title: Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma.
abstract: If diagnosed at early stages, patients with hepatocellular carcinoma (HCC) can receive curative therapies, whereas therapeutic options at later stages are very limited. Here, we addressed the potential of soluble Axl (sAxl) as a biomarker of early HCC by analyzing levels of sAxl in 311 HCC and 237 control serum samples from centers in Europe and China. Serum concentrations of sAxl were significantly increased in HCC (18.575 ng/mL) as compared to healthy (13.388 ng/mL) or cirrhotic (12.169 ng/mL) controls. Receiver operating characteristic curve analysis of sAxl in very early stage HCC patients (BCLC 0) showed an area under the curve (AUC) of 0.848, with a sensitivity of 76.9% and a specificity of 69.2%. α-Fetoprotein (AFP)-negative HCC patients displayed an AUC of 0.803, with sensitivity and specificity of 73% and 70.8%. Combination of sAxl and AFP improved diagnostic accuracy to 0.936 in very early HCC patients and to 0.937 in all HCC. Differential diagnosis of very early HCC versus liver cirrhosis showed a combined performance for sAxl and AFP of 0.901 with a sensitivity of 88.5% and a specificity of 76.7%. Furthermore, sAxl levels failed to be elevated in primary ovarian, colorectal and breast carcinomas as well as in secondary hepatic malignancies derived from colon. In summary, sAxl outperforms AFP in detecting very early HCC as compared to healthy or cirrhotic controls and shows high diagnostic accuracy for AFP-negative patients. sAxl is specific for HCC and suggested as a biomarker for routine clinical use.
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Reichl
authors.affiliation: Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Starlinger
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Staufer
authors.affiliation: Department of Pathology and Department of Laboratory Medicine, BBMRI Biobanking Unit, and Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Nenutil
authors.affiliation: Department of Pathology and Department of Laboratory Medicine, BBMRI Biobanking Unit, and Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Muller
authors.affiliation: Department of Pathology and Department of Laboratory Medicine, BBMRI Biobanking Unit, and Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Greplova
authors.affiliation: Department of Pathology and Department of Laboratory Medicine, BBMRI Biobanking Unit, and Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Valik
authors.affiliation: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruenberger
authors.affiliation: Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong SAR, China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong SAR, China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong SAR, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors.forename: Chun Fang
authors.initials: CF
authors.lastname: Gao
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000175:diagnosis*; D045744:Cell Line, Tumor; D003937:Diagnosis, Differential; D042241:Early Diagnosis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000097:blood* / Q000378:metabolism; D012372:ROC Curve; D020794:Receptor Protein-Tyrosine Kinases / Q000097:blood* / Q000378:metabolism; D012995:Solubility; D000509:alpha-Fetoproteins / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D000509:alpha-Fetoproteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: biomarker; hepatocellular carcinoma; soluble Axl; α-fetoprotein