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• W4212900284 abstract "Liver cancer (hepatocellular carcinoma [HCC]) is a fatal cancer worldwide and often is detected at an advanced stage when treatment options are very limited. This drives the development of techniques and platforms for early detection of HCC. In recent years, liquid biopsy has provided a means of noninvasive detection of cancers. By detecting plasma circulating tumor DNA (ctDNA) released from dying cancer cells, the presence of HCC can be detected in a noninvasive manner. In this review, we discuss the molecular characteristics of ctDNA and its various molecular landscapes in HCC. These include the mutational landscape, single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The consistency between the plasma ctDNA and the tumor tissue genomic DNA mutational profile is pivotal for the clinical utility of ctDNA in the clinical management of HCC. With strategic use of genetic information provided from plasma ctDNA profiling and procedure standardization to facilitate implementation in clinical practice, better clinical management would become permissible through more efficient detection and diagnosis of HCC, better prognostication, precision-matched treatment guidance, and more reliable disease monitoring. Liver cancer (hepatocellular carcinoma [HCC]) is a fatal cancer worldwide and often is detected at an advanced stage when treatment options are very limited. This drives the development of techniques and platforms for early detection of HCC. In recent years, liquid biopsy has provided a means of noninvasive detection of cancers. By detecting plasma circulating tumor DNA (ctDNA) released from dying cancer cells, the presence of HCC can be detected in a noninvasive manner. In this review, we discuss the molecular characteristics of ctDNA and its various molecular landscapes in HCC. These include the mutational landscape, single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The consistency between the plasma ctDNA and the tumor tissue genomic DNA mutational profile is pivotal for the clinical utility of ctDNA in the clinical management of HCC. With strategic use of genetic information provided from plasma ctDNA profiling and procedure standardization to facilitate implementation in clinical practice, better clinical management would become permissible through more efficient detection and diagnosis of HCC, better prognostication, precision-matched treatment guidance, and more reliable disease monitoring. SummaryPlasma circulating tumor DNA (ctDNA) offers a noninvasive means for the detection and clinical management of liver cancer. The different aspects of plasma ctDNA have been intensively explored in recent years. These include the mutational landscape such as single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The clinical utility of ctDNA depends on the concordance of the genetic information between the plasma and the tumor tissue in hepatocellular carcinoma (HCC). The use of ctDNA in clinical management of HCC is discussed in regard to the detection and diagnosis, prognosis, drug treatment guidance, and disease monitoring of HCC. The barrier to the implementation of liquid biopsy for cell-free DNA profiling and the coping strategies by standardization of relevant procedures also is discussed. Plasma circulating tumor DNA (ctDNA) offers a noninvasive means for the detection and clinical management of liver cancer. The different aspects of plasma ctDNA have been intensively explored in recent years. These include the mutational landscape such as single-nucleotide variations, copy number variations, methylation landscape, end motif/coordinate preference, hepatitis B virus integration, and mitochondrial DNA mutations. The clinical utility of ctDNA depends on the concordance of the genetic information between the plasma and the tumor tissue in hepatocellular carcinoma (HCC). The use of ctDNA in clinical management of HCC is discussed in regard to the detection and diagnosis, prognosis, drug treatment guidance, and disease monitoring of HCC. The barrier to the implementation of liquid biopsy for cell-free DNA profiling and the coping strategies by standardization of relevant procedures also is discussed. Liver cancer (hepatocellular carcinoma [HCC]) is a prevalent and lethal cancer worldwide.1Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Google Scholar HCC often presents at advanced stages and hence is inoperable. Although liver resection is the major curative therapy, the recurrence rate even after surgery is high.2Tran N.H. Kisiel J. Roberts L.R. Using cell-free DNA for HCC surveillance and prognosis.JHEP Rep. 2021; 3100304Google Scholar Therefore, early detection is pivotal to better clinical management and important to support recurrence surveillance, identify relevant molecular-targeted drugs, and predict drug response for patients. Circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) are noninvasive and promising strategies to assay the circulating DNA in the bloodstream. Together with other circulating biomarkers, they are referred to collectively as liquid biopsy. It relies on the detection of intrinsic molecular properties to distinguish the specific DNA originating from tumor cells (ie, ctDNA). ctDNA should share the same molecular alterations as their tumor source, and this makes ctDNA an ideal alternative to tissue biopsy. This review summarizes the most recent information about ctDNA characteristics, detection methods, genetic variation profiles, and its clinical applications for HCC to provide an overview of adopting liquid biopsy in the clinical management of HCC. Finally, possible implementation barriers, the coping procedure standardization, and future perspectives are discussed. Note that cfDNA refers to the input sample of assays while ctDNA represents the specific subset of cfDNA that carries specific molecular alterations; they may be used interchangeably in this article. ctDNA is a short DNA fragment of approximately 120 bp released from necrotic or apoptotic tumor cells. Although normal nontumor cells also shed cfDNA into the bloodstream, the cfDNA from tumor cells (ie, ctDNA) only accounts for less than 1% of total cfDNA in the blood.3Ye Q. Ling S. Zheng S. Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA.Mol Cancer. 2019; 18: 114Google Scholar,4Yang J.D. Liu M.C. Kisiel J.B. Circulating tumor DNA and hepatocellular carcinoma.Semin Liver Dis. 2019; 39: 452-462Google Scholar The short half-life of ctDNA3Ye Q. Ling S. Zheng S. Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA.Mol Cancer. 2019; 18: 114Google Scholar and the difficulty in distinguishing ctDNA from cfDNA released from normal cells complicates the clinical utility of ctDNA. Specialized tubes can be used for blood sample collection to reduce the chance of white blood cell rupture and genomic DNA contamination from the damaged white blood cells.5Parackal S. Zou D. Day R. Black M. Guilford P. Comparison of Roche Cell-Free DNA collection Tubes® to Streck Cell-Free DNA BCT® s for sample stability using healthy volunteers.Pract Lab Med. 2019; 16e00125Google Scholar, 6Zhao Y. Li Y. Chen P. Li S. Luo J. Xia H. Performance comparison of blood collection tubes as liquid biopsy storage system for minimizing cfDNA contamination from genomic DNA.J Clin Lab Anal. 2019; 33e22670Google Scholar, 7Bernabe R. Hickson N. Wallace A. Blackhall F.H. What do we need to make circulating tumour DNA (ctDNA) a routine diagnostic test in lung cancer?.Eur J Cancer. 2017; 81: 66-73Google Scholar, 8Deans Z.C. Butler R. Cheetham M. Dequeker E.M.C. Fairley J.A. Fenizia F. Hall J.A. Keppens C. Normanno N. Schuuring E. Patton S.J. IQN path ASBL report from the first European cfDNA consensus meeting: expert opinion on the minimal requirements for clinical ctDNA testing.Virchows Arch. 2019; 474: 681-689Google Scholar Plasma extracted then can be subjected to a column-based cfDNA extraction kit, which already has been approved by the US Food and Drug Administration for use in routine clinical practice. However, to date, there are no extraction methods that specifically enrich or harvest the tumor cfDNA fraction.8Deans Z.C. Butler R. Cheetham M. Dequeker E.M.C. Fairley J.A. Fenizia F. Hall J.A. Keppens C. Normanno N. Schuuring E. Patton S.J. IQN path ASBL report from the first European cfDNA consensus meeting: expert opinion on the minimal requirements for clinical ctDNA testing.Virchows Arch. 2019; 474: 681-689Google Scholar Therefore, tumor-specific genetic alteration information has to be extracted from the ctDNA by next-generation sequencing (NGS) methods, whole-genome sequencing, whole-exome sequencing, and target-panel sequencing often are used. The former is more exploratory in nature, while the latter requires a known predesigned gene panel with respective probes to help enrich the specific regions of interest for targeted library constructions and sequencing procedures. With regard to NGS, the sensitivity, specificity, and cost efficiency for detection of the tumor-specific genetic alterations in ctDNA need to be balanced. Raising sequencing coverage depth of ctDNA beyond the most optimal level may not improve the sensitivity of detecting tumor-specific genetic alterations further and becomes economically inefficient.9Shu Y. Wu X. Tong X. Wang X. Chang Z. Mao Y. Chen X. Sun J. Wang Z. Hong Z. Zhu L. Zhu C. Chen J. Liang Y. Shao H. Shao Y.W. Circulating tumor DNA mutation profiling by targeted next generation sequencing provides guidance for personalized treatments in multiple cancer types.Sci Rep. 2017; 7: 583Google Scholar In addition to NGS, other methods for detecting tumor-specific genetic alterations in ctDNA include droplet digital polymerase chain reaction (PCR) and quantitative real-time PCR, which are relatively cheaper and convenient detection methods but require prior knowledge of known tumor-specific genetic alterations for detection and are of relatively lower throughput (Table 1).Table 1A Brief Summary of the Technologies for ctDNA Detection in HCCMethodSensitivityCoverageVariationAdvantageLimitationddPCRHighSpecific and known regionsSNV, CNV,MethRapid, sensitiveRelatively lower throughput; does not detect novel targetsqPCRHighSpecific and known regionsSNV, CNV, MethCheaperRelatively lower throughput; does not detect novel targetsWGSModerateWhole genomeSNV, CNV,HBV, EMMultiplex capabilities; detects novel variations;high-throughput detectionRelatively high cost; needs bioinformatics analysis supportWESModerateWhole exomeSNV, CNV,HBV, EMMultiplex capabilities; detects novel variations;high-throughput detectionRelatively high cost; needs bioinformatics analysis supportTSRelatively highPanel sizeSNV, CNV,HBV, EMMultiplex capabilities; detects novel variations;high-throughput detectionRelatively high cost; needs bioinformatics analysis supportddPCR, droplet digital PCR; EM, end motif; HBV, HBV integration; Meth, methylation; qPCR, quantitative real-time PCR; TS target-panel sequencing; WGS, whole-genome sequencing; WES, whole-exome sequencing. Open table in a new tab ddPCR, droplet digital PCR; EM, end motif; HBV, HBV integration; Meth, methylation; qPCR, quantitative real-time PCR; TS target-panel sequencing; WGS, whole-genome sequencing; WES, whole-exome sequencing. Genetic and epigenetic aberrations were considered as important factors that drive HCC initiation, progression, and metastasis. With an overview of HCC-associated molecular landscape in ctDNA, it provides us with a better understanding of hepatocarcinogenesis and facilitates the mechanistic investigation of the underlying pathologic mechanism in HCC. Molecular alterations in the ctDNA of HCC mainly include single-nucleotide variation (SNVs), copy number variations (CNVs), DNA methylation aberrations, preferred end motifs or coordinates, and hepatitis B virus (HBV) integration (Table 2).Table 2A Summary of the Studies on the Various Types of Molecular Landscape of ctDNA in HCCReferenceVariationCohortApplicationMutation rateConsistencySample source for cfDNA extraction (volume, mL)Detection method45SNV, PEC90 HCC, 67 H, 36 C, 32 NCD––Plasma (4)WGS49SNV, CNV, HBV481 HCC, 517 CD––Blood (10)WGS, HBV11SNV, CNV26 HCCG, M89%50%–100%Whole blood (20)68-gene TS/70-gene TS13SNV, CNV206 HCCD88%–Whole blood (10)54-gene/68-gene/70-gene TS15SNV, CNV24 HCCP96%–Plasma (2)74-gene TS20SNV, CNV34 HCCP, M100%–Plasma (–)TS, WGS22SNV, CNV187 HCCG, P––Plasma (–)TS25SNV, CNV14 HCCG, P100%–Whole blood (20)68-gene TS, ddPCR58SNV, HBV65 HCC, 70 NCD––Plasma (2)TS10SNV48 HCCD56%22%Plasma (1)ddPCR, SS12SNV51 HCC, 10 CD35%29%Plasma (1)7-gene TS14SNV26 HCC, 10 C, 10 HD, P96%89%Plasma (0.6–1.8)354-gene TS16SNV59 HCCP56%97.3%–100%Blood (10)69-gene TS, ddPCR19SNV41 HCCP20%–Plasma (0.72)3-gene TS21SNV37 HCCD–52%–84%Blood (10)TS23SNV77 HCC, 8 CG83%83%Plasma (5), serum (1)25-gene TS, ddPCR, SS24SNV27 HCCG96%–Plasma (–)–51SNV8 HCCD75%71%Plasma (5), serum (1)58-gene TS65SNV895 HCCP20%–42%92%Whole blood (10)ddPCR, 1-gene TS66SNV81 HCCP––Plasma (–)ddPCR, SS48Meth, HBV45 HCC, 18 C, 18 H, 36 NCD, M––Whole blood (10)WGBS38Meth104 HCC, 174 NC, 95 at-risk diseaseD, P––Venous blood (10)MSP39Meth25 HCC, 35 C or H, 20 NCD, M92%–Plasma/serum (0.4)MSP40Meth237 HCCD, M37%–63%–Plasma (0.25)Pyrosequencing, MSP41Meth50 HCC, 50 NCD22%–70%–Blood (20)MSP42Meth36 HCC, 17 C, 38 NCD––Plasma (2)MCTA-sequencing technique43Meth80 HCC, 40 C, 40 H, 20 NCD34%-Serum (0.4)MSP55Meth28 HCCD89%68%–89%Plasma (–)MSP59Meth116 HCC, 60 CD––Plasma (>1)MSP61Meth144 HCC, 106 CM––Plasma (1)BS62Meth97 HCC, 46 H, 80 NCD––Plasma (1.2–1.5)ddPCR67Meth1098 HCC, 835 NCD, P––Plasma (1.5)BS68Meth68 NC, 66 H, 96 C, 109 HCCD, M––Plasma (–)MSP, BS47HBV50 HCCD, M88%–Plasma (1)TS50CNV, PEC, SNV10 NC, 10 H, 10 HCCD–100%Plasma (2)WGS, TS30CNV, EM63 HCC, 187 HD94%–Plasma (–)WGS46CNV, EM34 HCC, 17 H, 38 NCD, M––Plasma (4)BS29CNV151 HCCG, P27%–Plasma (1.5)WGS31CNV31 HCC, 8 H or CD42%–Plasma (–)–32CNV76 HCC, 274 NCD, P57%–Plasma (2)WGS33CNV90 HCC, 67 H, 36 C, 32 NCD84%63%Plasma (3–4.8)WGS34CNV117 HCCP––Plasma (–)WGS74CNV1 HCCG––Plasma (–)–645hmC, EM2250 C, 508 HCC, 476 NCD––Plasma (–)5hmC-sequencing, WGS575hmC1204 HCC, 392 H or C, 958 NCD––Peripheral blood (5–10)5hmC-seal profilingBS, bisulfite sequencing; C, cirrhosis (irrespective of etiology); D, detection and diagnosis; ddPCR, droplet digital PCR; EM, end motif; G, guiding drug administration; H, hepatitis (irrespective of etiology); HBV, HBV integration; M, monitoring; MCTA, ______; Meth, methylation; MSP, methylation-specific PCR; NC, normal control; P, prognosis; PEC, preferred ends coordinate; SS, sanger sequencing; TS, target-panel sequencing; WGBS, _____; WGS, whole-genome sequencing; 5hmC, 5hmC modification; –, not available. Open table in a new tab BS, bisulfite sequencing; C, cirrhosis (irrespective of etiology); D, detection and diagnosis; ddPCR, droplet digital PCR; EM, end motif; G, guiding drug administration; H, hepatitis (irrespective of etiology); HBV, HBV integration; M, monitoring; MCTA, ______; Meth, methylation; MSP, methylation-specific PCR; NC, normal control; P, prognosis; PEC, preferred ends coordinate; SS, sanger sequencing; TS, target-panel sequencing; WGBS, _____; WGS, whole-genome sequencing; 5hmC, 5hmC modification; –, not available. In the plasma of HCC patients, single-nucleotide mutations could be detected at variable proportions in HCC patients, ranging from 35% to 96%, and may be related to the size of the target gene panel examined and their treatment status.10Huang A. Zhang X. Zhou S.L. Cao Y. Huang X.W. Fan J. Yang X.R. Zhou J. Detecting circulating tumor DNA in hepatocellular carcinoma patients using droplet digital PCR is feasible and reflects intratumoral heterogeneity.J Cancer. 2016; 7: 1907-1914Google Scholar, 11Ikeda S. Lim J.S. Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics.Mol Cancer Ther. 2018; 17: 1114-1122Google Scholar, 12Howell J. Atkinson S.R. Pinato D.J. Knapp S. Ward C. Minisini R. Burlone M.E. Leutner M. Pirisi M. Buttner R. Khan S.A. Thursz M. Odenthal M. Sharma R. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma.Eur J Cancer. 2019; 116: 56-66Google Scholar, 13Kaseb A.O. Sanchez N.S. Sen S. Kelley R.K. Tan B. Bocobo A.G. Lim K.H. Abdel-Wahab R. Uemura M. Pestana R.C. Qiao W. Xiao L. Morris J. Amin H.M. Hassan M.M. Rashid A. Banks K.C. Lanman R.B. Talasaz A. Mills-Shaw K.R. George B. Haque A. Raghav K.P.S. Wolff R.A. Yao J.C. Meric-Bernstam F. Ikeda S. Kurzrock R. Molecular profiling of hepatocellular carcinoma using circulating cell-free DNA.Clin Cancer Res. 2019; 25: 6107-6118Google Scholar, 14An Y. Guan Y. Xu Y. Han Y. Wu C. Bao C. Zhou B. Wang H. Zhang M. Liu W. Qiu L. Han Z. Chen Y. Xia X. Wang J. Liu Z. Huang W. Yi X. Huang J. The diagnostic and prognostic usage of circulating tumor DNA in operable hepatocellular carcinoma.Am J Transl Res. 2019; 11: 6462-6474Google Scholar, 15Fujii Y. Ono A. Hayes C.N. Aikata H. Yamauchi M. Uchikawa S. Kodama K. Teraoka Y. Fujino H. Nakahara T. Murakami E. Miki D. Okamoto W. Kawaoka T. Tsuge M. Imamura M. Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib.J Exp Clin Cancer Res. 2021; 40: 215Google Scholar, 16Kim S.S. Eun J.W. Choi J.H. Woo H.G. Cho H.J. Ahn H.R. Suh C.W. Baek G.O. Cho S.W. Cheong J.Y. MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma.Sci Rep. 2020; 1017862Google Scholar By analyzing recent cfDNA studies of HCC (Figure 1A), the most commonly altered genes were hitting several pathways, including the PI3K/AKT/mTOR signaling pathway (PTEN, PIK3CA, KRAS, NF1, TSC2), Wnt/β-catenin signaling pathway (CTNNB1, AXIN1, APC), p53/cell-cycle pathway (TP53, ATM, RB1, CDKN2A), and chromatin remodeling (ARID2, ARID1A, NCOR1).17Totoki Y. Tatsuno K. Covington K.R. Ueda H. Creighton C.J. Kato M. Tsuji S. Donehower L.A. Slagle B.L. Nakamura H. Yamamoto S. Shinbrot E. Hama N. Lehmkuhl M. Hosoda F. Arai Y. Walker K. Dahdouli M. Gotoh K. Nagae G. Gingras M.C. Muzny D.M. Ojima H. Shimada K. Midorikawa Y. Goss J.A. Cotton R. Hayashi A. Shibahara J. Ishikawa S. Guiteau J. Tanaka M. Urushidate T. Ohashi S. Okada N. Doddapaneni H. Wang M. Zhu Y. Dinh H. Okusaka T. Kokudo N. Kosuge T. Takayama T. Fukayama M. Gibbs R.A. Wheeler D.A. Aburatani H. Shibata T. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.Nat Genet. 2014; 46: 1267-1273Google Scholar,18Guichard C. Amaddeo G. Imbeaud S. Ladeiro Y. Pelletier L. Maad I.B. Calderaro J. Bioulac-Sage P. Letexier M. Degos F. Clement B. Balabaud C. Chevet E. Laurent A. Couchy G. Letouze E. Calvo F. Zucman-Rossi J. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.Nat Genet. 2012; 44: 694-698Google Scholar TP53 and CTNNB1 are 2 of the most frequently mutated genes that were identified in every aforementioned study. On the other hand, TERT promoter mutations are also highly and recurrently detected.10Huang A. Zhang X. Zhou S.L. Cao Y. Huang X.W. Fan J. Yang X.R. Zhou J. Detecting circulating tumor DNA in hepatocellular carcinoma patients using droplet digital PCR is feasible and reflects intratumoral heterogeneity.J Cancer. 2016; 7: 1907-1914Google Scholar, 11Ikeda S. Lim J.S. Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics.Mol Cancer Ther. 2018; 17: 1114-1122Google Scholar, 12Howell J. Atkinson S.R. Pinato D.J. Knapp S. Ward C. Minisini R. Burlone M.E. Leutner M. Pirisi M. Buttner R. Khan S.A. Thursz M. Odenthal M. Sharma R. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma.Eur J Cancer. 2019; 116: 56-66Google Scholar, 13Kaseb A.O. Sanchez N.S. Sen S. Kelley R.K. Tan B. Bocobo A.G. Lim K.H. Abdel-Wahab R. Uemura M. Pestana R.C. Qiao W. Xiao L. Morris J. Amin H.M. Hassan M.M. Rashid A. Banks K.C. Lanman R.B. Talasaz A. Mills-Shaw K.R. George B. Haque A. Raghav K.P.S. Wolff R.A. Yao J.C. Meric-Bernstam F. Ikeda S. Kurzrock R. Molecular profiling of hepatocellular carcinoma using circulating cell-free DNA.Clin Cancer Res. 2019; 25: 6107-6118Google Scholar, 14An Y. Guan Y. Xu Y. Han Y. Wu C. Bao C. Zhou B. Wang H. Zhang M. Liu W. Qiu L. Han Z. Chen Y. Xia X. Wang J. Liu Z. Huang W. Yi X. Huang J. The diagnostic and prognostic usage of circulating tumor DNA in operable hepatocellular carcinoma.Am J Transl Res. 2019; 11: 6462-6474Google Scholar, 15Fujii Y. Ono A. Hayes C.N. Aikata H. Yamauchi M. Uchikawa S. Kodama K. Teraoka Y. Fujino H. Nakahara T. Murakami E. Miki D. Okamoto W. Kawaoka T. Tsuge M. Imamura M. Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib.J Exp Clin Cancer Res. 2021; 40: 215Google Scholar, 16Kim S.S. Eun J.W. Choi J.H. Woo H.G. Cho H.J. Ahn H.R. Suh C.W. Baek G.O. Cho S.W. Cheong J.Y. 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Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics.Mol Cancer Ther. 2018; 17: 1114-1122Google Scholar,13Kaseb A.O. Sanchez N.S. Sen S. Kelley R.K. Tan B. Bocobo A.G. Lim K.H. Abdel-Wahab R. Uemura M. Pestana R.C. Qiao W. Xiao L. Morris J. Amin H.M. Hassan M.M. Rashid A. Banks K.C. Lanman R.B. Talasaz A. Mills-Shaw K.R. George B. Haque A. Raghav K.P.S. Wolff R.A. Yao J.C. Meric-Bernstam F. Ikeda S. Kurzrock R. Molecular profiling of hepatocellular carcinoma using circulating cell-free DNA.Clin Cancer Res. 2019; 25: 6107-6118Google Scholar,15Fujii Y. Ono A. Hayes C.N. Aikata H. Yamauchi M. Uchikawa S. Kodama K. Teraoka Y. Fujino H. Nakahara T. Murakami E. Miki D. Okamoto W. Kawaoka T. Tsuge M. Imamura M. Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib.J Exp Clin Cancer Res. 2021; 40: 215Google Scholar,25Ikeda S. Tsigelny I.F. Skjevik A.A. Kono Y. Mendler M. Kuo A. Sicklick J.K. Heestand G. Banks K.C. Talasaz A. Lanman R.B. Lippman S. Kurzrock R. Next-generation sequencing of circulating tumor DNA reveals frequent alterations in advanced hepatocellular carcinoma.Oncologist. 2018; 23: 586-593Google Scholar The earlier-described chromosomes and genes are the common and conserved CNV signatures possessed by HCC patients and readily revealed by the CNV landscape obtained from patients’ cfDNA. Because there is only a scanty amount of ctDNA present in the bloodstream for HCC patients, this limits the detection of CNVs in cfDNA. To overcome the limitation, Jin et al30Jin C. Liu X. Zheng W. Su L. Liu Y. Guo X. Gu X. Li H. Xu B. Wang G. Yu J. Zhang Q. Bao D. Wan S. Xu F. Lai X. Liu J. Xing J. Characterization of fragment sizes, copy number aberrations and 4-mer end motifs in cell-free DNA of hepatocellular carcinoma for enhanced liquid biopsy-based cancer detection.Mol Oncol. 2021; 15: 2377-2389Google Scholar attempted to improve the detection of the CNV signal by applying fragment-size selection of less than 150 bp in a cohort of 197 HCC patients. Because CNV generally influences a larger fraction of the genome compared with SNV, copy number analysis and the detection of alterations usually are performed and evaluated at a relatively larg" @default.
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• W4212900284 date "2022-01-01" @default.
• W4212900284 modified "2023-10-18" @default.
• W4212900284 title "Liquid Biopsy Using Cell-Free or Circulating Tumor DNA in the Management of Hepatocellular Carcinoma" @default.
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• W4212900284 doi "https://doi.org/10.1016/j.jcmgh.2022.02.008" @default.
• W4212900284 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35183803" @default.
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