Combining multiple serum biomarkers in tumor diagnosis: A clinical assessment

Li,Xin; Lu,Jun; Ren,Hui; Chen,Tianjun; Gao,Lin; Di,Ligai; Song,Zhucui; Zhang,Ying; Yang,Tian; Thakur,Asmitananda; Zhou,Shu-Feng; Yin,Yanhai; Chen,Mingwei

doi:10.3892/mco.2012.23

Combining multiple serum biomarkers in tumor diagnosis: A clinical assessment

Authors:
- Xin Li
- Jun Lu
- Hui Ren
- Tianjun Chen
- Lin Gao
- Ligai Di
- Zhucui Song
- Ying Zhang
- Tian Yang
- Asmitananda Thakur
- Shu-Feng Zhou
- Yanhai Yin
- Mingwei Chen
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Affiliations: Department of Respiratory Medicine, The First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, School of Interdisciplinary Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1142, New Zealand, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
Published online on: September 19, 2012 https://doi.org/10.3892/mco.2012.23
Pages: 153-160

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Abstract

The present study aimed to assess the diagnostic/prognostic value of various clinical tumor markers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 (CYFRA21-1), α-fetoprotein (AFP), carbohydrate antigen-125 (CA-125), carbohydrate antigen-19.9 (CA-19.9) and ferritin, individually or in combination. The electro-chemiluminescence immunization method was performed to detect the levels of seven tumor markers in 560 cancer patients and 103 healthy subjects for comparison. The serum levels of the seven markers measured in cancer patients were higher compared to healthy subjects (P<0.05 for AFP and P<0.001 for the remaining six markers). Different markers had different sensitivity towards different types of tumors. Combining more markers significantly increased the ratios of positive diagnosis in the tumors. The diagnostic sensitivities of combining seven markers were particularly high in digestive, urinary and skeletal tumors (82, 92 and 83%, respectively). Gynecological tumors have exhibited a constant yet relatively low positive diagnosis irrespective of the use of a single marker or combined markers. However, the increase in sensitivity when combining markers was accompanied by a decrease in specificity. Generally, combining more markers increased the tumor detection rates, while a combination of the seven markers provided the highest detection rate. Combined detection showed a particularly high sensitivity in detecting respiratory, digestive and urinary system tumors, with the lowest sensitivity observed in gynecological tumors. As a result, combining tumor markers may play an important role in early tumor detection/diagnosis while the loss of specificity can be tolerated.

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1.	Welch HG, Schwartz LM and Woloshin S: Are increasing 5-year survival rates evidence of success against cancer? JAMA. 283:2975–2978. 2000.
2.	Bates SE and Longo DL: Use of serum tumor markers in cancer diagnosis and management. Semin Oncol. 14:102–138. 1987.
3.	Kluger HM, Hoyt K, Bacchiocchi A, et al: Plasma markers for identifying patients with metastatic melanoma. Clin Cancer Res. 17:2417–2425. 2011.
4.	Cohn SL, Lincoln ST and Rosen ST: Present status of serum tumor markers in diagnosis, prognosis, and evaluation of therapy. Cancer Invest. 4:305–327. 1986.
5.	Virji MA, Mercer DW and Herberman RB: Tumor markers in cancer diagnosis and prognosis. CA Cancer J Clin. 38:104–126. 1988.
6.	Maxwell P: Carcinoembryonic antigen: cell adhesion molecule and useful diagnostic marker. Br J Biomed Sci. 56:209–214. 1999.
7.	Molina R, Filella X, Auge JM, et al: Tumor markers (CEA, CA 125, CYFRA 21-1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis. Comparison with the main clinical and pathological prognostic factors. Tumour Biol. 24:209–218. 2003.
8.	Hammarstrom S: The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 9:67–81. 1999.
9.	Tan E, Gouvas N, Nicholls RJ, et al: Diagnostic precision of carcinoembryonic antigen in the detection of recurrence of colorectal cancer. Surg Oncol. 18:15–24. 2009.
10.	Carney DN and Teeling M: Neuron-specific enolase: how useful as a cancer marker? Eur J Cancer Clin Oncol. 24:825–828. 1988.
11.	Hatzakis KD, Froudarakis ME, Bouros D, et al: Prognostic value of serum tumor markers in patients with lung cancer. Respiration. 69:25–29. 2002.
12.	Cooper EH: Neuron-specific enolase. Int J Biol Markers. 9:205–210. 1994.
13.	Saloustros E and Mavroudis D: Cytokeratin 19-positive circulating tumor cells in early breast cancer prognosis. Future Oncol. 6:209–219. 2010.
14.	Uenishi T, Kubo S, Hirohashi K, et al: Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer. Br J Cancer. 88:1894–1899. 2003.
15.	Stieber P, Hasholzner U, Bodenmuller H, et al: CYFRA 21-1: a new marker in lung cancer. Cancer. 72:707–713. 1993.
16.	Jain R, Fischer S, Serra S, et al: The use of cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver. Appl Immunohistochem Mol Morphol. 18:9–15. 2010.
17.	Groover JR and Rogers AI: Immunologic tests for the detection of gastrointestinal cancers: status report on carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). Southern Med J. 66:1218–1221. 1973.
18.	Chen L, Ho DW, Lee NP, et al: Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker. Ann Surg Oncol. 17:2518–2525. 2010.
19.	Kemer T, Ormen M, Kuralay F, et al: Diagnostic usefulness of carbohydrate antigen-125 in cancerous and noncancerous peritoneal effusions. Tohoku J Exp Med. 205:11–18. 2005.
20.	Oktay G, Guner G, Karlikaya C and Akkoclu A: Serum levels of neuron-specific enolase, carbohydrate antigen 19-9 and carbohydrate antigen 125 in carcinoma of the lung. Biochem Soc Trans. 23:211S1995.
21.	Yeh LS, Hung YC, Kao A, et al: Tissue polypeptide specific antigen (TPS) and carbohydrate antigen 125 (CA-125) in the early prediction of recurrent ovarian cancer. Anticancer Res. 22:3669–3671. 2002.
22.	Encabo G, Genolla J, Gefaell R and Ruibal A: Serum carbohydrate antigen 19.9 in patients with digestive cancers. Presse Med. 14:23041985.(In French).
23.	Halloran CM, Ghaneh P, Connor S, et al: Carbohydrate antigen 19.9 accurately selects patients for laparoscopic assessment to determine resectability of pancreatic malignancy. Br J Surg. 95:453–459. 2008.
24.	van Ruth S, Hart AA, Bonfrer JM, et al: Prognostic value of baseline and serial carcinoembryonic antigen and carbohydrate antigen 19.9 measurements in patients with pseudomyxoma peritonei treated with cytoreduction and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 9:961–967. 2002.
25.	Torti SV and Torti FM: Iron and ferritin in inflammation and cancer. Adv Inorg Biochem. 10:119–137. 1994.
26.	Richardson DR: Iron and neoplasia: serum transferrin receptor and ferritin in prostate cancer. J Lab Clin Med. 144:173–175. 2004.
27.	Slodkowska J, Szturmowicz M, Rudzinski P, et al: Expression of CEA and trophoblastic cell markers by lung carcinoma in association with histological characteristics and serum marker levels. Eur J Cancer Prev. 7:51–60. 1998.
28.	Bergman B, Brezicka FT, Engstrom CP and Larsson S: Clinical usefulness of serum assays of neuron-specific enolase, carcinoembryonic antigen and CA-50 antigen in the diagnosis of lung cancer. Eur J Cancer. 29A:198–202. 1993.
29.	Seemann MD, Seemann O, Dienemann H, Schalhorn A, Prime G and Fink U: Diagnostic value of chest radiography, computed tomography and tumour markers in the differentiation of malignant from benign solitary pulmonary lesions. Eur J Med Res. 4:313–327. 1999.
30.	Schneider J and Schulze G: Comparison of tumor M2-pyruvate kinase (tumor M2-PK), carcinoembryonic antigen (CEA), carbohydrate antigens CA 19-9 and CA 72-4 in the diagnosis of gastrointestinal cancer. Anticancer Res. 23:5089–5093. 2003.
31.	Buccheri G, Torchio P and Ferrigno D: Clinical equivalence of two cytokeratin markers in non-small cell lung cancer: a study of tissue polypeptide antigen and cytokeratin 19 fragments. Chest. 124:622–632. 2003.
32.	Sung HJ and Cho JY: Biomarkers for the lung cancer diagnosis and their advances in proteomics. BMB Rep. 41:615–625. 2008.
33.	Muraki M, Tohda Y, Iwanaga T, Uejima H, Nagasaka Y and Nakajima S: Assessment of serum CYFRA 21-1 in lung cancer. Cancer. 77:1274–1277. 1996.
34.	Gaspar MJ, Arribas I, Coca MC and Diez-Alonso M: Prognostic value of carcinoembryonic antigen, CA 19-9 and CA 72-4 in gastric carcinoma. Tumour Biol. 22:318–322. 2001.
35.	Pujol JL, Boher JM, Grenier J, Quantin X, Saffont L and Daures JP: Neuron-specific enolase (NSE) in the surveillance of small cell cancers: an evaluation of the prognostic information using Markov’s model. Rev Mal Respir. 15:519–525. 1998.(In French).
36.	Chou SF and Chen CY: Monoclonal and polyclonal antibodies against human ferritin, a nonspecific tumor marker. Hybridoma. 20:59–62. 2001.
37.	Aulbert E and Schmidt CG: Ferritin - a tumor marker in myeloid leukemia. Cancer Detect Prev. 8:297–302. 1985.
38.	Dorner MH, Abel U, Fritze D, Manke HG and Drings P: Serum ferritin in relation to the course of Hodgkin’s disease. Cancer. 52:2308–2312. 1983.
39.	Bekci TT, Senol T and Maden E: The efficacy of serum carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3), alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels in determining the malignancy of solitary pulmonary nodules. J Int Med Res. 37:438–445. 2009.
40.	Wu GP, Ba J, Zhao YJ and Wang EH: Diagnostic value of CEA, CYFRA 21-1, NSE and CA 125 assay in serum and pleural effusion of patients with lung cancer. Acta Cytol. 51:679–680. 2007.
41.	Donach M, Yu Y, Artioli G, et al: Combined use of biomarkers for detection of ovarian cancer in high-risk women. Tumour Biol. 31:209–215. 2010.
42.	Goldenberg DM, Sharkey RM and Primus FJ: Immunocytochemical detection of carcinoembryonic antigen in conventional histopathology specimens. Cancer. 42:1546–1553. 1978.
43.	Nunez GR, Ito C and Del Giglio A: Increased serum CA-125 levels in patients with lung cancer post thoracotomy. Southern Med J. 102:427–428. 2009.
44.	Beneduce L, Castaldi F, Marino M, et al: Improvement of liver cancer detection with simultaneous assessment of circulating levels of free alpha-fetoprotein (AFP) and AFP-IgM complexes. Int J Biol Markers. 19:155–159. 2004.
45.	Beale G, Chattopadhyay D, Gray J, et al: AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer. 8:2002008.