Abstract
Introduction
The aim of this study was to investigate the role of thymidine kinase 1 (TK1) levels in hepatocellular carcinoma (HCC) prognosis and to develop a nomogram for predicting HCC prognosis.
Method
In this study, 1066 HCC patients were enrolled between August 2018 and April 2022. TK1 levels were measured within one week before enrollment, and the relationship with HCC prognosis was evaluated. Next, all patients were randomly assigned to the training set (70%, n = 746) and the validation set (30%, n = 320). We used multivariate Cox analysis to find independent prognostic factors in the training set to construct a nomogram. The predictive power of the nomogram was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The optimal critical value of TK1 was determined as 2.35 U/L using X-tile software.
Result
Before and after propensity score matching (PSM), the median overall survival (mOS) of the low-TK1 group (< 2.35 U/L) remained significantly longer than that of the high-TK1 group (≥ 2.35 U/L) (48.1 vs 16.5 months, p < 0.001; 75.7 vs 19.8 months, p = 0.001). Moreover, multivariate Cox analysis showed that the low TK1 level was an independent positive prognostic indicator. Additionally, the area under the ROC curve for predicting the 1-year, 2-year, and 3-year survival rates was 0.770, 0.758, and 0.805, respectively.
Conclusions
TK1 could serve as a prognostic marker for HCC. In addition, the nomogram showed good predictive capability for HCC prognosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analyzed in this study are in this article. Further inquiries can be directed to the corresponding author(lanpaoxiansheng@126.com).
References
Arita J, Ichida A, Nagata R, Mihara Y, Kawaguchi Y, Ishizawa T, Akamatsu N, Kaneko J, Hasegawa K (2022) Conversion surgery after preoperative therapy for advanced hepatocellular carcinoma in the era of molecular targeted therapy and immune checkpoint inhibitors. J Hepatobiliary Pancreat Sci 29(7):732–740. https://doi.org/10.1002/jhbp.1135. (Epub 2022 Mar 31)
Bitter EE, Townsend MH, Erickson R, Allen C, O’Neill KL (2020) Thymidine kinase 1 through the ages: a comprehensive review. Cell Biosci 10(1):138. https://doi.org/10.1186/s13578-020-00493-1
Cai Q, Zhu M, Duan J, Wang H, Chen J, Xiao Y, Wang Y, Wang J, Yu X, Yang H (2022) Comprehensive analysis of immune-related prognosis of TK1 in hepatocellular carcinoma. Front Oncol 11:786873. https://doi.org/10.3389/fonc.2021.786873
Chen Y-L, Eriksson S, Chang Z-F (2010) Regulation and functional contribution of thymidine kinase 1 in repair of DNA damage. J Biol Chem 285(35):27327–27335. https://doi.org/10.1074/jbc.M110.137042. (Epub 2010 Jun 16)
Chen S, Cao Q, Wen W, Wang H (2019) Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett 28(460):1–9. https://doi.org/10.1016/j.canlet.2019.114428. (Epub 2019 Jun 15)
Chen VL, Xu D, Wicha MS, Lok AS, Parikh ND (2020) Utility of liquid biopsy analysis in detection of hepatocellular carcinoma, determination of prognosis, and disease monitoring: a systematic review. Clin Gastroenterol Hepatol 18(13):2879–29029. https://doi.org/10.1016/j.cgh.2020.04.019. (e9; Epub 2020 Apr 11)
Cheng A-L, Hsu C, Chan SL, Choo S-P, Kudo M (2020) Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol 72(2):307–319. https://doi.org/10.1016/j.jhep.2019.09.025
Cucchetti A, Piscaglia F, Cescon M, Colecchia A, Ercolani G, Bolondi L, Pinna AD (2013) Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol 59(2):300–307. https://doi.org/10.1016/j.jhep.2013.04.009. (Epub 2013 Apr 18)
Fanelli GN, Scarpitta R, Cinacchi P, Fuochi B, Szumera-Ciećkiewicz A, De Ieso K, Ferrari P, Fontana A, Miccoli M, Naccarato AG, Scatena C (2021) Immunohistochemistry for thymidine kinase-1 (TK1): a potential tool for the prognostic stratification of breast cancer patients. J Clin Med 10(22):5416. https://doi.org/10.3390/jcm10225416
Farinati F, Marino D, De Giorgio M, Baldan A, Cantarini M, Cursaro C, Rapaccini G, Del Poggio P, Di Nolfo MA, Benvegnu L, Zoli M, Borzio F, Bernardi M, Trevisani F (2006) Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol 101(3):524–532. https://doi.org/10.1111/j.1572-0241.2006.00443.x
Gupta S, Ben S, Kohlwes J (2003) Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med 139(1):46–50. https://doi.org/10.7326/0003-4819-139-1-200307010-00012
Hanousková L, Řezáč J, Veselý Š, Průša R, Kotaška K (2020) Thymidine kinase-1 as additional diagnostic marker of prostate cancer. Clin Lab. https://doi.org/10.7754/Clin.Lab.2019.191026
He Q, Zou L, Zhang PA, Lui JX, Skog S, Fornander T (2000) The clinical significance of thymidine kinase 1 measurement in serum of breast. Int J Biol Markers 15(2):139–146. https://doi.org/10.1177/172460080001500203
Jagarlamudi KK, Shaw M (2018) Thymidine kinase 1 as a tumor biomarker: technical advances offer new potential to an old biomarker. Biomark Med 12(9):1035–1048. https://doi.org/10.2217/bmm-2018-0157. (Epub 2018 Jul 24)
Karaoğullarindan Ü, Gümürdülü Üsküdar Y, Üsküdar O, Odabaş E, Güler HS, Delik A, Kuran S (2022) Prognostic factors of elderly patients with hepatocellular carcinoma: should we be more courageous in treatment? Eur J Gastroenterol Hepatol 34(9):956–960. https://doi.org/10.1097/MEG.0000000000002396. (Epub 2022 Jul 5)
Ke Q, Xin F, Fang H, Zeng Y, Wang L, Liu J (2022b) The significance of transarterial chemo(embolization) combined with tyrosine kinase inhibitors and immune checkpoint inhibitors for unresectable hepatocellular carcinoma in the era of systemic therapy: a systematic review. Front Immunol 13:913464. https://doi.org/10.3389/fimmu.2022.913464. (Erratum in: Front Immunol. 2022 Jun 07;13:952446)
Kuang J, Wan D, Wan PP, Wu D (2021) Efficacy of sorafenib combined with transcatheter hepatic arterial chemoembolization in treating intermediate-advanced hepatocellular carcinoma. J BUON 26(3):868–874
Lau WY, Lai ECH (2007) Salvage surgery following downstaging of unresectable hepatocellular carcinoma—a strategy to increase resectability. Ann Surg Oncol 14(12):3301–3309. https://doi.org/10.1245/s10434-007-9549-7. (Epub 2007 Sep 22)
Li H, Wu Z, Chen J, Su K, Guo L, Xu K, Gu T, Jiang Y, Wang P, Zeng H, Chi H, He K, Han Y (2022) External radiotherapy combined with sorafenib has better efficacy in unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Clin Exp Med. https://doi.org/10.1007/s10238-022-00972-4. (Epub ahead of print)
Liu L, Chen A, Chen S, Song W, Yao Q, Wang P, Zhou S (2020) CCNB2, NUSAP1 and TK1 are associated with the prognosis and progression of hepatocellular carcinoma, as revealed by co-expression analysis. Exp Ther Med 19(4):2679–2689. https://doi.org/10.3892/etm.2020.8522. (Epub 2020 Feb 11)
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS (2021) Hepatocellular carcinoma. Nat Rev Dis Primers 7(1):6. https://doi.org/10.1038/s41572-020-00240-3
Masao N, Tokumitsu Y, Shindo Y, Matsui H, Matsukuma S, Iida M, Suzuki N, Takeda S, Ioka T, Nagano H (2021) The recent development of the surgical treatment for hepatocellular carcinoma[J]. Appl Sci. https://doi.org/10.3390/app11052023
Su K, Gu T, Xu K, Wang J, Liao H, Li X, Wen L, Song Y, Zhong J, He B, Liu X, He J, Liu Y, Li Q, Feng X, Chen S, Yang B, Huang W, Jin H, Luo X, Hu T, Chen J, Wu Z, Lu S, Zhang J, Rao M, Xie Y, Wang J, Zhu X, Chen L, Li B, Su S, Yang X, Wang J, Zeng H, Wang P, Yan M, Chen X, He K, Han Y (2022a) Gamma knife radiosurgery versus transcatheter arterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a propensity score matching study. Hepatol Int 16(4):858–867. https://doi.org/10.1007/s12072-022-10339-2. (Epub 2022 Jun 21)
Su K, Guo L, Ma W, Wang J, Xie Y, Rao M, Zhang J, Li X, Wen L, Li B, Yang X, Song Y, Huang W, Chi H, Gu T, Xu K, Liu Y, Chen J, Wu Z, Jiang Y, Li H, Zeng H, Wang P, Feng X, Chen S, Yang B, Jin H, He K, Han Y (2022a) PD-1 inhibitors plus anti-angiogenic therapy with or without intensity-modulated radiotherapy for advanced hepatocellular carcinoma: A propensity score matching study. Front Immunol 13:972503. https://doi.org/10.3389/fimmu.2022.972503
Su K, Guo L, He K, Rao M, Zhang J, Yang X, Huang W, Gu T, Xu K, Liu Y, Wang J, Chen J, Wu Z, Hu L, Zeng H, Li H, Tong J, Li X, Yang X, Liu H, Xu Y, Tan Z, Tang X, Feng X, Chen S, Yang B, Jin H, Zhu L, Li B, Han Y (2022b) PD-L1 expression on circulating tumor cells can be a predictive biomarker to PD-1 inhibitors combined with radiotherapy and antiangiogenic therapy in advanced hepatocellular carcinoma. Front Oncol 12:873830. https://doi.org/10.3389/fonc.2022.873830
Su K, Liu Y, Wang P, He K, Wang F, Chi H, Rao M, Li X, Wen L, Song Y, Zhang J, Gu T, Xu K, Li Q, Chen J, Wu Z, Li H, Huang W, Chen L, Tong J, Li H, Feng X, Chen S, Yang B, Jin H, Yang Y, Liu H, Yang C, Wu M, Xiong F, Peng K, Zhu L, Xu Y, Tang X, Tan Z, Luo X, Zheng H, Zhang Y, Guo L, Han Y (2022c) Heat-shock protein 90α is a potential prognostic and predictive biomarker in hepatocellular carcinoma: a large-scale and multicenter study. Hepatol Int 16(5):1208–1219. https://doi.org/10.1007/s12072-022-10391-y. (Epub 2022 Aug 16)
Su K, Huang W, Li X, Xu K, Gu T, Liu Y, Song J, Qian K, Xu Y, Zeng H, Yang Y, Guo L, Han Y (2023) Evaluation of lactate dehydrogenase and alkaline phosphatase as predictive biomarkers in the prognosis of hepatocellular carcinoma and development of a new nomogram. J Hepatocell Carcinoma 14(10):69–79. https://doi.org/10.2147/JHC.S398632
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660. (Epub 2021 Feb 4)
Tang Y, Li K, Cai Z, Xie Y, Tan X, Chenglin Su, Li J (2020) HSP90α combined with AFP and TK1 improved the diagnostic value for hepatocellular carcinoma. Biomark Med 14(10):869–878. https://doi.org/10.2217/bmm-2019-0484. (Epub 2020 Jun 3)
Terentiev AA, Moldogazieva NT (2013) Alpha-fetoprotein: a renaissance. Tumour Biol 34(4):2075–2091. https://doi.org/10.1007/s13277-013-0904-y. (Epub 2013 Jun 14)
Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T (2015) Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 21(37):10573–10583. https://doi.org/10.3748/wjg.v21.i37.10573
Wang Na, Cao Y, Song W, He K, Li T, Wang J, Bin Xu, Si H-Y, Cheng-Jin Hu, Li A-L (2014) Serum peptide pattern that differentially diagnoses hepatitis B virus-related hepatocellular carcinoma from liver cirrhosis. J Gastroenterol Hepatol 29(7):1544–1550. https://doi.org/10.1111/jgh.12545
Wang Y, Jiang X, Dong S, Shen J, Haixia Yu, Zhou Ji, Li J, Ma H, He E, Skog S (2016) Serum TK1 is a more reliable marker than CEA and AFP for cancer screening in a study of 56,286 people. Cancer Biomark 16(4):529–536. https://doi.org/10.3233/CBM-160594
Wang G, Xiaolan Lu, Qin Du, Zhang G, Wang D, Wang Q, Guo X (2020) Diagnostic value of the γ-glutamyltransferase and alanine transaminase ratio, α-fetoprotein, and protein induced by vitamin K absence or antagonist II in hepatitis B virus-related hepatocellular carcinoma. Sci Rep 10(1):020–70241
Wang L, Sharif H, Saellström S, Rönnberg H, Eriksson S (2021) Feline thymidine kinase 1: molecular characterization and evaluation of its serum form as a diagnostic biomarker. BMC Vet Res 17(1):316. https://doi.org/10.1186/s12917-021-03030-5
Wei Y-T, Luo Y-Z, Feng Z-Q, Huang Q-X, Mo A-S, Mo S-X (2018) TK1 overexpression is associated with the poor outcomes of lung cancer patients: a systematic review and meta-analysis. Biomark Med 12(4):403–413. https://doi.org/10.2217/bmm-2017-0249. (Epub 2018 Mar 26)
Xie H, Guo L, Wang Z, Peng S, Ma Q, Yang Z, Shang Z, Niu Y (2022) Assessing the potential prognostic and immunological role of TK1 in prostate. Front Genet. https://doi.org/10.3389/fgene.2022.778850
Xu Y, Liu B, Shi Q-L, Huang P-L, Zhou X-J, Ma H-H, Lu Z-F, Bo Y, Eriksson S, He E, Skog S (2014) Thymidine kinase 1 is a better prognostic marker than Ki-67 for pT1 adenocarcinoma of the lung. Int J Clin Exp Med 7(8):2120–2128
Xu F, Jin T, Zhu Y, Dai C (2018) Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res 37(1):110. https://doi.org/10.1186/s13046-018-0777-4
Yang S-L, Liu L-P, Yang S, Liu L, Ren J-W, Fang X, Chen GG, Lai PBS (2016) Preoperative serum α-fetoprotein and prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg 103(6):716–724. https://doi.org/10.1002/bjs.10093. (Epub 2016 Mar 21)
Yeo W, Mo FKF, Koh J, Chan ATC, Leung T, Hui P, Chan L, Tang A, Lee JJ, Mok TSK, Lai PBS, Johnson PJ, Zee B (2006) Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol 17(7):1083–1089. https://doi.org/10.1093/annonc/mdl065. (Epub 2006 Apr 6)
Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, Xia C, Sun K, Yang Z, Li H, Wang N, Han R, Liu S, Li H, Mu H, He Y, Xu Y, Fu Z, Zhou Y, Jiang J, Yang Y, Chen J, Wei K, Fan D, Wang J, Fu F, Zhao D, Song G, Chen J, Jiang C, Zhou X, Gu X, Jin F, Li Q, Li Y, Wu T, Yan C, Dong J, Hua Z, Baade P, Bray F, Jemal A, Yu X, He J (2018) Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 6(5):e555–e567. https://doi.org/10.1016/S2214-109X(18)30127-X
Zhang J, Jia Q, Zou S, Zhang P, Zhang X, Skog S, Luo P, Zhang W, He Q (2006) Thymidine kinase 1: a proliferation marker for determining prognosis and monitoring the surgical outcome of primary bladder carcinoma patients. Oncol Rep 15(2):455–461
Zhang S-Y, Lin B-D, Li B-R (2015) Evaluation of the diagnostic value of α-l-fucosidase, alpha-fetoprotein and thymidine kinase 1 with ROC and logistic regression for hepatocellular carcinoma. FEBS Open Bio 26(5):240–244. https://doi.org/10.1016/j.fob.2015.03.010
Zhang J-X, Chen Y-X, Zhou C-G, Liu J, Liu S, Shi H-B, Qing-Quan Zu (2022) Transarterial chemoembolization combined with lenvatinib versus transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: a comparative retrospective study. Hepatol Res 52(9):794–803. https://doi.org/10.1111/hepr.13801. (Epub 2022 Jun 30)
Zhao S, Zhou M, Wang P, Yang J, Zhang D, Yin F, Song P (2022) Sorafenib, lenvatinib, or lenvatinib combining PD-1 inhibitors plus TACE in unresectable hepatocellular carcinoma: a retrospective analysis. Technol Cancer Res Treat 21:15330338221133640. https://doi.org/10.1177/15330338221133640
Zhou J, He E, Skog S (2013) The proliferation marker thymidine kinase 1 in clinical use. Mol Clin Oncol 1(1):18–28. https://doi.org/10.3892/mco.2012.19. (Epub 2012 Sep 4)
Zhou H, Jiang Le, Wang G, Linlin Su, Hou L, Xue X (2021) Identification of MCM4 as a prognostic marker of hepatocellular carcinoma. Biomed Res Int 18(2021):7479326. https://doi.org/10.1155/2021/7479326
Funding
This work was supported by a grant from the Project of Sichuan Science and Technology Program (2022YFS0622).
Author information
Authors and Affiliations
Contributions
YJ, LG, LH, HL, CL, LW, YS, Zhaoyang Wang, PW, QG, WZ, ML, JC, Zhenying Wu, YY, KX, TG, XW, KH, KS, and YH collected the data. YH and KS designed the research study. YJ, LG, and HL wrote the manuscript and analyzed the data. All authors approved the final version of the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest regarding the content of this paper.
Ethical statement
Approval of the research protocol by an Institutional Reviewer Board: This retrospective study was approved by the Ethics Committee of The Affiliated Hospital of Southwest Medical University (approval number KY2020254).
Informed consent
No.
Registry and the registration no. of the study/trial
No.
Animal studies
No.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary Fig. 1:
Kaplan–Meier plots for overall survival in the transcatheter arterial chemoembolization (TACE) group (A) and surgery group (B). Abbreviation: TACE transcatheter arterial chemoembolization. Supplementary Fig. 2: Calibration curves for 1-year (A), 2-year (B) and 3-year (C) and decision curve analyses (D) in the validation cohort (DOCX 263 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jiang, Y., Guo, L., Han, L. et al. Thymidine kinase 1 appears to be a marker for the prognosis of hepatocellular carcinoma based on a large-scale, multicenter study. J Cancer Res Clin Oncol 149, 14271–14282 (2023). https://doi.org/10.1007/s00432-023-05089-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-05089-z