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A novel urinary microRNA biomarker panel for detecting gastric cancer

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Abstract

Background

Gastric cancer (GC) is one of the most common causes of cancer deaths worldwide; however, reliable and non-invasive screening methods for GC are not established. Therefore, we conducted this study to develop a biomarker for GC detection, consisting of urinary microRNAs (miRNAs).

Methods

We matched 306 participants by age and sex [153 pairs consisting of patients with GC and healthy controls (HCs)], then randomly divided them across three groups: (1) the discovery cohort (4 pairs); (2) the training cohort (95 pairs); and (3) the validation cohort (54 pairs).

Results

There were 22 urinary miRNAs with significantly aberrant expressions between the two groups in the discovery cohort. Upon multivariate analysis of the training cohort, urinary expression levels of miR-6807-5p and miR-6856-5p were significantly independent biomarkers for diagnosis of GC, in addition to Helicobacter pylori (H. pylori) status. A diagnostic panel that combined these 2 miRNAs and H. pylori status distinguished between HC and GC samples with an area under the curve (AUC) = 0.736. In the validation cohort, urinary miR-6807-5p and miR-6856-5p showed significantly higher expression levels in the GC group, and the combination biomarker panel of miR-6807-5p, miR-6856-5p, and H. pylori status also showed excellent performance (AUC = 0.885). In addition, this biomarker panel could distinguish between HC and stage I GC patients with an AUC = 0.748. Urinary expression levels of miR-6807-5p and miR-6856-5p significantly decreased to undetectable level after curative resection of GC.

Conclusions

This novel biomarker panel enables early and non-invasive detection of GC.

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References

  1. Fitzmaurice C, Akinyemiju TF, Al Lami FH, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553–688.

    Article  Google Scholar 

  2. Tashiro A, Sano M, Kinameri K, et al. Comparing mass screening techniques for gastric cancer in Japan. World J Gastroenterol. 2006;12:4873–4.

    PubMed  PubMed Central  Google Scholar 

  3. Jun JK, Choi KS, Lee HY, et al. Effectiveness of the Korean National cancer screening program in reducing gastric cancer mortality. Gastroenterology. 2017;152:1319–28 e7.

    Article  Google Scholar 

  4. Feng F, Tian Y, Xu G, et al. Diagnostic and prognostic value of CEA, CA19-9, AFP and CA125 for early gastric cancer. BMC Cancer. 2017;17:737.

    Article  Google Scholar 

  5. Calin GA, Croce CM. Chromosomal rearrangements and microRNAs: a new cancer link with clinical implications. J Clin Invest. 2007;117:2059–66.

    Article  CAS  Google Scholar 

  6. Xiao C, Rajewsky K. MicroRNA control in the immune system: basic principles. Cell. 2009;136:26–36.

    Article  CAS  Google Scholar 

  7. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.

    Article  CAS  Google Scholar 

  8. Arroyo JD, Chevillet JR, Kroh EM, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA. 2011;108:5003–8.

    Article  CAS  Google Scholar 

  9. Liu R, Zhang C, Hu Z, et al. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 2011;47:784–91.

    Article  CAS  Google Scholar 

  10. Liu H, Zhu L, Liu B, et al. Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer. Cancer Lett. 2012;316:196–203.

    Article  CAS  Google Scholar 

  11. Li C, Li JF, Cai Q, et al. miRNA-199a-3p in plasma as a potential diagnostic biomarker for gastric cancer. Ann Surg Oncol. 2013;20(Suppl 3):S397–405.

    Article  Google Scholar 

  12. Zeng Z, Wang J, Zhao L, et al. Potential role of microRNA-21 in the diagnosis of gastric cancer: a meta-analysis. PLoS One. 2013;8:e73278.

    Article  CAS  Google Scholar 

  13. Zhu C, Ren C, Han J, et al. A five-microRNA panel in plasma was identified as potential biomarker for early detection of gastric cancer. Br J Cancer. 2014;110:2291–9.

    Article  CAS  Google Scholar 

  14. Shin VY, Ng EK, Chan VW, et al. A three-miRNA signature as promising non-invasive diagnostic marker for gastric cancer. Mol Cancer. 2015;14:202.

    Article  Google Scholar 

  15. Zhou X, Zhu W, Li H, et al. Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. Sci Rep. 2015;5:11251.

    Article  CAS  Google Scholar 

  16. Qiu X, Zhang J, Shi W, et al. Circulating MicroRNA-26a in plasma and its potential diagnostic value in gastric cancer. PLoS One. 2016;11:e0151345.

    Article  Google Scholar 

  17. Azarbarzin S, Feizi MAH, Safaralizadeh R, et al. The value of MiR-383, an intronic MiRNA, as a diagnostic and prognostic biomarker in intestinal-type gastric cancer. Biochem Genet. 2017;55:244–52.

    Article  CAS  Google Scholar 

  18. Kao HW, Pan CY, Lai CH, et al. Urine miR-21-5p as a potential non-invasive biomarker for gastric cancer. Oncotarget. 2017;8:56389–97.

    PubMed  PubMed Central  Google Scholar 

  19. Hung PS, Chen CY, Chen WT, et al. miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma. PLoS One. 2017;12:e0177346.

    Article  Google Scholar 

  20. McShane LM, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005;23:9067–72.

    Article  Google Scholar 

  21. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18:805–35.

    Article  Google Scholar 

  22. Shimura T, Dagher A, Sachdev M, et al. Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer. Cancer Prev Res (Phila). 2015;8:240–8.

    Article  CAS  Google Scholar 

  23. Shimura T, Ebi M, Yamada T, et al. Urinary kallikrein 10 predicts the incurability of gastric cancer. Oncotarget. 2017;8:29247–57.

    Article  Google Scholar 

  24. Shimura T, Iwasaki H, Kitagawa M, et al. Urinary cysteine-rich protein 61 and trefoil factor 3 as diagnostic biomarkers for colorectal cancer. Transl Oncol. 2019;12:539–44.

    Article  Google Scholar 

  25. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Hoboken: Wiley; 2009.

    Google Scholar 

  26. Thery C, Amigorena S, Raposo G, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006; Chapter 3:Unit 3 22.

  27. Mestdagh P, Van Vlierberghe P, De Weer A, et al. A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol. 2009;10:R64.

    Article  Google Scholar 

  28. Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56:1733–41.

    Article  CAS  Google Scholar 

  29. Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

    Article  CAS  Google Scholar 

  30. Mall C, Rocke DM, Durbin-Johnson B, et al. Stability of miRNA in human urine supports its biomarker potential. Biomark Med. 2013;7:623–31.

    Article  CAS  Google Scholar 

  31. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–9.

    Article  CAS  Google Scholar 

  32. Miah S, Dudziec E, Drayton RM, et al. An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer. Br J Cancer. 2012;107:123–8.

    Article  CAS  Google Scholar 

  33. Mengual L, Lozano JJ, Ingelmo-Torres M, et al. Using microRNA profiling in urine samples to develop a non-invasive test for bladder cancer. Int J Cancer. 2013;133:2631–41.

    CAS  PubMed  Google Scholar 

  34. Cardenas-Gonzalez M, Srivastava A, Pavkovic M, et al. Identification, confirmation, and replication of novel urinary MicroRNA biomarkers in lupus nephritis and diabetic nephropathy. Clin Chem. 2017;63:1515–26.

    Article  CAS  Google Scholar 

  35. Erbes T, Hirschfeld M, Rucker G, et al. Feasibility of urinary microRNA detection in breast cancer patients and its potential as an innovative non-invasive biomarker. BMC Cancer. 2015;15:193.

    Article  Google Scholar 

  36. Debernardi S, Massat NJ, Radon TP, et al. Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma. Am J Cancer Res. 2015;5:3455–66.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Yukimi Hashidume-Itoh for handling of urine sample and Takako Onodera for data management of enrolled patients in this study (Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences). We also thank Masahide Ebi at Aichi Medical University, Tomonori Yamada at Nagoya Daini Red Cross Hospital and other clinical colleagues who assisted for the sample collection. This study was supported, in part, by Japan Agency for Medical Research and Development under Grant Number JP19lm0203005j0003 (to T. S.) and the Takeda Science Foundation (to T. S.)

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Correspondence to Takaya Shimura.

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Iwasaki, H., Shimura, T., Yamada, T. et al. A novel urinary microRNA biomarker panel for detecting gastric cancer. J Gastroenterol 54, 1061–1069 (2019). https://doi.org/10.1007/s00535-019-01601-w

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  • DOI: https://doi.org/10.1007/s00535-019-01601-w

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