Currently, nucleic acids for molecular profiling for patients diagnosed with hepatocellular carcinoma (HCC) are typically obtained from resected tumor materials or transplanted neoplastic liver and occasionally from biopsies. Given the intrinsic risks associated with such invasive procedures, circulating cell-free DNA (cfDNA) has been proposed as an alternative source for tumor DNA. Circulating cfDNA is a type of cell-free nucleic acid that derives from apoptotic, necrotic, as well as living eukaryotic cells. Importantly, the detection of abnormal forms of circulating cfDNA that originate from cancer cells provides a new tool for cancer detection, disease monitoring, and molecular profiling. Currently, cfDNA is beginning to be adopted into clinical practice as a non-invasive tool to monitor disease by tracking the evolution of disease-specific genetic alterations in several major cancer types. Moreover, cfDNA is demonstrating potential clinical value as a surrogate to assess the molecular makeup of tumors and to overcome the sampling biases inherent to intra-tumor genetic heterogeneity, especially in the metastatic setting. With the improvements in ‘omics and molecular biology techniques, coupled with the increasing understanding in the molecular pathogenesis of cancer, it can be anticipated that the detection and analysis of cfDNA will become more specific and sensitive and thus enable cfDNA analysis to be used as a diagnostic aid in patients with early-stage disease and perhaps even in a screening setting. In this review, we provide an overview of the latest findings on the role and potential utility of cfDNA analysis in the diagnosis, management, and screening of HCC.
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Affiliation(s)
- Charlotte K Y Ng
- Institute of Pathology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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Stewart CM, Kothari PD, Mouliere F, Mair R, Somnay S, Benayed R, Zehir A, Weigelt B, Dawson SJ, Arcila ME, Berger MF, Tsui DW. The value of cell-free DNA for molecular pathology. J Pathol 2018; 244:616-627. [PMID: 29380875 DOI: 10.1002/path.5048] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/23/2018] [Accepted: 01/25/2018] [Indexed: 02/06/2023]
Abstract
Over the past decade, advances in molecular biology and genomics techniques have revolutionized the diagnosis and treatment of cancer. The technological advances in tissue profiling have also been applied to the study of cell-free nucleic acids, an area of increasing interest for molecular pathology. Cell-free nucleic acids are released from tumour cells into the surrounding body fluids and can be assayed non-invasively. The repertoire of genomic alterations in circulating tumour DNA (ctDNA) is reflective of both primary tumours and distant metastatic sites, and ctDNA can be sampled multiple times, thereby overcoming the limitations of the analysis of single biopsies. Furthermore, ctDNA can be sampled regularly to monitor response to treatment, to define the evolution of the tumour genome, and to assess the acquisition of resistance and minimal residual disease. Recently, clinical ctDNA assays have been approved for guidance of therapy, which is an exciting first step in translating cell-free nucleic acid research tests into clinical use for oncology. In this review, we discuss the advantages of cell-free nucleic acids as analytes in different body fluids, including blood plasma, urine, and cerebrospinal fluid, and their clinical applications in solid tumours and haematological malignancies. We will also discuss practical considerations for clinical deployment, such as preanalytical factors and regulatory requirements. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Caitlin M Stewart
- Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Prachi D Kothari
- Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Florent Mouliere
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.,Cancer Research UK Major Centre - Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK
| | - Richard Mair
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.,Cancer Research UK Major Centre - Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK.,Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK
| | - Saira Somnay
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ryma Benayed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sarah-Jane Dawson
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.,Centre for Cancer Research, University of Melbourne, Victoria, Australia
| | - Maria E Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael F Berger
- Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Dana Wy Tsui
- Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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45
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Wang J, Jain S, Chen D, Song W, Hu CT, Su YH. Development and Evaluation of Novel Statistical Methods in Urine Biomarker-Based Hepatocellular Carcinoma Screening. Sci Rep 2018; 8:3799. [PMID: 29491388 PMCID: PMC5830457 DOI: 10.1038/s41598-018-21922-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 02/13/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma is one of the fastest growing cancers in the US and has a low survival rate, partly due to difficulties in early detection. Because of HCC's high heterogeneity, it has been suggested that multiple biomarkers would be needed to develop a sensitive HCC screening test. This study applied random forest (RF), a machine learning technique, and proposed two novel models, fixed sequential (FS) and two-step (TS), for comparison with two commonly used statistical techniques, logistic regression (LR) and classification and regression trees (CART), in combining multiple urine DNA biomarkers for HCC screening using biomarker values obtained from 137 HCC and 431 non-HCC (224 hepatitis and 207 cirrhosis) subjects. The sensitivity, specificity, area under the receiver operating curve, and variability were estimated through repeated 10-fold cross-validation to compare the models' performances in accuracy and robustness. We show that RF and TS have higher accuracy and stability; specifically, they reach 90% specificity and 86%/87% sensitivity respectively along with 15% higher sensitivity and 10% higher specificity than LR in cross-validation. The potential of RF and TS to develop a panel of multiple biomarkers and the possibility for self-training, cloud-based models for HCC screening are discussed.
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Affiliation(s)
- Jeremy Wang
- JBS Science, Inc., Doylestown, Pennsylvania, United States
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, Pennsylvania, United States
| | - Dion Chen
- ClinPharma Consulting, Inc, Phoenixville, Pennsylvania, United States
| | - Wei Song
- JBS Science, Inc., Doylestown, Pennsylvania, United States
| | - Chi-Tan Hu
- Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, 970, Taiwan R.O.C..
| | - Ying-Hsiu Su
- JBS Science, Inc., Doylestown, Pennsylvania, United States.
- The Baruch S. Blumberg Institute, Doylestown, Pennsylvania, United States.
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Nörthen A, Asendorf T, Walson PD, Oellerich M. Diagnostic value of alpha-1-fetoprotein (AFP) as a biomarker for hepatocellular carcinoma recurrence after liver transplantation. Clin Biochem 2018; 52:20-25. [DOI: 10.1016/j.clinbiochem.2017.10.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/18/2017] [Accepted: 10/15/2017] [Indexed: 12/19/2022]
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47
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Chen D, Jain S, Su YH, Song W. Building Classification Models with Combined Biomarker Tests: Application to Early Detection of Liver Cancer. ACTA ACUST UNITED AC 2017; 5:91-103. [PMID: 29152526 DOI: 10.17265/2328-224x/2017.0506.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Early detection of hepatocellular carcinoma (HCC) is critical for the effective treatment. Alpha fetoprotein (AFP) serum level is currently used for HCC screening, but the cutoff of the AFP test has limited sensitivity (~50%), indicating a high false negative rate. We have successfully demonstrated that cancer derived DNA biomarkers can be detected in urine of patients with cancer and can be used for the early detection of cancer (Jain et al., 2015; Lin et al., 2011; Song et al., 2012; Su, Lin, Song, & Jain, 2014; Su, Wang, Norton, Brenner, & Block, 2008). By combining urine biomarkers (uBMK) values and serum AFP (sAFP) level, a new classification model has been proposed for more efficient HCC screening. Several criterions have been discussed to optimal the cutoff for uBMK score and sAFP score. A joint distribution of sAFP and uBMK with point mass has been fitted using maximum likelihood method. Numerical results show that the sAFP data and uBMK data are very well described by proposed model. A tree-structured sequential test can be optimized by selecting the cutoffs. Bootstrap simulations also show the robust classification results with the optimal cutoff.
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Affiliation(s)
- Dion Chen
- Biostatistics, Janssen R&D, LLC, Spring House, PA 19477, USA
| | - Surbhi Jain
- Biomarkers, JBS Science, Inc., Doylestown, PA 18902, USA
| | - Ying-Hsu Su
- Biomarkers, The Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Wei Song
- Biomarkers, JBS Science, Inc., Doylestown, PA 18902, USA
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