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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2019

Open Access 01-12-2019 | Epstein-Barr Virus | Research

Identification of two microRNA signatures in whole blood as novel biomarkers for diagnosis of nasopharyngeal carcinoma

Authors: Wen Wen, Shi-Juan Mai, Huan-Xin Lin, Mei-Yin Zhang, Jia-Ling Huang, Xin Hua, Chao Lin, Zhi-Qing Long, Zi-Jian Lu, Xiao-Qing Sun, Sai-Lan Liu, Qi Yang, Qian Zhu, Hui-Yun Wang, Ling Guo

Published in: Journal of Translational Medicine | Issue 1/2019

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Abstract

Background

Early diagnosis is critical to reduce the mortality caused by nasopharyngeal carcinoma (NPC). MicroRNAs (miRNAs) are dysregulated and play important roles in carcinogenesis. Therefore, this study aimed to identify diagnostically relevant circulating miRNA signatures in patients with NPC.

Methods

Total RNA was extracted from whole blood samples obtained from 120 patients with NPC, 30 patients with head-neck tumors (HNT), and 30 healthy subjects (HSs), and examined by using a custom microarray. The expression levels of four miRNAs identified by using the microarray were validated with quantitative real-time reverse transcription polymerase chain reaction. The 120 patients with NPC and 30 HSs were randomly assigned to training group-1 and validation group-1, respectively. By using significance analysis of microarray (SAM), the specific miRNA expression profiles in whole blood from patients with NPC are obtained. By using lasso regression and adaptive boosting, a diagnostic signature was identified in training group-1, and its accuracy was verified in validation group-1. By using the same methods, another signature to distinguish patients with NPC from those with HNT and HSs was identified in training group-2 and confirmed in validation group-2.

Results

There were 117 differentially expressed miRNAs (upregulated and downregulated fold change ≥ 1.5) between the patients with NPC and HSs, among which an 8-miRNA signature was identified with 96.43% sensitivity and 100% specificity [area under the curve (AUC) = 0.995] to diagnose NPC in training group-1 and 86.11% sensitivity and 88.89% specificity (AUC = 0.941) in validation group-1. Compared with traditional Epstein–Barr virus (EBV) seromarkers, this signature was more specific for NPC. Furthermore, a 16-miRNA signature to differentiate NPC from HNT and HS (HNT-HS) was established from 164 differentially expressed miRNAs, which diagnosed NPC and HNT-HS with 100% accuracy (AUC = 1.000) in training group-2 and 87.04% (AUC = 0.924) in validation group-2.

Conclusions

The present study identified two miRNA signatures for the highly accurate diagnosis and differential diagnosis of patients with NPC from HSs and patients with HNT. The identified miRNAs might represent novel serological biomarkers and potential therapeutic targets for NPC.
Appendix
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Literature
1.
Lee AW, Ng WT, Chan YH, Sze H, Chan C, Lam TH. The battle against nasopharyngeal cancer. Radiother Oncol. 2012;104(3):272–8.PubMedCrossRef
2.
Zhang L, Chen QY, Liu H, Tang LQ, Mai HQ. Emerging treatment options for nasopharyngeal carcinoma. Drug Des Dev Ther. 2013;7:37–52.
3.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.PubMedCrossRef
4.
Lv JW, Huang XD, Chen YP, Zhou GQ, Tang LL, Mao YP, Li WF, Lin AH, Ma J, Sun Y. A National Study of survival trends and conditional survival in nasopharyngeal carcinoma: analysis of the national population-based surveillance epidemiology and end results registry. Cancer Res Treat. 2018;50(2):324–34.PubMedCrossRef
5.
Chan AT, Gregoire V, Lefebvre JL, Licitra L, Hui EP, Leung SF, Felip E. Nasopharyngeal cancer: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii83–5.PubMedCrossRef
6.
7.
Paramita DK, Fachiroh J, Haryana SM, Middeldorp JM. Two-step Epstein-Barr virus immunoglobulin A enzyme-linked immunosorbent assay system for serological screening and confirmation of nasopharyngeal carcinoma. Clin Vaccine Immunol CVI. 2009;16(5):706–11.PubMedCrossRef
8.
Tsao SW, Tsang CM, Lo KW. Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond Ser B Biol Sci. 2017;372(1732):20160270.CrossRef
9.
Chen Y, Xin X, Cui Z, Zheng Y, Guo J, Chen Y, Lin Y, Su G. Diagnostic value of serum Epstein-Barr virus capsid antigen-IgA for nasopharyngeal carcinoma: a meta-analysis based on 21 studies. Clin Lab. 2016;62(6):1155–66.PubMed
10.
Pearson GR. Epstein-Barr virus and nasopharyngeal carcinoma. J Cell Biochem Suppl. 1993;17f:150–4.PubMedCrossRef
11.
Han BL, Xu XY, Zhang CZ, Wu JJ, Han CF, Wang H, Wang X, Wang GS, Yang SJ, Xie Y. Systematic review on Epstein-Barr virus (EBV) DNA in diagnosis of nasopharyngeal carcinoma in Asian populations. Asian Pac J Cancer Prev APJCP. 2012;13(6):2577–81.PubMedCrossRef
12.
Abdulamir AS, Hafidh RR, Abdulmuhaimen N, Abubakar F, Abbas KA. The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types. BMC Public Health. 2008;8:400.PubMedPubMedCentralCrossRef
13.
Busson P, Keryer C, Ooka T, Corbex M. EBV-associated nasopharyngeal carcinomas: from epidemiology to virus-targeting strategies. Trends Microbiol. 2004;12(8):356–60.PubMedCrossRef
14.
Jiang W, Cai R, Chen QQ. DNA methylation biomarkers for nasopharyngeal carcinoma: diagnostic and prognostic tools. Asian Pac J Cancer Prev APJCP. 2015;16(18):8059–65.PubMedCrossRef
15.
Sen F, Yildiz I, Odabas H, Tambas M, Kilic L, Karadeniz A, Altun M, Ekenel M, Serilmez M, Duranyildiz D, et al. Diagnostic value of serum M30 and M65 in patients with nasopharyngeal carcinoma. Tumour Biol. 2015;36(2):1039–44.PubMedCrossRef
16.
Tan G, Liu Q, Tang X, Kang T, Li Y, Lu J, Zhao X, Tang F. Diagnostic values of serum cathepsin B and D in patients with nasopharyngeal carcinoma. BMC Cancer. 2016;16:241.PubMedPubMedCentralCrossRef
17.
M’hamdi H, Baizig NM, ELHadj OE, M’hamdi N, Attia Z, Gritli S, Gamoudi A, El May MV, May AE. Usefulness of IGF-1 serum levels as diagnostic marker of nasopharyngeal carcinoma. Immunobiology. 2016;221(11):1304–8.PubMedCrossRef
18.
Li Y, Wang W, Liu Z, Jiang Y, Lu J, Xie H, Tang F. AGR2 diagnostic value in nasopharyngeal carcinoma prognosis. Clin Chim Acta Int J Clin Chem. 2017;484:323–7.CrossRef
19.
Lin LH, Xu YW, Huang LS, Hong CQ, Zhai TT, Liao LD, Lin WJ, Xu LY, Zhang K, Li EM, et al. Serum proteomic-based analysis identifying autoantibodies against PRDX2 and PRDX3 as potential diagnostic biomarkers in nasopharyngeal carcinoma. Clin Proteom. 2017;14:6.CrossRef
20.
He B, Zeng J, Chao W, Chen X, Huang Y, Deng K, Huang Z, Li J, Dai M, Chen S, et al. Serum long non-coding RNAs MALAT1, AFAP1-AS1 and AL359062 as diagnostic and prognostic biomarkers for nasopharyngeal carcinoma. Oncotarget. 2017;8(25):41166–77.PubMedPubMedCentral
21.
22.
Liu J. Control of protein synthesis and mRNA degradation by microRNAs. Curr Opin Cell Biol. 2008;20(2):214–21.PubMedCrossRef
23.
Markopoulos GS, Roupakia E, Tokamani M, Chavdoula E, Hatziapostolou M, Polytarchou C, Marcu KB, Papavassiliou AG, Sandaltzopoulos R, Kolettas E. A step-by-step microRNA guide to cancer development and metastasis. Cell Oncol (Dordrecht). 2017;40(4):303–39.CrossRef
24.
25.
Cheng H, Zhang L, Cogdell DE, Zheng H, Schetter AJ, Nykter M, Harris CC, Chen K, Hamilton SR, Zhang W. Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS ONE. 2011;6(3):e17745.PubMedPubMedCentralCrossRef
26.
Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28(10):1721–6.PubMedCrossRef
27.
Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58(10):1375–81.PubMedCrossRef
28.
Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S. A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS ONE. 2010;5(10):e13735.PubMedPubMedCentralCrossRef
29.
Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol. 2011;29(36):4781–8.PubMedCrossRef
30.
Zuo Z, Calin GA, de Paula HM, Medeiros LJ, Fernandez MH, Shimizu M, Garcia-Manero G, Bueso-Ramos CE. Circulating microRNAs let-7a and miR-16 predict progression-free survival and overall survival in patients with myelodysplastic syndrome. Blood. 2011;118(2):413–5.PubMedPubMedCentralCrossRef
31.
Chen HC, Chen GH, Chen YH, Liao WL, Liu CY, Chang KP, Chang YS, Chen SJ. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma. Br J Cancer. 2009;100(6):1002–11.PubMedPubMedCentralCrossRef
32.
Liu N, Chen NY, Cui RX, Li WF, Li Y, Wei RR, Zhang MY, Sun Y, Huang BJ, Chen M, et al. Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol. 2012;13(6):633–41.PubMedCrossRef
33.
Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, Chen CJ, Hildesheim A, Sugden B, Ahlquist P. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci USA. 2008;105(15):5874–8.PubMedCrossRefPubMedCentral
34.
Wang Z, Chen W, Zhang Y, Xu L, Wang Q. Diagnostic value of circulating microRNAs for nasopharyngeal cancer: a systematic review and meta-analysis. J Cancer Res Ther. 2014;10(Suppl):C173–8.PubMedCrossRef
35.
Zeng X, Xiang J, Wu M, Xiong W, Tang H, Deng M, Li X, Liao Q, Su B, Luo Z, et al. Circulating miR-17, miR-20a, miR-29c, and miR-223 combined as non-invasive biomarkers in nasopharyngeal carcinoma. PLoS ONE. 2012;7(10):e46367.PubMedPubMedCentralCrossRef
36.
Bauer AS, Keller A, Costello E, Greenhalf W, Bier M, Borries A, Beier M, Neoptolemos J, Buchler M, Werner J, et al. Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue. PLoS ONE. 2012;7(4):e34151.PubMedPubMedCentralCrossRef
37.
Ganepola GA, Rutledge JR, Suman P, Yiengpruksawan A, Chang DH. Novel blood-based microRNA biomarker panel for early diagnosis of pancreatic cancer. World J Gastrointest Oncol. 2014;6(1):22–33.PubMedPubMedCentralCrossRef
38.
Schultz NA, Dehlendorff C, Jensen BV, Bjerregaard JK, Nielsen KR, Bojesen SE, Calatayud D, Nielsen SE, Yilmaz M, Hollander NH, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA. 2014;311(4):392–404.PubMedCrossRef
39.
Hausler SF, Keller A, Chandran PA, Ziegler K, Zipp K, Heuer S, Krockenberger M, Engel JB, Honig A, Scheffler M, et al. Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening. Br J Cancer. 2010;103(5):693–700.PubMedPubMedCentralCrossRef
40.
Gyoba J, Shan S, Roa W, Bedard EL. Diagnosing lung cancers through examination of micro-RNA biomarkers in blood, plasma, serum and sputum: a review and summary of current literature. Int J Mol Sci. 2016;17(4):494.PubMedPubMedCentralCrossRef
41.
Patnaik SK, Yendamuri S, Kannisto E, Kucharczuk JC, Singhal S, Vachani A. MicroRNA expression profiles of whole blood in lung adenocarcinoma. PLoS ONE. 2012;7(9):e46045.PubMedPubMedCentralCrossRef
42.
Li G, Pu Y. MicroRNA signatures in total peripheral blood of gallbladder cancer patients. Tumour Biol. 2015;36(9):6985–90.PubMedCrossRef
43.
Frampton AE, Fletcher CE, Gall TM, Castellano L, Bevan CL, Stebbing J, Krell J. Circulating peripheral blood mononuclear cells exhibit altered miRNA expression patterns in pancreatic cancer. Expert Rev Mol Diagn. 2013;13(5):425–30.PubMedCrossRef
44.
Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg. 2010;251(3):499–505.PubMedCrossRef
45.
Riley CA, Marino MJ, Hawkey N, Lawlor CM, McCoul ED. Sinonasal tract inflammation as a precursor to nasopharyngeal carcinoma: a systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2016;154(5):810–6.PubMedCrossRef
46.
Wang HY, Luo M, Tereshchenko IV, Frikker DM, Cui X, Li JY, Hu G, Chu Y, Azaro MA, Lin Y, et al. A genotyping system capable of simultaneously analyzing > 1000 single nucleotide polymorphisms in a haploid genome. Genome Res. 2005;15(2):276–83.PubMedPubMedCentralCrossRef
47.
Wei R, Huang GL, Zhang MY, Li BK, Zhang HZ, Shi M, Chen XQ, Huang L, Zhou QM, Jia WH, et al. Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. Clin Cancer Res. 2013;19(17):4780–91.PubMedCrossRef
48.
Sabarimurugan S, Kumarasamy C, Baxi S, Devi A, Jayaraj R. Systematic review and meta-analysis of prognostic microRNA biomarkers for survival outcome in nasopharyngeal carcinoma. PLoS ONE. 2019;14(2):e0209760.PubMedPubMedCentralCrossRef
49.
Zheng XH, Cui C, Ruan HL, Xue WQ, Zhang SD, Hu YZ, Zhou XX, Jia WH. Plasma microRNA profiling in nasopharyngeal carcinoma patients reveals miR-548q and miR-483-5p as potential biomarkers. Chin J Cancer. 2014;33(7):330–8.PubMedPubMedCentral
50.
Liu N, Cui RX, Sun Y, Guo R, Mao YP, Tang LL, Jiang W, Liu X, Cheng YK, He QM, et al. A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma. Int J Cancer. 2014;134(6):1359–68.PubMedCrossRef
51.
Wang HY, Yan LX, Shao Q, Fu S, Zhang ZC, Ye W, Zeng YX, Shao JY. Profiling plasma microRNA in nasopharyngeal carcinoma with deep sequencing. Clin Chem. 2014;60(5):773–82.PubMedCrossRef
52.
53.
Kaneda A, Matsusaka K, Aburatani H, Fukayama M. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Can Res. 2012;72(14):3445–50.CrossRef
54.
Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein-Barr virus in epithelial malignancies. J Pathol. 2015;235(2):323–33.PubMedCrossRef
55.
Zhang H, Wang J, Yu D, Liu Y, Xue K, Zhao X. Role of Epstein-Barr Virus in the Development of Nasopharyngeal Carcinoma. Open Med (Warsaw, Poland). 2017;12:171–6.
56.
Tang B, Liu Q, Cui Y, Hong M, Zhu X, Yue H. Protocols of screening, early detection and diagnosis for nasopharyngeal carcinoma. In: Dong Z, Qiao Y, editors. Protocols of screening, early detection and diagnosis for cancer in PRChina. Beijing: People’s Medical Publishing House of P.R. China; 2009. p. 187–8.
57.
58.
Coghill AE, Hildesheim A. Epstein-Barr virus antibodies and the risk of associated malignancies: review of the literature. Am J Epidemiol. 2014;180(7):687–95.PubMedPubMedCentralCrossRef
59.
Hooykaas MJ, Kruse E, Wiertz EJ, Lebbink RJ. Comprehensive profiling of functional Epstein-Barr virus miRNA expression in human cell lines. BMC Genom. 2016;17:644.CrossRef
60.
Kim KY, Le QT, Yom SS, Pinsky BA, Bratman SV, Ng RH, El Mubarak HS, Chan KC, Sander M, Conley BA. Current state of PCR-based Epstein-Barr virus DNA testing for nasopharyngeal cancer. J Natl Cancer Inst. 2017;109(4):djx007.PubMedCentralCrossRef
61.
Munoz-Culla M, Irizar H, Gorostidi A, Alberro A, Osorio-Querejeta I, Ruiz-Martinez J, Olascoaga J, Lopez de Munain A, Otaegui D. Progressive changes in non-coding RNA profile in leucocytes with age. Aging. 2017;9(4):1202–18.PubMedPubMedCentralCrossRef
62.
Turunen A, Rautava J, Grenman R, Syrjanen K, Syrjanen S. Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) associated with poor prognosis of head and neck carcinomas. Oncotarget. 2017;8(16):27328–38.PubMed
63.
Yu KH, Lo YM, Tse GM, Chan KC, Chan AB, Chow KC, Ma TK, Vlantis AC, Leung SF, van Hasselt CA, et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nonnasopharyngeal head and neck carcinomas. Clin Cancer Res. 2004;10(5):1726–32.PubMedCrossRef
64.
Xia X, Li Y, Wang W, Tang F, Tan J, Sun L, Li Q, Sun L, Tang B, He S. MicroRNA-1908 functions as a glioblastoma oncogene by suppressing PTEN tumor suppressor pathway. Mol Cancer. 2015;14:154.PubMedPubMedCentralCrossRef
Metadata
Title
Identification of two microRNA signatures in whole blood as novel biomarkers for diagnosis of nasopharyngeal carcinoma
Authors
Wen Wen
Shi-Juan Mai
Huan-Xin Lin
Mei-Yin Zhang
Jia-Ling Huang
Xin Hua
Chao Lin
Zhi-Qing Long
Zi-Jian Lu
Xiao-Qing Sun
Sai-Lan Liu
Qi Yang
Qian Zhu
Hui-Yun Wang
Ling Guo
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-019-1923-2

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