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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Serum Biomarker Panel for Rapid Early Diagnosis of Lung Cancer

Author(s): Shucai Wu, Jiawen Zhang, Hongyan Wei, Ying Liu, Xianli Dai, Jinyu Xue, Ting Shen and Xinyan Liu*

Volume 23, Issue 7, 2023

Published on: 07 April, 2023

Page: [534 - 546] Pages: 13

DOI: 10.2174/1568009622666220523154333

Price: $65

Abstract

Background: Lung cancer is the leading cause of cancer death in most countries. Although early diagnosis and treatment critically influence prognosis, lung cancers are generally only discovered in the late stages of the disease.

Objective: Widely-used screening and diagnostic methods are not suitable for preventive screening, and high-throughput technologies based on serum biomarkers are needed.

Methods: We screened 501 serum samples, including 224 lung cancer (LC), 126 disease control (DC), and 151 healthy donor (HC) samples for new serum autoantibodies as biomarkers in the early diagnosis of lung cancer. In phase I, we used HuProtTM microarrays to perform preliminary serum antibody screening on 24 LC and 24 HC samples. In phase II, we screened 60 LC, 60 DC, and 60 HC serum samples using focused arrays constructed with 22 of the candidate autoantibody biomarkers screened out in phase I.

Results: After data modeling and validation, we selected four potential early LC protein biomarker candidates, IL2RB, CENPB, TP53, and XAGE1A, with individual specificities >90% and sensitivities ranging from 21.2% to 32.2%. These four biomarkers had a specificity of >90% and a sensitivity of >65.5% for early LC when they combined in a panel. Further evaluation of these four biomarker candidates using ELISA assays and 273 serum samples (140 LC, 66 DC, and 67 HC) gave similar results (specificity of >91.7%, sensitivity >61.43%).

Conclusion: IL2RB, CENPB, TP53, and XAGE1A combined biomarker panel holds potential for rapid screening and improving the diagnosis of early-stage LC, thus potentially also improving its prognosis.

Keywords: Lung cancer, rapid early diagnosis, biomarker, serum, microarrays, ELISA.

Graphical Abstract
[1]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[4]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[5]
Cao, M.; Chen, W. Epidemiology of lung cancer in China. Thorac. Cancer, 2019, 10(1), 3-7.
[http://dx.doi.org/10.1111/1759-7714.12916] [PMID: 30485694]
[6]
Wardwell, N.R.; Massion, P.P. Novel strategies for the early detection and prevention of lung cancer. Semin. Oncol., 2005, 32(3), 259-268.
[http://dx.doi.org/10.1053/j.seminoncol.2005.02.009] [PMID: 15988680]
[7]
Goldstraw, P.; Crowley, J.; Chansky, K.; Giroux, D.J.; Groome, P.A.; Rami-Porta, R.; Postmus, P.E.; Rusch, V.; Sobin, L. International association for the study of lung cancer international staging. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J. Thorac. Oncol., 2007, 2(8), 706-714.
[8]
Davidson, M.R.; Gazdar, A.F.; Clarke, B.E. The pivotal role of pathology in the management of lung cancer. J. Thorac. Dis., 2013, 5(Suppl. 5), S463-S478.
[PMID: 24163740]
[9]
Mantovani, C.; Novello, S.; Ragona, R.; Beltramo, G.; Giglioli, F.R.; Ricardi, U. Chemo-radiotherapy in lung cancer: State of the art with focus on the elderly population. Ann. Oncol., 2006, 17(Suppl. 2), ii61-ii63.
[http://dx.doi.org/10.1093/annonc/mdj926] [PMID: 16608987]
[10]
Oser, M.G.; Niederst, M.J.; Sequist, L.V.; Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol., 2015, 16(4), e165-e172.
[http://dx.doi.org/10.1016/S1470-2045(14)71180-5] [PMID: 25846096]
[11]
Aberle, D.R.; Berg, C.D.; Black, W.C.; Church, T.R.; Fagerstrom, R.M.; Galen, B.; Gareen, I.F.; Gatsonis, C.; Goldin, J.; Gohagan, J.K.; Hillman, B.; Jaffe, C.; Kramer, B.S.; Lynch, D.; Marcus, P.M.; Schnall, M.; Sullivan, D.C.; Sullivan, D.; Zylak, C.J. National Lung Screening Trial Research Team. The National Lung Screening Trial: overview and study design. Radiology, 2011, 258(1), 243-253.
[http://dx.doi.org/10.1148/radiol.10091808] [PMID: 21045183]
[12]
Henschke, C.I. International Early Lung Cancer Action Program Investigators. Survival of patients with clinical stage I lung cancer diagnosed by computed tomography screening for lung cancer. Clin. Cancer Res., 2007, 13(17), 4949-4950.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0317] [PMID: 17785541]
[13]
Gohagan, J.K.; Marcus, P.M.; Fagerstrom, R.M.; Pinsky, P.F.; Kramer, B.S.; Prorok, P.C.; Ascher, S.; Bailey, W.; Brewer, B.; Church, T.; Engelhard, D.; Ford, M.; Fouad, M.; Freedman, M.; Gelmann, E.; Gierada, D.; Hocking, W.; Inampudi, S.; Irons, B.; Johnson, C.C.; Jones, A.; Kucera, G.; Kvale, P.; Lappe, K.; Manor, W.; Moore, A.; Nath, H.; Neff, S.; Oken, M.; Plunkett, M.; Price, H.; Reding, D.; Riley, T.; Schwartz, M.; Spizarny, D.; Yoffie, R.; Zylak, C. Lung Screening Study Research Group. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer, 2005, 47(1), 9-15.
[http://dx.doi.org/10.1016/j.lungcan.2004.06.007] [PMID: 15603850]
[14]
Aberle, D.R.; Adams, A.M.; Berg, C.D.; Black, W.C.; Clapp, J.D.; Fagerstrom, R.M.; Gareen, I.F.; Gatsonis, C.; Marcus, P.M.; Sicks, J.D. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med., 2011, 365(5), 395-409.
[http://dx.doi.org/10.1056/NEJMoa1102873] [PMID: 21714641]
[15]
Brenner, D.J.; Hall, E.J. Computed tomography-an increasing source of radiation exposure. N. Engl. J. Med., 2007, 357(22), 2277-2284.
[http://dx.doi.org/10.1056/NEJMra072149] [PMID: 18046031]
[16]
Swensen, S.J.; Jett, J.R.; Hartman, T.E.; Midthun, D.E.; Mandrekar, S.J.; Hillman, S.L.; Sykes, A.M.; Aughenbaugh, G.L.; Bungum, A.O.; Allen, K.L. CT screening for lung cancer: five-year prospective experience. Radiology, 2005, 235(1), 259-265.
[http://dx.doi.org/10.1148/radiol.2351041662] [PMID: 15695622]
[17]
Broodman, I.; Lindemans, J.; van Sten, J.; Bischoff, R.; Luider, T. Serum protein markers for the early detection of lung cancer: A focus on autoantibodies. J. Proteome Res., 2017, 16(1), 3-13.
[http://dx.doi.org/10.1021/acs.jproteome.6b00559] [PMID: 27769114]
[18]
Larsen, J.E.; Minna, J.D. Molecular biology of lung cancer: Clinical implications. Clin. Chest Med., 2011, 32(4), 703-740.
[http://dx.doi.org/10.1016/j.ccm.2011.08.003] [PMID: 22054881]
[19]
Wistuba, I.I.; Gazdar, A.F. Lung cancer preneoplasia. Annu. Rev. Pathol., 2006, 1, 331-348.
[http://dx.doi.org/10.1146/annurev.pathol.1.110304.100103] [PMID: 18039118]
[20]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[21]
Zhong, L.; Coe, S.P.; Stromberg, A.J.; Khattar, N.H.; Jett, J.R.; Hirschowitz, E.A. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J. Thorac. Oncol., 2006, 1(6), 513-519.
[22]
Pan, J.; Song, G.; Chen, D.; Li, Y.; Liu, S.; Hu, S.; Rosa, C.; Eichinger, D.; Pino, I.; Zhu, H.; Qian, J.; Huang, Y. Identification of serological biomarkers for early diagnosis of lung cancer using a protein array-based approach. Mol. Cell. Proteomics, 2017, 16(12), 2069-2078.
[http://dx.doi.org/10.1074/mcp.RA117.000212] [PMID: 29021294]
[23]
Zhang, H.; Zhang, S. Present situation of lung cancer screening methods. Zhongguo Fei Ai Za Zhi, 2016, 19(10), 715-720.
[PMID: 27760605]
[24]
Hu, S.; Wan, J.; Su, Y.; Song, Q.; Zeng, Y.; Nguyen, H.N.; Shin, J.; Cox, E.; Rho, H.S.; Woodard, C.; Xia, S.; Liu, S.; Lyu, H.; Ming, G-L.; Wade, H.; Song, H.; Qian, J.; Zhu, H. DNA methylation presents distinct binding sites for human transcription factors. eLife, 2013, 2, e00726.
[http://dx.doi.org/10.7554/eLife.00726] [PMID: 24015356]
[25]
Hu, C.J.; Pan, J.B.; Song, G.; Wen, X.T.; Wu, Z.Y.; Chen, S.; Mo, W.X.; Zhang, F.C.; Qian, J.; Zhu, H.; Li, Y.Z. Identification of novel biomarkers for Behcet Disease diagnosis using HuProt array approach. Mol. Cell. Proteomics, 2017, 16(2), 147-156.
[http://dx.doi.org/10.1074/mcp.M116.061002] [PMID: 27777341]
[26]
Yang, L.; Wang, J.; Li, J.; Zhang, H.; Guo, S.; Yan, M.; Zhu, Z.; Lan, B.; Ding, Y.; Xu, M.; Li, W.; Gu, X.; Qi, C.; Zhu, H.; Shao, Z.; Liu, B.; Tao, S.C. Identification of serum biomarkers for gastric cancer diagnosis using a human proteome microarray. Mol. Cell. Proteomics, 2016, 15(2), 614-623.
[http://dx.doi.org/10.1074/mcp.M115.051250] [PMID: 26598640]
[27]
Syed, P.; Gupta, S.; Choudhary, S.; Pandala, N.G.; Atak, A.; Richharia, A. K p, M.; Zhu, H.; Epari, S.; Noronha, S.B.; Moiyadi, A.; Srivastava, S. Autoantibody profiling of glioma serum samples to identify biomarkers using human proteome arrays. Sci. Rep., 2015, 5, 13895.
[http://dx.doi.org/10.1038/srep13895] [PMID: 26370624]
[28]
Zhou, Y.; Guo, T.; Tang, G.; Wu, H.; Wong, N.K.; Pan, Z. Site-selective protein immobilization by covalent modification of GST fusion proteins. Bioconjug. Chem., 2014, 25(11), 1911-1915.
[http://dx.doi.org/10.1021/bc500347b] [PMID: 25340706]
[29]
Huang, C.G.; Li, F.X.; Pan, S.; Xu, C.B.; Dai, J.Q.; Zhao, X.H. Identification of genes associated with castration resistant prostate cancer by gene expression profile analysis. Mol. Med. Rep., 2017, 16(5), 6803-6813.
[http://dx.doi.org/10.3892/mmr.2017.7488] [PMID: 28901445]
[30]
Song, G.; Hu, C.; Zhu, H.; Wang, L.; Zhang, F.; Li, Y.; Wu, L. New centromere autoantigens identified in systemic sclerosis using centromere protein microarrays. J. Rheumatol., 2013, 40(4), 461-468.
[http://dx.doi.org/10.3899/jrheum.120264] [PMID: 23418382]
[31]
Tusher, V.G.; Tibshirani, R.; Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA, 2001, 98(9), 5116-5121.
[32]
Kanehisa, M.; Furumichi, M.; Tanabe, M.; Sato, Y.; Morishima, K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res., 2017, 45(D1), D353-D361.
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[33]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[34]
Haakensen, V.D.; Khadse, A.; Sandhu, V.; Halvorsen, A.R.; Solberg, S.K.; Jørgensen, L.H.; Brustugun, O.T.; Kure, E.H.; Helland, Å. Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy. Int. J. Cancer, 2020, 147(10), 2957-2966.
[http://dx.doi.org/10.1002/ijc.33121] [PMID: 32468587]
[35]
Liu, Y.; Wang, M. Advances in early diagnosis of lung cancer. Zhongguo Fei Ai Za Zhi, 2011, 14(5), 429-434.
[PMID: 21569649]
[36]
Jeong, J.S.; Jiang, L.; Albino, E.; Marrero, J.; Rho, H.S.; Hu, J.; Hu, S.; Vera, C.; Bayron-Poueymiroy, D.; Rivera-Pacheco, Z.A.; Ramos, L.; Torres-Castro, C.; Qian, J.; Bonaventure, J.; Boeke, J.D.; Yap, W.Y.; Pino, I.; Eichinger, D.J. Heng, Zhu.; Blackshaw, S. Rapid identification of monospecific monoclonal antibodies using a human proteome microarray. Mol. Cell. Proteomics, 2012, 11(6), O111.
[http://dx.doi.org/10.1074/mcp.O111.016253]
[37]
Olivier, M.; Hollstein, M.; Hainaut, P. TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol., 2010, 2(1), a001008.
[http://dx.doi.org/10.1101/cshperspect.a001008] [PMID: 20182602]
[38]
Aubrey, B.J.; Strasser, A.; Kelly, G.L. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb. Perspect. Med., 2016, 6(5), a026062.
[http://dx.doi.org/10.1101/cshperspect.a026062] [PMID: 27141080]
[39]
Soussi, T. p53 Antibodies in the sera of patients with various types of cancer: A review. Cancer Res., 2000, 60(7), 1777-1788.
[PMID: 10766157]
[40]
Simpson, A.J.; Caballero, O.L.; Jungbluth, A.; Chen, Y.T.; Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer, 2005, 5(8), 615-625.
[http://dx.doi.org/10.1038/nrc1669] [PMID: 16034368]
[41]
Brinkmann, U.; Vasmatzis, G.; Lee, B.; Pastan, I. Novel genes in the PAGE and GAGE family of tumor antigens found by homology walking in the dbEST database. Cancer Res., 1999, 59(7), 1445-1448.
[PMID: 10197611]
[42]
Zendman, A.J.; Van Kraats, A.A.; Weidle, U.H.; Ruiter, D.J.; Van Muijen, G.N. The XAGE family of cancer/testis-associated genes: Alignment and expression profile in normal tissues, melanoma lesions and Ewing’s sarcoma. Int. J. Cancer, 2002, 99(3), 361-369.
[http://dx.doi.org/10.1002/ijc.10371] [PMID: 11992404]
[43]
Egland, K.A.; Kumar, V.; Duray, P.; Pastan, I. Characterization of overlapping XAGE-1 transcripts encoding a cancer testis antigen expressed in lung, breast, and other types of cancers. Mol. Cancer Ther., 2002, 1(7), 441-450.
[PMID: 12479262]
[44]
Nakagawa, K.; Noguchi, Y.; Uenaka, A.; Sato, S.; Okumura, H.; Tanaka, M.; Shimono, M.; Ali Eldib, A.M.; Ono, T.; Ohara, N.; Yoshino, T.; Yamashita, K.; Tsunoda, T.; Aoe, M.; Shimizu, N.; Nakayama, E. XAGE-1 expression in non-small cell lung cancer and antibody response in patients. Clin. Cancer Res., 2005, 11(15), 5496-5503.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-0216] [PMID: 16061866]
[45]
Waldmann, T.A. The biology of interleukin-2 and interleukin-15: Implications for cancer therapy and vaccine design. Nat. Rev. Immunol., 2006, 6(8), 595-601.
[http://dx.doi.org/10.1038/nri1901] [PMID: 16868550]
[46]
Leonard, W.J.; Depper, J.M.; Crabtree, G.R.; Rudikoff, S.; Pumphrey, J.; Robb, R.J.; Krönke, M.; Svetlik, P.B.; Peffer, N.J.; Waldmann, T.A. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature, 1984, 311(5987), 626-631.
[http://dx.doi.org/10.1038/311626a0] [PMID: 6090948]
[47]
Wang, X.; Lupardus, P.; Laporte, S.L.; Garcia, K.C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol., 2009, 27, 29-60.
[http://dx.doi.org/10.1146/annurev.immunol.24.021605.090616] [PMID: 18817510]
[48]
Fernandez, I.Z.; Baxter, R.M.; Garcia-Perez, J.E.; Vendrame, E.; Hsieh, E.W.Y. Correction: A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation. J. Exp. Med., 2019, 216(6), 1465.
[http://dx.doi.org/10.1084/jem.2018201505102019c]
[49]
Garaci, E.; Sinibaldi, P.; Rasi, G. A new tumour associated antigen of non-small cell lung cancer: Tumour liberated proteins (TLP)--a possible new tumor marker. Anticancer Res., 1996, 16(4B), 2253-2255.
[PMID: 8694552]
[50]
Pan, J.; Yu, L.; Wu, Q.; Lin, X.; Liu, S.; Hu, S.; Rosa, C.; Eichinger, D.; Pino, I.; Zhu, H.; Qian, J.; Huang, Y. Integration of IgA and IgG autoantigens improves performance of biomarker panels for early diagnosis of lung cancer. Mol. Cell. Proteomics, 2020, 19(3), 490-500.
[http://dx.doi.org/10.1074/mcp.RA119.001905] [PMID: 31924693]
[51]
Türeci, O.; Mack, U.; Luxemburger, U.; Heinen, H.; Krummenauer, F.; Sester, M.; Sester, U.; Sybrecht, G.W.; Sahin, U. Humoral immune responses of lung cancer patients against tumor antigen NY-ESO-1. Cancer Lett., 2006, 236(1), 64-71.
[http://dx.doi.org/10.1016/j.canlet.2005.05.008] [PMID: 15992994]
[52]
Chapman, C.J.; Murray, A.; McElveen, J.E.; Sahin, U.; Luxemburger, U.; Türeci, O.; Wiewrodt, R.; Barnes, A.C.; Robertson, J.F. Autoantibodies in lung cancer: Possibilities for early detection and subsequent cure. Thorax, 2008, 63(3), 228-233.
[http://dx.doi.org/10.1136/thx.2007.083592] [PMID: 17932110]
[53]
Chapman, C.J.; Healey, G.F.; Murray, A.; Boyle, P.; Robertson, C.; Peek, L.J.; Allen, J.; Thorpe, A.J.; Hamilton-Fairley, G.; Parsy-Kowalska, C.B.; MacDonald, I.K.; Jewell, W.; Maddison, P.; Robertson, J.F. EarlyCDT®-Lung test: Improved clinical utility through additional autoantibody assays. Tumour Biol., 2012, 33(5), 1319-1326.
[http://dx.doi.org/10.1007/s13277-012-0379-2] [PMID: 22492236]

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