Search for Effective Serum Tumor Markers for Early Diagnosis of Hepatocellular Carcinoma Associated with Hepatitis C

S I Malov; I V Malov; A G Kuvshinov; P N Marche; T Decaens; Z Macek-Jilkova; N D Yushchuk

doi:10.17691/stm2021.13.1.03

Search for Effective Serum Tumor Markers for Early Diagnosis of Hepatocellular Carcinoma Associated with Hepatitis C

Sovrem Tekhnologii Med. 2021;13(1):27-33. doi: 10.17691/stm2021.13.1.03. Epub 2021 Feb 28.

Authors

S I Malov¹, I V Malov², A G Kuvshinov³, P N Marche⁴, T Decaens⁵, Z Macek-Jilkova⁶, N D Yushchuk⁷

Affiliations

¹ Associate Professor, Department of Infectious Diseases, Irkutsk State Medical University, 1 Krasnogo Vosstaniya St., Irkutsk, 664003, Russia, Senior Researcher, Central Scientific Research Laboratory, Irkutsk State Medical Academy of Post-Graduate Education, a Branch of the Russian Medical Academy of Continuing Professional Education, 100 Yubileyny Microdistrict, Irkutsk, 664049, Russia.
² Professor, Head of the Department of Infectious Diseases, Irkutsk State Medical University, 1 Krasnogo Vosstaniya St., Irkutsk, 664003, Russia.
³ Assistant, Department of Oncology and Radiation Therapy, Irkutsk State Medical University, 1 Krasnogo Vosstaniya St., Irkutsk, 664003, Russia.
⁴ Professor, Vice Director of Research Center, Institute for Advanced Biosciences, Site Santé, Allée des Alpes, La Tronche, 38700, France.
⁵ Professor, Research Director, Laboratory Head of Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Avenue Maquis du Grésivaudan, La Tronche, 38700, France.
⁶ Researcher, Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Avenue Maquis du Grésivaudan, La Tronche, 38700, France.
⁷ Professor, Academician of the Russian Academy of Sciences, Head of the Department of Infectious Diseases and Epidemiology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 20/1 Delegatskaya St., Moscow, 127473, Russia.

Abstract

The aim of the study was to identify the most effective serum tumor markers for early diagnosis of hepatocellular carcinoma based on the combination of diagnostic characteristics and correlations.

Materials and methods: There were observed 55 patients with chronic hepatitis C in the stage of liver cirrhosis with a verified diagnosis of hepatocellular carcinoma. The control group consisted of 55 patients with chronic hepatitis C at the stage of liver cirrhosis without hepatocellular carcinoma, comparable to the experimental group in terms of basic clinical profile. The following tumor markers were estimated in both groups: alpha-fetoprotein (AFP), alpha-fetoprotein-L3 (AFP-L3), annexin A2 (ANXA2), heparin-binding growth factor Midkine (MDK), glypican-3 (GPC3), des-gamma-carboxyprothrombin (DCP, PIVKA-II), dickkopf-related protein 1 (DKK-1), osteopontin (OPN), and Golgi protein 73 (GP73). There were also evaluated such indices as diagnostic sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test, the possible correlation between alpha-fetoprotein and other tumor markers. The area under the ROC curve (AUC) was calculated at the 95% confidence interval.

Results: The greatest sensitivity was revealed when using heparin-binding growth factor, annexin A2, osteopontin. Alpha-fetoprotein, alpha-fetoprotein-L3, glypican-3, des-gamma-carboxyprothrombin, dickkopf-related protein 1 had the best specificity. AUC>0.75 was found in annexin A2, heparin-binding growth factor, glypican-3, des-gamma-carboxyprothrombin, osteopontin, Golgi protein 73. The likelihood ratio of a positive test result was the highest for glypican-3. A significant correlation was found between alpha-fetoprotein and alpha-fetoprotein-L3, annexin A2, des-gamma-carboxyprothrombin.

Conclusion: According to the aggregate indicators of diagnostic efficiency, heparin-binding growth factor, glypican-3, and osteopontin are the most promising tumor markers of those studied. When they are used, integral AUC values are above the average, the level of these tumor markers in the blood of patients with hepatocellular cancer does not correlate with alpha-fetoprotein. They are applicable for diagnosing liver cancer in AFP-negative patients. The combined use of AFP + GPC3, AFP + OPN has already shown their advantages. However, the efficacy of the combination of AFP + MDK, GPC3 + OPN has not been determined yet; therefore, significance of the combined use of these tumor markers in the diagnosis of liver cancer should be investigated in the near future.

Keywords: hepatitis C; hepatocellular carcinoma; proteomics; tumor markers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor
Carcinoma, Hepatocellular* / diagnosis
Early Detection of Cancer
Glypicans
Hepatitis C*
Humans
Liver Neoplasms* / diagnosis

Substances

Biomarkers, Tumor
GPC3 protein, human
Glypicans

Grants and funding

Study funding. The work was supported by the Ministry of Science and Higher Education of the Russian Federation in the framework of the Federal Target Program of Research and Development in Priority Areas with participation of research organizations and universities as part of the joint French-Russian PHC Kolmogorov project (agreement No.14.616.21.0098; project ID: RFMEFI61618X0098).