Diagnosis of the Initial Stage of Hepatocellular Carcinoma: A Review

Krishana   Kumar   Sharma; Mohd.      Mohsin; Piyush      Mittal; Zeeshan      Ali; Nishat      Fatma; Prashant      Upadhyay; Ritu      Gupta; Anurag      Verma; Gajendra      Kumar
doi:10.2174/0113816128298875240321073907
Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There may be more than a million instances of hepatocellular carcinoma by 2025, making it a persistent concern for global health. The most common form of hepatocellular carcinoma accounts for more than 90% of cases. There is no known cure for hepatocellular carcinoma, which is usually detected late in life. Unlike most other common malignancies, such as lung, prostate, and breast cancers, where mortality rates are declining, rates of death are rising by around 2-3% every year. It is extremely difficult to diagnose hepatocellular carcinoma in its early stages. Alpha-fetoprotein serology studies and ultrasonography (US) monitoring were historically the primary methods for early detection of hepatocellular cancer. However, the sensitivity or specificity of ultrasonography/alpha-fetoprotein (US/AFP) is not high enough to detect hepatocellular carcinoma in its early stages. Alpha-fetoprotein, or AFP, is an amino acid that is normally produced by the liver or yolk sac of an embryonic baby. In adults, AFP levels are typically modest. Adults with high levels of AFP have been associated with several illnesses, the most well-known of which are certain types of cancer. It is still possible to diagnose hepatocellular carcinoma early because of current technological advancements. We address the advancements in the diagnosis of hepatocellular carcinoma in this article, with a focus on new imaging techniques and diagnostic markers for early-stage tumor identification.
Keywords: Biomarkers, early diagnostics, hepatocellular carcinoma, imaging, fluid biopsy, cancer.
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[1]
Moldogazieva N, Mokhosoev I, Zavadskiy S, Terentiev A. Proteomic profiling and artificial intelligence for Hepatocellular carcinoma translational medicine. Biomedicines  2021; 9(2): 159.
 [http://dx.doi.org/10.3390/biomedicines9020159] [PMID: 33562077]

[2]
Villanueva A. Hepatocellular carcinoma. N Engl J Med  2019; 380(15): 1450-62.
 [http://dx.doi.org/10.1056/NEJMra1713263]

[3]
Akinyemiju T, Abera S, Ahmed M, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol  2017; 3(12): 1683-91.
 [http://dx.doi.org/10.1001/jamaoncol.2017.3055] [PMID: 28983565]

[4]
Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology  2017; 153(4): 996-1005.e1.
 [http://dx.doi.org/10.1053/j.gastro.2017.06.012] [PMID: 28642197]

[5]
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology  2018; 67(1): 123-33.
 [http://dx.doi.org/10.1002/hep.29466] [PMID: 28802062]

[6]
Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of Hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet  2015; 47(5): 505-11.
 [http://dx.doi.org/10.1038/ng.3252] [PMID: 25822088]

[7]
Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T. Biomarkers for the early diagnosis of Hepatocellular carcinoma. World J Gastroenterol  2015; 21(37): 10573-83.
 [http://dx.doi.org/10.3748/wjg.v21.i37.10573] [PMID: 26457017]

[8]
Masuzaki R, Karp SJ, Omata M. New serum markers of Hepatocellular carcinoma. Semin Oncol  2012; 39(4): 434-9.
 [http://dx.doi.org/10.1053/j.seminoncol.2012.05.009] [PMID: 22846860]

[9]
Maxim LD, Niebo R, Utell MJ. Screening tests: A review with examples. Inhal Toxicol  2014; 26(13): 811-28.
 [http://dx.doi.org/10.3109/08958378.2014.955932] [PMID: 25264934]

[10]
IJzerman MJ, de Boer J, Azad A, et al. Towards routine implementation of liquid biopsies in cancer management: It is always too early, until suddenly it is too late. Diagnostics  2021; 11(1): 103.
 [http://dx.doi.org/10.3390/diagnostics11010103] [PMID: 33440749]

[11]
Kumar S, Mohan A, Guleria R. Biomarkers in cancer screening, research and detection: Present and future: A review. Biomarkers  2006; 11(5): 385-405.
 [http://dx.doi.org/10.1080/13547500600775011] [PMID: 16966157]

[12]
Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol  2004; 159(9): 882-90.
 [http://dx.doi.org/10.1093/aje/kwh101] [PMID: 15105181]

[13]
Wu L, Qu X. Cancer biomarker detection: Recent achievements and challenges. Chem Soc Rev  2015; 44(10): 2963-97.
 [http://dx.doi.org/10.1039/C4CS00370E] [PMID: 25739971]

[14]
De Guire V, Robitaille R, Tétreault N, et al. Circulating miRNAs as sensitive and specific biomarkers for the diagnosis and monitoring of human diseases: Promises and challenges. Clin Biochem  2013; 46(10-11): 846-60.
 [http://dx.doi.org/10.1016/j.clinbiochem.2013.03.015] [PMID: 23562576]

[15]
Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol  1990; 15(4): 827-32.
 [http://dx.doi.org/10.1016/0735-1097(90)90282-T] [PMID: 2407762]

[16]
Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of Hepatocellular carcinoma: A 2017 update. Hepatol Int  2017; 11(4): 317-70.
 [http://dx.doi.org/10.1007/s12072-017-9799-9] [PMID: 28620797]

[17]
Kudo M, Matsui O, Izumi N, et al. JSH consensus-based clinical practice guidelines for the management of Hepatocellular carcinoma: 2014 update by the liver cancer study group of Japan. Liver Cancer  2014; 3(3-4): 458-68.
 [http://dx.doi.org/10.1159/000343875] [PMID: 26280007]

[18]
Bruix J, Sherman M. Management of Hepatocellular carcinoma: An update. Hepatology  2011; 53(3): 1020-2.
 [http://dx.doi.org/10.1002/hep.24199] [PMID: 21374666]

[19]
Galle PR, Forner A, Llovet JM, et al. EASL clinical practice guidelines: Management of Hepatocellular carcinoma. J Hepatol  2018; 69(1): 182-236.
 [http://dx.doi.org/10.1016/j.jhep.2018.03.019] [PMID: 29628281]

[20]
Wald C, Russo MW, Heimbach JK, Hussain HK, Pomfret EA, Bruix J. New OPTN/UNOS policy for liver transplant allocation: Standardization of liver imaging, diagnosis, classification, and reporting of Hepatocellular carcinoma. Radiology  2013; 266(2): 376-82.
 [http://dx.doi.org/10.1148/radiol.12121698] [PMID: 23362092]

[21]
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of Hepatocellular carcinoma. Hepatology  2018; 67(1): 358-80.
 [http://dx.doi.org/10.1002/hep.29086] [PMID: 28130846]

[22]
Benson AB III, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: Hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw  2017; 15(5): 563-73.
 [http://dx.doi.org/10.6004/jnccn.2017.0059] [PMID: 28476736]

[23]
Xie DY, Ren ZG, Zhou J, Fan J, Gao Q. Critical appraisal of Chinese 2017 guideline on the management of Hepatocellular carcinoma. Hepatobiliary Surg Nutr  2017; 6(6): 387-96.
 [http://dx.doi.org/10.21037/hbsn.2017.11.01] [PMID: 29312973]

[24]
Kudo M, Izumi N, Kokudo N, et al. Management of Hepatocellular carcinoma in Japan: Consensus-based clinical practice guidelines proposed by the japan society of hepatology (JSH) 2010 updated version. Dig Dis  2011; 29(3): 339-64.
 [http://dx.doi.org/10.1159/000327577] [PMID: 21829027]

[25]
Yeh YP, Hu TH, Cho PY, et al. Evaluation of abdominal ultrasonography mass screening for Hepatocellular carcinoma in Taiwan. Hepatology  2014; 59(5): 1840-9.
 [http://dx.doi.org/10.1002/hep.26703] [PMID: 24002724]

[26]
Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for Hepatocellular carcinoma surveillance in patients with cirrhosis: A meta-analysis.  PLoS Med  2014; 11(4): e1001624.

[27]
Pandya P, Kanwal F. Adding to the evidence base: Effectiveness of Hepatocellular carcinoma surveillance in clinical practice. Hepatol Commun  2017; 1(8): 723-5.
 [http://dx.doi.org/10.1002/hep4.1087] [PMID: 29404488]

[28]
Mittal S, Kanwal F, Ying J, et al. Effectiveness of surveillance for Hepatocellular carcinoma in clinical practice: A United States cohort. J Hepatol  2016; 65(6): 1148-54.
 [http://dx.doi.org/10.1016/j.jhep.2016.07.025] [PMID: 27476765]

[29]
Zhang B, Yang B. Combined α fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen  1999; 6(2): 108-10.
 [http://dx.doi.org/10.1136/jms.6.2.108] [PMID: 10444731]

[30]
Pocha C, Dieperink E, McMaken KA, Knott A, Thuras P, Ho SB. Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography - A randomised study. Aliment Pharmacol Ther  2013; 38(3): 303-12.
 [http://dx.doi.org/10.1111/apt.12370] [PMID: 23750991]

[31]
Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alpha fetoprotein for early detection of Hepatocellular carcinoma in patients with cirrhosis: A meta-analysis. Gastroenterology  2018; 154(6): 1706-1718.e1.
 [http://dx.doi.org/10.1053/j.gastro.2018.01.064] [PMID: 29425931]

[32]
Singal A, Volk ML, Waljee A. Meta-analysis: Surveillance with ultrasound for early-stage Hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther   2009; 30(1): 37-47.

[33]
European Association for the Study of the Liver. EASL-EORTC Clinical Practice Guidelines: Management of Hepatocellular carcinoma. J Hepatol  2012; 56(4): 908-43.
 [http://dx.doi.org/10.1016/j.jhep.2011.12.001] [PMID: 22424438]

[34]
Morgan TA, Maturen KE, Dahiya N, Sun MRM, Kamaya A. US LI-RADS: Ultrasound liver imaging reporting and data system for screening and surveillance of Hepatocellular carcinoma. Abdom Radiol  2018; 43(1): 41-55.
 [http://dx.doi.org/10.1007/s00261-017-1317-y] [PMID: 28936543]

[35]
Kim SY, An J, Lim YS, et al. MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of Hepatocellular carcinoma. JAMA Oncol  2017; 3(4): 456-63.
 [http://dx.doi.org/10.1001/jamaoncol.2016.3147] [PMID: 27657493]

[36]
Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing Hepatocellular carcinoma: A systematic review. Am J Gastroenterol  2006; 101(3): 513-23.
 [http://dx.doi.org/10.1111/j.1572-0241.2006.00467.x] [PMID: 16542288]

[37]
Hanna RF, Miloushev VZ, Tang A, et al. Comparative 13-year meta-analysis of the sensitivity and positive predictive value of ultrasound, CT, and MRI for detecting Hepatocellular carcinoma. Abdom Radiol  2016; 41(1): 71-90.
 [http://dx.doi.org/10.1007/s00261-015-0592-8] [PMID: 26830614]

[38]
Zheng SG, Xu HX, Liu LN. Management of Hepatocellular carcinoma: The role of contrast-enhanced ultrasound. World J Radiol  2014; 6(1): 7-14.
 [http://dx.doi.org/10.4329/wjr.v6.i1.7] [PMID: 24578787]

[39]
Burak KW, Sherman M. Hepatocellular carcinoma: Consensus, controversies and future directions. A report from the canadian association for the study of the liver Hepatocellular carcinoma meeting. Can J Gastroenterol Hepatol  2015; 29(4): 178-84.
 [http://dx.doi.org/10.1155/2015/824263] [PMID: 25965437]

[40]
Tanaka H, Iijima H, Nouso K, et al. Cost-effectiveness analysis on the surveillance for Hepatocellular carcinoma in liver cirrhosis patients using contrast-enhanced ultrasonography. Hepatol Res  2012; 42(4): 376-84.
 [http://dx.doi.org/10.1111/j.1872-034X.2011.00936.x] [PMID: 22221694]

[41]
Claudon M, Dietrich C, Choi B, Cosgrove D, Kudo M, Nolsøe C. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver - Update 2012. Eur J Ultrasound  2012; 34(1): 11-29.

[42]
Goossens N, Singal AG, King LY, et al. Cost-effectiveness of risk score-stratified Hepatocellular carcinoma screening in patients with cirrhosis. Clin Transl Gastroenterol  2017; 8(6): e101.
 [http://dx.doi.org/10.1038/ctg.2017.26] [PMID: 28640287]

[43]
Canellas R, Rosenkrantz AB, Taouli B, et al. Abbreviated MRI protocols for the abdomen. Radiographics  2019; 39(3): 744-58.
 [http://dx.doi.org/10.1148/rg.2019180123] [PMID: 30901285]

[44]
Besa C, Lewis S, Pandharipande PV, et al. Hepatocellular carcinoma detection: diagnostic performance of a simulated abbreviated MRI protocol combining diffusion-weighted and T1-weighted imaging at the delayed phase post gadoxetic acid. Abdom Radiol  2017; 42(1): 179-90.
 [http://dx.doi.org/10.1007/s00261-016-0841-5] [PMID: 27448609]

[45]
Tillman BG, Gorman JD, Hru JM, et al. Diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI protocol for Hepatocellular carcinoma screening. Clin Radiol  2018; 73(5): 485-93.
 [http://dx.doi.org/10.1016/j.crad.2017.11.013] [PMID: 29246586]

[46]
Taouli B, Johnson RS, Hajdu CH, et al. Hepatocellular carcinoma: Perfusion quantification with dynamic contrast-enhanced MRI. AJR Am J Roentgenol  2013; 201(4): 795-800.
 [http://dx.doi.org/10.2214/AJR.12.9798] [PMID: 24059368]

[47]
Robertis RD, Martini PT, Demozzi E, et al. Prognostication and response assessment in liver and pancreatic tumors: The new imaging. World J Gastroenterol  2015; 21(22): 6794-808.
 [http://dx.doi.org/10.3748/wjg.v21.i22.6794] [PMID: 26078555]

[48]
Chen CW, Hsu LS, Weng JC, et al. Assessment of small Hepatocellular carcinoma: Perfusion quantification and time-concentration curve evaluation using color-coded and quantitative digital subtraction angiography. Medicine (Baltimore)  2018; 97(48): e13392.
 [http://dx.doi.org/10.1097/MD.0000000000013392] [PMID: 30508937]

[49]
Lim KS. Diffusion-weighted MRI of Hepatocellular carcinoma in cirrhosis. Clin Radiol  2014; 69(1): 1-10.
 [http://dx.doi.org/10.1016/j.crad.2013.07.022] [PMID: 24034549]

[50]
Li X, Li C, Wang R, Ren J, Yang J, Zhang Y. Combined application of gadoxetic acid disodium-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the diagnosis of chronic liver disease-induced Hepatocellular carcinoma: A meta-analysis.  PLoS One   2015; 10(12): e0144247.

[51]
Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: Technique, analysis, and clinical applications. J Magn Reson Imaging  2013; 37(3): 544-55.
 [http://dx.doi.org/10.1002/jmri.23731] [PMID: 23423795]

[52]
Hennedige TP, Hallinan JTPD, Leung FP, et al. Comparison of magnetic resonance elastography and diffusion-weighted imaging for differentiating benign and malignant liver lesions. Eur Radiol  2016; 26(2): 398-406.
 [http://dx.doi.org/10.1007/s00330-015-3835-8] [PMID: 26032879]

[53]
Venkatesh SK, Yin M, Glockner JF, et al. MR elastography of liver tumors: Preliminary results. AJR Am J Roentgenol  2008; 190(6): 1534-40.
 [http://dx.doi.org/10.2214/AJR.07.3123] [PMID: 18492904]

[54]
Li YW, Chen ZG, Wang JC, Zhang ZM. Superparamagnetic iron oxide-enhanced magnetic resonance imaging for focal hepatic lesions: Systematic review and meta-analysis. World J Gastroenterol  2015; 21(14): 4334-44.
 [http://dx.doi.org/10.3748/wjg.v21.i14.4334] [PMID: 25892885]

[55]
Daldrup-Link HE. Ten things you might not know about iron oxide nanoparticles. Radiology  2017; 284(3): 616-29.
 [http://dx.doi.org/10.1148/radiol.2017162759] [PMID: 28825888]

[56]
Xiao YD, Paudel R, Liu J, Ma C, Zhang ZS, Zhou SK. MRI contrast agents: Classification and application (Review). Int J Mol Med  2016; 38(5): 1319-26.
 [http://dx.doi.org/10.3892/ijmm.2016.2744] [PMID: 27666161]

[57]
Zhao M, Liu Z, Dong L, et al. A GPC3-specific aptamer-mediated magnetic resonance probe for Hepatocellular carcinoma. Int J Nanomed  2018; 13: 4433-43.
 [http://dx.doi.org/10.2147/IJN.S168268] [PMID: 30122918]

[58]
Li W, Xiao X, Li X, et al. Detecting GPC3-expressing Hepatocellular carcinoma with L5 peptide-guided pretargeting approach: In vitro and in vivo MR imaging experiments. Contrast Media Mol Imaging  2018; 2018: 1-11.
 [http://dx.doi.org/10.1155/2018/9169072] [PMID: 30275801]

[59]
Zhang Z. Preparation and in vitro studies of MRI-specific superparamagnetic iron oxide antiGPC3 probe for Hepatocellular carcinoma. Int J Nanomed  2012; 4593(Aug): 4593.
 [http://dx.doi.org/10.2147/IJN.S32196]

[60]
Shen JM, Li XX, Fan LL, et al. Heterogeneous dimer peptide-conjugated polylysine dendrimer-Fe3O4 composite as a novel nanoscale molecular probe for early diagnosis and therapy in Hepatocellular carcinoma. Int J Nanomed  2017; 12: 1183-200.
 [http://dx.doi.org/10.2147/IJN.S126887] [PMID: 28243083]

[61]
Ma XH, Wang S, Liu SY, et al. Development and in vitro study of a bi-specific magnetic resonance imaging molecular probe for Hepatocellular carcinoma. World J Gastroenterol  2019; 25(24): 3030-43.
 [http://dx.doi.org/10.3748/wjg.v25.i24.3030] [PMID: 31293339]

[62]
Fischer MA, Kartalis N, Grigoriadis A, et al. Perfusion computed tomography for detection of Hepatocellular carcinoma in patients with liver cirrhosis. Eur Radiol  2015; 25(11): 3123-32.
 [http://dx.doi.org/10.1007/s00330-015-3732-1] [PMID: 25903707]

[63]
Ippolito D, Sironi S, Pozzi M, et al. Perfusion CT in cirrhotic patients with early stage Hepatocellular carcinoma: Assessment of tumor-related vascularization. Eur J Radiol  2010; 73(1): 148-52.
 [http://dx.doi.org/10.1016/j.ejrad.2008.10.014] [PMID: 19054640]

[64]
Gao SY, Zhang XP, Cui Y, et al. Fused monochromatic imaging acquired by single source dual energy CT in Hepatocellular carcinoma during arterial phase: An initial experience. Chin J Cancer Res  2014; 26(4): 437-43.
 [PMID: 25232217]

[65]
Kaufmann S, Sauter A, Spira D, et al. Tin-filter enhanced dual-energy-CT: Image quality and accuracy of CT numbers in virtual noncontrast imaging. Acad Radiol  2013; 20(5): 596-603.
 [http://dx.doi.org/10.1016/j.acra.2013.01.010] [PMID: 23490736]

[66]
Matsuda M, Tsuda T, Kido T, et al. Dual-energy computed tomography in patients with small Hepatocellular carcinoma: Utility of noise-reduced monoenergetic images for the evaluation of washout and image quality in the equilibrium phase. J Comput Assist Tomogr  2018; 42(6): 937-43.
 [http://dx.doi.org/10.1097/RCT.0000000000000752] [PMID: 29659425]

[67]
Haug AR. Imaging of primary liver tumors with positron-emission tomography. Q J Nucl Med Mol Imaging  2017; 61(3): 292-300.
 [http://dx.doi.org/10.23736/S1824-4785.17.02994-6] [PMID: 28686007]

[68]
Cheung TT, Ho CL, Lo CM, et al. 11C-acetate and 18F-FDG PET/CT for clinical staging and selection of patients with Hepatocellular carcinoma for liver transplantation on the basis of Milan criteria: Surgeon’s perspective. J Nucl Med  2013; 54(2): 192-200.
 [http://dx.doi.org/10.2967/jnumed.112.107516] [PMID: 23321459]

[69]
Zhao J, Zhang Z, Nie D, et al. PET imaging of Hepatocellular carcinomas: 18F-fluoropropionic acid as a complementary radiotracer for 18F-fluorodeoxyglucose. Mol Imaging  2019; 18: 1536012118821032.
 [http://dx.doi.org/10.1177/1536012118821032] [PMID: 30799682]

[70]
Castilla-Lièvre MA, Franco D, Gervais P, et al. Diagnostic value of combining 11C-choline and 18F-FDG PET/CT in Hepatocellular carcinoma. Eur J Nucl Med Mol Imaging  2016; 43(5): 852-9.
 [http://dx.doi.org/10.1007/s00259-015-3241-0] [PMID: 26577938]

[71]
Zhang C, Zhao Y, Zhao N, et al. NIRF optical/PET dual-modal imaging of Hepatocellular carcinoma using heptamethine carbocyanine dye. Contrast Media Mol Imaging  2018; 2018: 1-12.
 [http://dx.doi.org/10.1155/2018/4979746] [PMID: 29706843]

[72]
Danciu M, Alexa-Stratulat T, Stefanescu C, et al. Terahertz spectroscopy and imaging: A cutting-edge method for diagnosing digestive cancers. Materials  2019; 12(9): 1519.
 [http://dx.doi.org/10.3390/ma12091519] [PMID: 31075912]

[73]
Rong L, Latychevskaia T, Chen C, et al. Terahertz in-line digital holography of human Hepatocellular carcinoma tissue. Sci Rep  2015; 5(1): 8445.
 [http://dx.doi.org/10.1038/srep08445] [PMID: 25676705]

[74]
Duan F, Wang YY, Xu DG, et al. Feasibility of terahertz imaging for discrimination of human Hepatocellular carcinoma. World J Gastrointest Oncol  2019; 11(2): 153-60.
 [http://dx.doi.org/10.4251/wjgo.v11.i2.153] [PMID: 30788041]

[75]
Chayvialle JAP, Ganguli PC. Radioimmunoassay of alpha-fetoprotein in human plasma. Lancet  1973; 301(7816): 1355-7.
 [http://dx.doi.org/10.1016/S0140-6736(73)91676-0] [PMID: 4122743]

[76]
Waldmann TA, McIntire KR. The use of a radioimmunoassay for alpha-fetoprotein in the diagnosis of malignancy. Cancer  1974; 34(S8) (Suppl.): 1510-5.
 [http://dx.doi.org/10.1002/1097-0142(197410)34:8+<1510::AID-CNCR2820340824>3.0.CO;2-Y] [PMID: 4138906]

[77]
Gupta S, Bent S, Kohlwes J. Test characteristics of α-fetoprotein for detecting Hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med  2003; 139(1): 46-50.
 [http://dx.doi.org/10.7326/0003-4819-139-1-200307010-00012] [PMID: 12834318]

[78]
Trevisani F, D’Intino PE, Morselli-Labate AM, et al. Serum α-fetoprotein for diagnosis of Hepatocellular carcinoma in patients with chronic liver disease: Influence of HBsAg and anti-HCV status. J Hepatol  2001; 34(4): 570-5.
 [http://dx.doi.org/10.1016/S0168-8278(00)00053-2] [PMID: 11394657]

[79]
Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early Hepatocellular carcinoma. Gastroenterology  2009; 137(1): 110-8.
 [http://dx.doi.org/10.1053/j.gastro.2009.04.005] [PMID: 19362088]

[80]
Gopal P, Yopp AC, Waljee AK, et al. Factors that affect accuracy of α-fetoprotein test in detection of Hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol  2014; 12(5): 870-7.
 [http://dx.doi.org/10.1016/j.cgh.2013.09.053] [PMID: 24095974]

[81]
El-Serag HB, Kanwal F, Davila JA, Kramer J, Richardson P. A new laboratory-based algorithm to predict development of Hepatocellular carcinoma in patients with hepatitis C and cirrhosis. Gastroenterology  2014; 146(5): 1249-1255.e1.
 [http://dx.doi.org/10.1053/j.gastro.2014.01.045] [PMID: 24462733]

[82]
Wang M, Devarajan K, Singal AG, et al. The doylestown algorithm: A test to improve the performance of AFP in the detection of Hepatocellular carcinoma. Cancer Prev Res  2016; 9(2): 172-9.
 [http://dx.doi.org/10.1158/1940-6207.CAPR-15-0186] [PMID: 26712941]

[83]
Wang K, Bai Y, Chen S, et al. Genetic correction of serum AFP level improves risk prediction of primary Hepatocellular carcinoma in the Dongfeng-Tongji cohort study. Cancer Med  2018; 7(6): 2691-8.
 [http://dx.doi.org/10.1002/cam4.1481] [PMID: 29696820]

[84]
Sato Y, Nakata K, Kato Y, et al. Early recognition of Hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med  1993; 328(25): 1802-6.
 [http://dx.doi.org/10.1056/NEJM199306243282502] [PMID: 7684823]

[85]
Li D, Mallory T, Satomura S. AFP-L3: A new generation of tumor marker for Hepatocellular carcinoma. Clin Chim Acta  2001; 313(1-2): 15-9.
 [http://dx.doi.org/10.1016/S0009-8981(01)00644-1] [PMID: 11694234]

[86]
Zhou Y, Qiu J, Liu S, et al. CFDP1 promotes Hepatocellular carcinoma progression through activating NEDD4/PTEN/PI3K/AKT signaling pathway. Cancer Med  2023; 12(1): 425-44.
 [http://dx.doi.org/10.1002/cam4.4919] [PMID: 35861040]

[87]
Yi X, Yu S, Bao Y. Alpha-fetoprotein-L3 in Hepatocellular carcinoma: A meta-analysis. Clin Chim Acta  2013; 425: 212-20.
 [http://dx.doi.org/10.1016/j.cca.2013.08.005] [PMID: 23954771]

[88]
Ido A. Highly sensitive lens culinaris agglutinin-reactive α-fetoprotein is useful for early detection of Hepatocellular carcinoma in patients with chronic liver disease. Oncol Rep   2011; 26(5): 1227-33.
 [http://dx.doi.org/10.3892/or.2011.1425]

[89]
Chen H, Zhang Y, Li S, et al. Direct comparison of five serum biomarkers in early diagnosis of Hepatocellular carcinoma. Cancer Manag Res  2018; 10: 1947-58.
 [http://dx.doi.org/10.2147/CMAR.S167036] [PMID: 30022853]

[90]
Fu J, Li Y, Li Z, Li N. Clinical utility of decarboxylation prothrombin combined with α-fetoprotein for diagnosing primary Hepatocellular carcinoma. Biosci Rep  2018; 38(5): BSR20180044.
 [http://dx.doi.org/10.1042/BSR20180044] [PMID: 29717027]

[91]
Yu R, Ding S, Tan W, et al. Performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for Hepatocellular carcinoma screening in Chinese population. Hepat Mon  2015; 15(7): e28806.
 [http://dx.doi.org/10.5812/hepatmon.28806v2] [PMID: 26300931]

[92]
Zhang K, Song P, Gao J, Li G, Zhao X, Zhang S. Perspectives on a combined test of multi serum biomarkers in China: Towards screening for and diagnosing Hepatocellular carcinoma at an earlier stage. Drug Discov Ther  2014; 8(3): 102-9.
 [http://dx.doi.org/10.5582/ddt.2014.01026] [PMID: 25031041]

[93]
Caviglia GP, Ribaldone DG, Abate ML, et al. Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for Hepatocellular carcinoma detection: A meta-analysis. Scand J Gastroenterol  2018; 53(6): 734-40.
 [http://dx.doi.org/10.1080/00365521.2018.1459824] [PMID: 29667463]

[94]
Johnson PJ, Pirrie SJ, Cox TF, et al. The detection of Hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol Biomarkers Prev  2014; 23(1): 144-53.
 [http://dx.doi.org/10.1158/1055-9965.EPI-13-0870] [PMID: 24220911]

[95]
Caviglia GP, Abate ML, Petrini E, Gaia S, Rizzetto M, Smedile A. Highly sensitive alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin for Hepatocellular carcinoma detection. Hepatol Res  2016; 46(3): E130-5.
 [http://dx.doi.org/10.1111/hepr.12544] [PMID: 26082262]

[96]
Best J, Bilgi H, Heider D, et al. The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage Hepatocellular carcinoma. Z Gastroenterol  2016; 54(12): 1296-305.
 [http://dx.doi.org/10.1055/s-0042-119529] [PMID: 27936479]

[97]
Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of Hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol  2016; 14(6): 875-886.e6.
 [http://dx.doi.org/10.1016/j.cgh.2015.12.042] [PMID: 26775025]

[98]
Yang JD, Addissie BD, Mara KC, et al. GALAD score for Hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol Biomarkers Prev  2019; 28(3): 531-8.
 [http://dx.doi.org/10.1158/1055-9965.EPI-18-0281] [PMID: 30464023]

[99]
Capurro M, Wanless IR, Sherman M, et al. Glypican-3: A novel serum and histochemical marker for Hepatocellular carcinoma. Gastroenterology  2003; 125(1): 89-97.
 [http://dx.doi.org/10.1016/S0016-5085(03)00689-9] [PMID: 12851874]

[100]
Chen IP, Ariizumi S, Nakano M, Yamamoto M. Positive glypican-3 expression in early Hepatocellular carcinoma predicts recurrence after hepatectomy. J Gastroenterol  2014; 49(1): 117-25.
 [http://dx.doi.org/10.1007/s00535-013-0793-2] [PMID: 23532638]

[101]
Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for Hepatocellular carcinoma diagnosis and treatment. Med Res Rev  2018; 38(2): 741-67.
 [http://dx.doi.org/10.1002/med.21455] [PMID: 28621802]

[102]
Zhu AX, Gold PJ, El-Khoueiry AB, et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced Hepatocellular carcinoma. Clin Cancer Res  2013; 19(4): 920-8.
 [http://dx.doi.org/10.1158/1078-0432.CCR-12-2616] [PMID: 23362325]

[103]
Zhang Q, Han Z, Tao J, et al. An innovative peptide with high affinity to GPC3 for Hepatocellular carcinoma diagnosis. Biomater Sci  2019; 7(1): 159-67.
 [http://dx.doi.org/10.1039/C8BM01016A] [PMID: 30417190]

[104]
Li J, Wang T, Jin B, et al. Diagnosis accuracy of serum glypican-3 level in patients with Hepatocellular carcinoma: A systematic review with meta-analysis. Int J Biol Markers  2018; 33(4): 353-63.
 [http://dx.doi.org/10.1177/1724600818784409] [PMID: 30071741]

[105]
Jia X, Liu J, Gao Y, Huang Y, Du Z. Diagnosis accuracy of serum glypican-3 in patients with Hepatocellular carcinoma: A systematic review with meta-analysis. Arch Med Res  2014; 45(7): 580-8.
 [http://dx.doi.org/10.1016/j.arcmed.2014.11.002] [PMID: 25446613]

[106]
Sun B, Huang Z, Wang B, et al. Significance of Glypican-3 (GPC3) expression in Hepatocellular cancer diagnosis. Med Sci Monit  2017; 23: 850-5.
 [http://dx.doi.org/10.12659/MSM.899198] [PMID: 28207681]

[107]
Tahon AM, El-Ghanam MZ, Zaky S, et al. Significance of Glypican-3 in early detection of Hepatocellular carcinoma in cirrhotic patients. J Gastrointest Cancer  2019; 50(3): 434-41.
 [http://dx.doi.org/10.1007/s12029-018-0095-2] [PMID: 29623600]

[108]
Ba MC, Long H, Tang YQ, Cui SZ. GP73 expression and its significance in the diagnosis of Hepatocellular carcinoma: A review. Int J Clin Exp Pathol  2012; 5(9): 874-81.
 [PMID: 23119104]

[109]
Dai M, Chen X, Liu X, Peng Z, Meng J, Dai S. Diagnostic value of the combination of golgi protein 73 and alpha-fetoprotein in Hepatocellular carcinoma: A meta-analysis PLoS One  2015; 10(10): e0140067.
 [http://dx.doi.org/10.1371/journal.pone.0140067]

[110]
Jiao C, Cui L, Piao J, Qi Y, Yu Z. Clinical significance and expression of serum Golgi protein 73 in primary Hepatocellular carcinoma. J Cancer Res Ther   2018; 14(6): 1239-44.

[111]
Witjes CDM, van Aalten SM, Steyerberg EW, et al. Recently introduced biomarkers for screening of Hepatocellular carcinoma: A systematic review and meta-analysis. Hepatol Int  2013; 7(1): 59-64.
 [http://dx.doi.org/10.1007/s12072-012-9374-3] [PMID: 23519638]

[112]
Xu WJ, Guo BL, Han YG, Shi L, Ma WS. Diagnostic value of alpha-fetoprotein-L3 and Golgi protein 73 in Hepatocellular carcinomas with low AFP levels. Tumour Biol  2014; 35(12): 12069-74.
 [http://dx.doi.org/10.1007/s13277-014-2506-8] [PMID: 25209179]

[113]
Xu W, Zhang Z, Zhang Y, Wang Y, Xu L. Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative Hepatocellular carcinoma. OncoTargets Ther  2015; 123(Dec): 123.
 [http://dx.doi.org/10.2147/OTT.S90732]

[114]
Tian L, Wang Y, Xu D, et al. Serological AFP/Golgi protein 73 could be a new diagnostic parameter of hepatic diseases. Int J Cancer  2011; 129(8): 1923-31.
 [http://dx.doi.org/10.1002/ijc.25838] [PMID: 21140449]

[115]
Li B, Li B, Guo T, et al. The clinical values of serum markers in the early prediction of Hepatocellular carcinoma. BioMed Res Int  2017; 2017: 1-11.
 [http://dx.doi.org/10.1155/2017/5358615] [PMID: 28540298]

[116]
Xiao J, Long F, Peng T, et al. Development and potential application of a simultaneous multiplex assay of Golgi protein 73 and alpha-fetoprotein for Hepatocellular carcinoma diagnosis. Eur Rev Med Pharmacol Sci  2019; 23(8): 3302-10.
 [PMID: 31081083]

[117]
Wen Y, Jeong S, Xia Q, Kong X. Role of osteopontin in liver diseases. Int J Biol Sci  2016; 12(9): 1121-8.
 [http://dx.doi.org/10.7150/ijbs.16445] [PMID: 27570486]

[118]
Shang S, Plymoth A, Ge S, et al. Identification of osteopontin as a novel marker for early Hepatocellular carcinoma. Hepatology  2012; 55(2): 483-90.
 [http://dx.doi.org/10.1002/hep.24703] [PMID: 21953299]

[119]
Abu El Makarem MA, Abdel-Aleem A, Ali A, et al. Diagnostic significance of plasma osteopontin in hepatitis C virus-related Hepatocellular carcinoma. Ann Hepatol  2011; 10(3): 296-305.
 [http://dx.doi.org/10.1016/S1665-2681(19)31541-8] [PMID: 21677331]

[120]
Kim J, Ki SS, Lee SD, et al. Elevated plasma osteopontin levels in patients with Hepatocellular carcinoma. Am J Gastroenterol  2006; 101(9): 2051-9.
 [http://dx.doi.org/10.1111/j.1572-0241.2006.00679.x] [PMID: 16848813]

[121]
Duarte-Salles T, Misra S, Stepien M, et al. Circulating osteopontin and prediction of Hepatocellular carcinoma development in a large European population. Cancer Prev Res  2016; 9(9): 758-65.
 [http://dx.doi.org/10.1158/1940-6207.CAPR-15-0434] [PMID: 27339170]

[122]
Sun T, Tang Y, Sun D, Bu Q, Li P. Osteopontin versus alpha-fetoprotein as a diagnostic marker for Hepatocellular carcinoma: A meta-analysis. OncoTargets Ther  2018; 11: 8925-35.
 [http://dx.doi.org/10.2147/OTT.S186230] [PMID: 30573979]

[123]
Ge T, Shen Q, Wang N, et al. Diagnostic values of alpha-fetoprotein, dickkopf-1, and osteopontin for Hepatocellular carcinoma. Med Oncol  2015; 32(3): 59.
 [http://dx.doi.org/10.1007/s12032-014-0367-z] [PMID: 25652109]

[124]
Chae WJ, Bothwell ALM. Dickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation. Differentiation  2019; 108: 33-9.
 [http://dx.doi.org/10.1016/j.diff.2019.05.003] [PMID: 31221431]

[125]
Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of Hepatocellular carcinoma: A large-scale, multicentre study. Lancet Oncol  2012; 13(8): 817-26.
 [http://dx.doi.org/10.1016/S1470-2045(12)70233-4] [PMID: 22738799]

[126]
Zhou Y, Li W, Tseng Y, Zhang J, Liu J. Developing slow-off dickkopf-1 aptamers for early-diagnosis of Hepatocellular carcinoma. Talanta  2019; 194: 422-9.
 [http://dx.doi.org/10.1016/j.talanta.2018.10.014] [PMID: 30609553]

[127]
Yang N, Ekanem NR, Sakyi CA, Ray SD. Hepatocellular carcinoma and microRNA: New perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev  2015; 81: 62-74.
 [http://dx.doi.org/10.1016/j.addr.2014.10.029] [PMID: 25450260]

[128]
Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol  2012; 6(6): 590-610.
 [http://dx.doi.org/10.1016/j.molonc.2012.09.006] [PMID: 23102669]

[129]
Thurnherr T, Mah WC, Lei Z, Jin Y, Rozen SG, Lee CG. Differentially expressed miRNAs in Hepatocellular carcinoma target genes in the genetic information processing and metabolism pathways. Sci Rep  2016; 6(1): 20065.
 [http://dx.doi.org/10.1038/srep20065] [PMID: 26817861]

[130]
Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol  2014; 11(3): 145-56.
 [http://dx.doi.org/10.1038/nrclinonc.2014.5] [PMID: 24492836]

[131]
Li W, Xie L, He X, et al. Diagnostic and prognostic implications of microRNAs in human Hepatocellular carcinoma. Int J Cancer  2008; 123(7): 1616-22.
 [http://dx.doi.org/10.1002/ijc.23693] [PMID: 18649363]

[132]
Schütte K, Schulz C, Link A, Malfertheiner P. Current biomarkers for Hepatocellular carcinoma: Surveillance, diagnosis and prediction of prognosis. World J Hepatol  2014; 7(2): 139-49.
 [http://dx.doi.org/10.4254/wjh.v7.i2.139] [PMID: 25729470]

[133]
Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA  2008; 105(30): 10513-8.
 [http://dx.doi.org/10.1073/pnas.0804549105] [PMID: 18663219]

[134]
Peng C, Ye Y, Wang Z, et al. Circulating microRNAs for the diagnosis of Hepatocellular carcinoma. Dig Liver Dis  2019; 51(5): 621-31.
 [http://dx.doi.org/10.1016/j.dld.2018.12.011] [PMID: 30744930]

[135]
Ning S, Liu H, Gao B, Wei W, Yang A, Li J. MiR-155, miR-96 and miR-99a as potential diagnostic and prognostic tools for the clinical management of Hepatocellular carcinoma. Oncol Lett   2019; 18(3): 3381-7.

[136]
Huang JT, Liu SM, Ma H, et al. Systematic review and meta-analysis: Circulating miRNAs for diagnosis of Hepatocellular carcinoma. J Cell Physiol  2016; 231(2): 328-35.
 [http://dx.doi.org/10.1002/jcp.25135] [PMID: 26291451]

[137]
Tat Trung N, Duong DC, Van Tong H, Hien TTT, Hoan PQ, Bang MH. Optimisation of quantitative miRNA panels to consolidate the diagnostic surveillance of HBV-related Hepatocellular carcinoma. PLoS One  2018; 13(4): e0196081.

[138]
Elemeery MN, Badr AN, Mohamed MA, Ghareeb DA. Validation of a serum microRNA panel as biomarkers for early diagnosis of Hepatocellular carcinoma post-hepatitis C infection in Egyptian patients. World J Gastroenterol  2017; 23(21): 3864-75.
 [http://dx.doi.org/10.3748/wjg.v23.i21.3864] [PMID: 28638226]

[139]
Zuo D, Chen L, Liu X, et al. Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP-based diagnosis of Hepatocellular carcinoma. Tumour Biol  2016; 37(5): 6539-49.
 [http://dx.doi.org/10.1007/s13277-015-4545-1] [PMID: 26637228]

[140]
Chen L, Chu F, Cao Y, Shao J, Wang F. Serum miR-182 and miR-331-3p as diagnostic and prognostic markers in patients with Hepatocellular carcinoma. Tumour Biol  2015; 36(10): 7439-47.
 [http://dx.doi.org/10.1007/s13277-015-3430-2] [PMID: 25903466]

[141]
Pfeffer SR, Yang CH, Pfeffer LM. The role of miR-21 in cancer. Drug Dev Res  2015; 76(6): 270-7.
 [http://dx.doi.org/10.1002/ddr.21257] [PMID: 26082192]

[142]
Wang H, Hou L, Li A, Duan Y, Gao H, Song X. Expression of serum exosomal microRNA-21 in human Hepatocellular carcinoma. BioMed Res Int  2014; 2014: 1-5.
 [http://dx.doi.org/10.1155/2014/864894] [PMID: 24963487]

[143]
Fornari F, Ferracin M, Trerè D, Milazzo M, Marinelli S, Galassi M. Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, identify cirrhotic patients with HCC. PLoS One   2015; 10(10): e0141448.

[144]
Sohn W, Kim J, Kang SH, et al. Serum exosomal microRNAs as novel biomarkers for Hepatocellular carcinoma. Exp Mol Med  2015; 47(9): e184-4.
 [http://dx.doi.org/10.1038/emm.2015.68] [PMID: 26380927]

[145]
Xue X, Zhao Y, Wang X, Qin L, Hu R. Development and validation of serum exosomal microRNAs as diagnostic and prognostic biomarkers for Hepatocellular carcinoma. J Cell Biochem  2019; 120(1): 135-42.
 [http://dx.doi.org/10.1002/jcb.27165] [PMID: 30238497]

[146]
Wang Y, Zhang C, Zhang P, et al. Serum exosomal micro RNA s combined with alpha-fetoprotein as diagnostic markers of Hepatocellular carcinoma. Cancer Med  2018; 7(5): 1670-9.
 [http://dx.doi.org/10.1002/cam4.1390] [PMID: 29573235]

[147]
Moldogazieva NT, Zavadskiy SP, Astakhov DV, et al. Differentially expressed non-coding RNAs and their regulatory networks in liver cancer. Heliyon  2023; 9(9): e19223.
 [http://dx.doi.org/10.1016/j.heliyon.2023.e19223] [PMID: 37662778]

[148]
Qi P, Du X. The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Mod Pathol  2013; 26(2): 155-65.
 [http://dx.doi.org/10.1038/modpathol.2012.160] [PMID: 22996375]

[149]
Di Gesualdo F, Capaccioli S, Lulli M. A pathophysiological view of the long non-coding RNA world. Oncotarget  2014; 5(22): 10976-96.
 [http://dx.doi.org/10.18632/oncotarget.2770] [PMID: 25428918]

[150]
Qiu L, Tang Q, Li G, Chen K. Long non-coding RNAs as biomarkers and therapeutic targets: Recent insights into Hepatocellular carcinoma. Life Sci  2017; 191: 273-82.
 [http://dx.doi.org/10.1016/j.lfs.2017.10.007] [PMID: 28987633]

[151]
Peng L, Yuan XQ, Zhang CY, et al. The emergence of long non- coding RNAs in Hepatocellular carcinoma: An update. J Cancer  2018; 9(14): 2549-58.
 [http://dx.doi.org/10.7150/jca.24560] [PMID: 30026854]

[152]
Li J, Wang X, Tang J, et al. HULC and Linc00152 act as novel biomarkers in predicting diagnosis of Hepatocellular carcinoma. Cell Physiol Biochem  2015; 37(2): 687-96.
 [http://dx.doi.org/10.1159/000430387] [PMID: 26356260]

[153]
Zheng Z, Pang C, Yang Y, Duan Q, Zhang J, Liu W. Serum long noncoding RNA urothelial carcinoma-associated 1: A novel biomarker for diagnosis and prognosis of Hepatocellular carcinoma. J Int Med Res  2018; 46(1): 348-56.
 [http://dx.doi.org/10.1177/0300060517726441] [PMID: 28856933]

[154]
Konishi H, Ichikawa D, Yamamoto Y, et al. Plasma level of metastasis-associated lung adenocarcinoma transcript 1 is associated with liver damage and predicts development of Hepatocellular carcinoma. Cancer Sci  2016; 107(2): 149-54.
 [http://dx.doi.org/10.1111/cas.12854] [PMID: 26614531]

[155]
Li Y, He X, Zhang X, et al. RMI2 is a prognostic biomarker and promotes tumor growth in Hepatocellular carcinoma. Clin Exp Med  2022; 22(2): 229-43.
 [http://dx.doi.org/10.1007/s10238-021-00742-8] [PMID: 34275027]

[156]
Chao Y, Zhou D. lncRNA-D16366 is a potential biomarker for diagnosis and prognosis of Hepatocellular carcinoma. Med Sci Monit  2019; 25: 6581-6.
 [http://dx.doi.org/10.12659/MSM.915100] [PMID: 31475695]

[157]
Chen S, Zhang Y, Wu X, Zhang C, Li G. Diagnostic value of lncRNAs as biomarker in Hepatocellular carcinoma: An updated meta- analysis. Can J Gastroenterol Hepatol  2018; 2018: 1-12.
 [http://dx.doi.org/10.1155/2018/8410195] [PMID: 30410873]

[158]
Tang J, Jiang R, Deng L, Zhang X, Wang K, Sun B. Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in Hepatocellular carcinoma. Oncotarget  2015; 6(6): 4505-15.
 [http://dx.doi.org/10.18632/oncotarget.2934] [PMID: 25714016]

[159]
Zhang C, Yang X, Qi Q, Gao Y, Wei Q, Han S. lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related Hepatocellular carcinoma. Cancer Biomark  2018; 21(3): 651-9.
 [http://dx.doi.org/10.3233/CBM-170727] [PMID: 29286922]

[160]
Xu H, Chen Y, Dong X, Wang X. Serum exosomal long noncoding RNAs ENSG00000258332.1 and LINC00635 for the diagnosis and prognosis of Hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev  2018; 27(6): 710-6.
 [http://dx.doi.org/10.1158/1055-9965.EPI-17-0770] [PMID: 29650788]

[161]
Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol  2003; 163(4): 1371-8.
 [http://dx.doi.org/10.1016/S0002-9440(10)63495-5] [PMID: 14507645]

[162]
Li J, Han X, Yu X, et al. Clinical applications of liquid biopsy as prognostic and predictive biomarkers in Hepatocellular carcinoma: Circulating tumor cells and circulating tumor DNA. J Exp Clin Cancer Res  2018; 37(1): 213.
 [http://dx.doi.org/10.1186/s13046-018-0893-1] [PMID: 30176913]

[163]
Jain S, Xie L, Boldbaatar B, et al. Differential methylation of the promoter and first exon of the RASSF1A gene in hepatocarcinogenesis. Hepatol Res  2015; 45(11): 1110-23.
 [http://dx.doi.org/10.1111/hepr.12449] [PMID: 25382672]

[164]
Jain S, Wojdacz TK, Su YH. Challenges for the application of DNA methylation biomarkers in molecular diagnostic testing for cancer. Expert Rev Mol Diagn  2013; 13(3): 283-94.
 [http://dx.doi.org/10.1586/erm.13.9] [PMID: 23570406]

[165]
Toyota M, Issa JPJ. Epigenetic changes in solid and hematopoietic tumors. Semin Oncol  2005; 32(5): 521-30.
 [http://dx.doi.org/10.1053/j.seminoncol.2005.07.003] [PMID: 16210093]

[166]
Liao W, Mao Y, Ge P, et al. Value of quantitative and qualitative analyses of circulating cell-free DNA as diagnostic tools for Hepatocellular carcinoma: A meta-analysis. Medicine  2015; 94(14): e722.
 [http://dx.doi.org/10.1097/MD.0000000000000722] [PMID: 25860220]

[167]
Zhang YJ, Wu HC, Shen J, et al. Predicting Hepatocellular carcinoma by detection of aberrant promoter methylation in serum DNA. Clin Cancer Res  2007; 13(8): 2378-84.
 [http://dx.doi.org/10.1158/1078-0432.CCR-06-1900] [PMID: 17438096]

[168]
Huang ZH, Hu Y, Hua D, Wu YY, Song MX, Cheng ZH. Quantitative analysis of multiple methylated genes in plasma for the diagnosis and prognosis of Hepatocellular carcinoma. Exp Mol Pathol  2011; 91(3): 702-7.
 [http://dx.doi.org/10.1016/j.yexmp.2011.08.004] [PMID: 21884695]

[169]
Xu RH, Wei W, Krawczyk  M. Circulating tumour DNA methylation markers for diagnosis and prognosis of Hepatocellular carcinoma. Nat Mater  2017; 16(11): 1155-61.

[170]
Rao CV, Asch AS, Yamada HY. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer. Carcinogenesis  2017; 38(1): 2-11.
 [http://dx.doi.org/10.1093/carcin/bgw118] [PMID: 27838634]

[171]
Liao W, Yang H, Xu H, et al. Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in Hepatocellular carcinoma patients by targeted deep sequencing. Oncotarget  2016; 7(26): 40481-90.
 [http://dx.doi.org/10.18632/oncotarget.9629] [PMID: 27248174]

[172]
Kirk GD, Lesi OA, Mendy M, et al. 249ser TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of Hepatocellular carcinoma. Oncogene  2005; 24(38): 5858-67.
 [http://dx.doi.org/10.1038/sj.onc.1208732] [PMID: 16007211]

[173]
Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L. Detection and localization of surgically resectable cancers with a multi-analyte blood test.  Science  2018; 359(6378): 926-30.
 [http://dx.doi.org/10.1126/science.aar3247]

[174]
Huang A, Zhang X, Zhou SL, et al. Detecting circulating tumor DNA in Hepatocellular carcinoma patients using droplet digital PCR is feasible and reflects intratumoral heterogeneity. J Cancer  2016; 7(13): 1907-14.
 [http://dx.doi.org/10.7150/jca.15823] [PMID: 27698932]

[175]
Feng J, Zhu R, Chang C, Yu L, Cao F, Zhu G. CK19 and glypican 3 expression profiling in the prognostic indication for patients with HCC after surgical resection.  PLoS One  2016; 11(3): e0151501.

[176]
Yu JP, Xu XG, Ma RJ, et al. Development of a clinical chemiluminescent immunoassay for serum GPC3 and simultaneous measurements alone with AFP and CK19 in diagnosis of Hepatocellular carcinoma. J Clin Lab Anal  2015; 29(2): 85-93.
 [http://dx.doi.org/10.1002/jcla.21733] [PMID: 24687454]

[177]
Sun DW, Zhang YY, Sun XD. Prognostic value of cytokeratin 19 in Hepatocellular carcinoma: A meta-analysis. Clin Chim Acta  2015; 448: 161-9.

[178]
Lee JI, Lee JW, Kim JM, Kim JK, Chung HJ, Kim YS. Prognosis of Hepatocellular carcinoma expressing cytokeratin 19: Comparison with other liver cancers. World J Gastroenterol  2012; 18(34): 4751-7.
 [http://dx.doi.org/10.3748/wjg.v18.i34.4751] [PMID: 23002345]

[179]
Kowalik MA, Sulas P, Ledda-Columbano GM, Giordano S, Columbano A, Perra A. Cytokeratin-19 positivity is acquired along cancer progression and does not predict cell origin in rat hepatocarcinogenesis. Oncotarget  2015; 6(36): 38749-63.
 [http://dx.doi.org/10.18632/oncotarget.5501] [PMID: 26452031]

[180]
Muramatsu T. Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases. Proc Jpn Acad, Ser B, Phys Biol Sci  2010; 86(4): 410-25.
 [http://dx.doi.org/10.2183/pjab.86.410] [PMID: 20431264]

[181]
Muramatsu T. Midkine and pleiotrophin: Two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem  2002; 132(3): 359-71.
 [http://dx.doi.org/10.1093/oxfordjournals.jbchem.a003231] [PMID: 12204104]

[182]
Zhu WW, Guo JJ, Guo L, et al. Evaluation of midkine as a diagnostic serum biomarker in Hepatocellular carcinoma. Clin Cancer Res  2013; 19(14): 3944-54.
 [http://dx.doi.org/10.1158/1078-0432.CCR-12-3363] [PMID: 23719264]

[183]
Shaheen KYA, Abdel-Mageed AI, Safwat E, AlBreedy AM. The value of serum midkine level in diagnosis of Hepatocellular carcinoma. Int J Hepatol  2015; 2015: 1-6.
 [http://dx.doi.org/10.1155/2015/146389] [PMID: 25737783]

[184]
Lokman NA, Ween MP, Oehler MK, Ricciardelli C. The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron  2011; 4(2): 199-208.
 [http://dx.doi.org/10.1007/s12307-011-0064-9] [PMID: 21909879]

[185]
Zhang H, Yao M, Wu W, et al. Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in Hepatocellular carcinoma. Tumour Biol  2015; 36(12): 9373-83.
 [http://dx.doi.org/10.1007/s13277-015-3678-6] [PMID: 26109000]

[186]
Sun Y, Gao G, Cai J, et al. Annexin A2 is a discriminative serological candidate in early Hepatocellular carcinoma. Carcinogenesis  2013; 34(3): 595-604.
 [http://dx.doi.org/10.1093/carcin/bgs372] [PMID: 23188673]

[187]
Biasiolo A, Trotta E, Fasolato S, et al. Squamous cell carcinoma antigen-IgM is associated with Hepatocellular carcinoma in patients with cirrhosis: A prospective study. Dig Liver Dis  2016; 48(2): 197-202.
 [http://dx.doi.org/10.1016/j.dld.2015.10.022] [PMID: 26614642]

[188]
Pozzan C, Cardin R, Piciocchi M, et al. Diagnostic and prognostic role of SCCA-IgM serum levels in Hepatocellular carcinoma (HCC). J Gastroenterol Hepatol  2014; 29(8): 1637-44.
 [http://dx.doi.org/10.1111/jgh.12576] [PMID: 24635038]

[189]
Giannelli G, Marinosci F, Trerotoli P, et al. SCCA antigen combined with alpha-fetoprotein as serologic markers of HCC. Int J Cancer  2005; 117(3): 506-9.
 [http://dx.doi.org/10.1002/ijc.21189] [PMID: 15906357]

[190]
Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res  1977; 37(3): 646-50.
 [PMID: 837366]

[191]
Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost  2011; 9(11): 2313-21.
 [http://dx.doi.org/10.1111/j.1538-7836.2011.04465.x] [PMID: 21838758]

[192]
García-Olmo DC, Domínguez C, García-Arranz M, et al. Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells. Cancer Res  2010; 70(2): 560-7.
 [http://dx.doi.org/10.1158/0008-5472.CAN-09-3513] [PMID: 20068178]

[193]
Jackson PE, Qian GS, Friesen MD, et al. Specific p53 mutations detected in plasma and tumors of Hepatocellular carcinoma patients by electrospray ionization mass spectrometry. Cancer Res  2001; 61(1): 33-5.
 [PMID: 11196182]

[194]
Kirk GD, Camus-Randon AM, Mendy M, et al. Ser-249 p53 mutations in plasma DNA of patients with Hepatocellular carcinoma from The Gambia. J Natl Cancer Inst  2000; 92(2): 148-53.
 [http://dx.doi.org/10.1093/jnci/92.2.148] [PMID: 10639517]

[195]
Lesi OA, Kirk GD, Sam O. Ser-249TP53 mutation in tumour and plasma DNA of Hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa.  Int J Cancer   2004; 110(3): 374-9.

[196]
Kirk GD, Lesi OA, Mendy M, et al. The gambia liver cancer study: Infection with hepatitis B and C and the risk of Hepatocellular carcinoma in West Africa. Hepatology  2004; 39(1): 211-9.
 [http://dx.doi.org/10.1002/hep.20027] [PMID: 14752840]

[197]
Hosny G, Farahat N, Tayel H, Hainaut P. Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with Hepatocellular carcinoma versus chronic liver diseases. Cancer Lett  2008; 264(2): 201-8.
 [http://dx.doi.org/10.1016/j.canlet.2008.01.031] [PMID: 18313840]

[198]
Wang J, Qin Y, Li B, Sun Z, Yang B. Detection of aberrant promoter methylation of GSTP1 in the tumor and serum of Chinese human primary Hepatocellular carcinoma patients. Clin Biochem  2006; 39(4): 344-8.
 [http://dx.doi.org/10.1016/j.clinbiochem.2006.01.008] [PMID: 16527261]

[199]
Wong IHN, Lo YM, Yeo W, Lau WY, Johnson PJ. Frequent p15 promoter methylation in tumor and peripheral blood from Hepatocellular carcinoma patients. Clin Cancer Res  2000; 6(9): 3516-21.
 [PMID: 10999738]

[200]
Wong IHN, Lo YM, Zhang J, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res  1999; 59(1): 71-3.
 [PMID: 9892188]

[201]
Yeo W, Wong N, Wong WL, Lai PBS, Zhong S, Johnson PJ. High frequency of promoter hypermethylation of RASSF1A in tumor and plasma of patients with Hepatocellular carcinoma. Liver Int  2005; 25(2): 266-72.
 [http://dx.doi.org/10.1111/j.1478-3231.2005.01084.x] [PMID: 15780049]

[202]
Chan KCA, Lai PBS, Mok TSK, et al. Quantitative analysis of circulating methylated DNA as a biomarker for Hepatocellular carcinoma. Clin Chem  2008; 54(9): 1528-36.
 [http://dx.doi.org/10.1373/clinchem.2008.104653] [PMID: 18653827]

[203]
Shi M, Chen MS, Sekar K, Tan CK, Ooi LL, Hui KM. A blood-based three-gene signature for the non-invasive detection of early human Hepatocellular carcinoma. Eur J Cancer  2014; 50(5): 928-36.
 [http://dx.doi.org/10.1016/j.ejca.2013.11.026] [PMID: 24332572]

[204]
Banales JM, Iñarrairaegui M, Arbelaiz A, et al. Serum metabolites as diagnostic biomarkers for cholangiocarcinoma, Hepatocellular carcinoma, and primary sclerosing cholangitis. Hepatology  2019; 70(2): 547-62.
 [http://dx.doi.org/10.1002/hep.30319] [PMID: 30325540]

[205]
Chen T, Xie G, Wang X, Fan J, Qiu Y, Zheng X. Serum and urine metabolite profiling reveals potential biomarkers of human Hepatocellular carcinoma. Mol Cell Proteomics  2011; 10(7): M110.004945. .

[206]
Wang W, Wei C. Advances in the early diagnosis of Hepatocellular carcinoma. Genes Dis  2020; 7(3): 308-19.
 [http://dx.doi.org/10.1016/j.gendis.2020.01.014] [PMID: 32884985]

[207]
Ladep NG, Dona AC, Lewis MR, et al. Discovery and validation of urinary metabotypes for the diagnosis of Hepatocellular carcinoma in West Africans. Hepatology  2014; 60(4): 1291-301.
 [http://dx.doi.org/10.1002/hep.27264] [PMID: 24923488]

[208]
Deng K, Xing J, Xu G, et al. Urinary biomarkers for Hepatocellular carcinoma: Current knowledge for clinicians. Cancer Cell Int  2023; 23(1): 239.
 [http://dx.doi.org/10.1186/s12935-023-03092-5] [PMID: 37833757]

[209]
Shao Y, Zhu B, Zheng R, et al. Development of urinary pseudotargeted LC-MS-based metabolomics method and its application in Hepatocellular carcinoma biomarker discovery. J Proteome Res  2015; 14(2): 906-16.
 [http://dx.doi.org/10.1021/pr500973d] [PMID: 25483141]

[210]
Sterling RK, Jeffers L, Gordon F, et al. Utility of Lens culinaris agglutinin-reactive fraction of α-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for Hepatocellular carcinoma. Clin Gastroenterol Hepatol  2009; 7(1): 104-13.
 [http://dx.doi.org/10.1016/j.cgh.2008.08.041] [PMID: 18849011]

[211]
Giannelli G, Fransvea E, Trerotoli P, et al. Clinical validation of combined serological biomarkers for improved Hepatocellular carcinoma diagnosis in 961 patients. Clin Chim Acta  2007; 383(1-2): 147-52.
 [http://dx.doi.org/10.1016/j.cca.2007.05.014] [PMID: 17582392]

[212]
Xia Q, Li Z, Zheng J, et al. Identification of novel biomarkers for Hepatocellular carcinoma using transcriptome analysis. J Cell Physiol  2019; 234(4): 4851-63.
 [http://dx.doi.org/10.1002/jcp.27283] [PMID: 30272824]

[213]
Liu J, Han F, Ding J, Liang X, Liu J, Huang D. Identification of multiple hub genes and pathways in Hepatocellular carcinoma: A bioinformatics analysis. Biomed Res Int  2021; 2021: 8849415.
 [http://dx.doi.org/10.1155/2021/8849415]

[214]
Teng L, Wang K, Liu Y, Ma Y, Chen W, Bi L. Based on integrated bioinformatics analysis identification of biomarkers in Hepatocellular carcinoma patients from different regions. BioMed Res Int  2019; 2019: 1-17.
 [http://dx.doi.org/10.1155/2019/1742341] [PMID: 31886176]

[215]
Li L, Lei Q, Zhang S, Kong L, Qin B. Screening and identification of key biomarkers in Hepatocellular carcinoma: Evidence from bioinformatic analysis. Oncol Rep  2017; 38(5): 2607-18.
 [http://dx.doi.org/10.3892/or.2017.5946] [PMID: 28901457]

[216]
Shen S, Kong J, Qiu Y, Yang X, Wang W, Yan L. Identification of core genes and outcomes in Hepatocellular carcinoma by bioinformatics analysis. J Cell Biochem  2019; 120(6): 10069-81.
 [http://dx.doi.org/10.1002/jcb.28290] [PMID: 30525236]

[217]
Ren Z, Li A, Jiang J, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early Hepatocellular carcinoma. Gut  2019; 68(6): 1014-23.
 [http://dx.doi.org/10.1136/gutjnl-2017-315084] [PMID: 30045880]
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DOI https://dx.doi.org/10.2174/0113816128298875240321073907	Print ISSN 1381-6128
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