Skip to main content

Advertisement

Log in

Serum microRNA is a biomarker for post-operative monitoring in glioma

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

A Correction to this article was published on 01 September 2020

This article has been updated

Abstract

Purpose

A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients.

Methods

A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging.

Results

A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions.

Conclusions

We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data generated or analysed during this study are included in this published article (and its supplementary information files).

Change history

  • 07 October 2020

    For the reference citation '[57]' in the second paragraph of the <Emphasis Type="Bold">Results</Emphasis> section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

References

  1. Kaye AH, Morokoff A (2014) The continuing evolution: biology and treatment of brain tumors. Neurosurgery 61(Suppl 1):100–104. https://doi.org/10.1227/NEU.0000000000000388

    Article  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  Google Scholar 

  3. Ellingson BM, Wen PY, Cloughesy TF (2017) Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics. https://doi.org/10.1007/s13311-016-0507-6

    Article  Google Scholar 

  4. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavare S (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 110:4009–4014. https://doi.org/10.1073/pnas.1219747110

    Article  Google Scholar 

  5. Gourlay J, Morokoff AP, Luwor RB, Zhu HJ, Kaye AH, Stylli SS (2017) The emergent role of exosomes in glioma. J Clin Neurosci 35:13–23. https://doi.org/10.1016/j.jocn.2016.09.021

    Article  CAS  Google Scholar 

  6. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518. https://doi.org/10.1073/pnas.0804549105

    Article  Google Scholar 

  7. Yang C, Wang C, Chen X, Chen S, Zhang Y, Zhi F, Wang J, Li L, Zhou X, Li N, Pan H, Zhang J, Zen K, Zhang CY, Zhang C (2013) Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int J Cancer 132:116–127. https://doi.org/10.1002/ijc.27657

    Article  CAS  Google Scholar 

  8. Zhi F, Shao N, Wang R, Deng D, Xue L, Wang Q, Zhang Y, Shi Y, Xia X, Wang S, Lan Q, Yang Y (2015) Identification of 9 serum microRNAs as potential noninvasive biomarkers of human astrocytoma. Neuro Oncol 17:383–391. https://doi.org/10.1093/neuonc/nou169

    Article  CAS  Google Scholar 

  9. Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, Weller M, Keller A (2011) A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 118:449–457. https://doi.org/10.1111/j.1471-4159.2011.07307.x

    Article  CAS  Google Scholar 

  10. Dong L, Li Y, Han C, Wang X, She L, Zhang H (2014) miRNA microarray reveals specific expression in the peripheral blood of glioblastoma patients. Int J Oncol 45:746–756. https://doi.org/10.3892/ijo.2014.2459

    Article  CAS  Google Scholar 

  11. Lai NS, Wu DG, Fang XG, Lin YC, Chen SS, Li ZB, Xu SS (2015) Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma. Br J Cancer 112:1241–1246. https://doi.org/10.1038/bjc.2015.91

    Article  CAS  Google Scholar 

  12. Regazzo G, Terrenato I, Spagnuolo M, Carosi M, Cognetti G, Cicchillitti L, Sperati F, Villani V, Carapella C, Piaggio G, Pelosi A, Rizzo MG (2016) A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. J Exp Clin Cancer Res 35:124. https://doi.org/10.1186/s13046-016-0393-0

    Article  CAS  Google Scholar 

  13. Ma C, Nguyen HPT, Luwor RB, Stylli SS, Gogos A, Paradiso L, Kaye AH, Morokoff AP (2018) A comprehensive meta-analysis of circulation miRNAs in glioma as potential diagnostic biomarker. PLoS ONE 13:e0189452. https://doi.org/10.1371/journal.pone.0189452

    Article  CAS  Google Scholar 

  14. Areeb Z, Stylli SS, Koldej R, Ritchie DS, Siegal T, Morokoff AP, Kaye AH, Luwor RB (2015) MicroRNA as potential biomarkers in glioblastoma. J Neurooncol 125:237–248. https://doi.org/10.1007/s11060-015-1912-0

    Article  CAS  Google Scholar 

  15. Tabibkhooei A, Izadpanahi M, Arab A, Zare-Mirzaei A, Minaeian S, Rostami A, Mohsenian A (2020) Profiling of novel circulating microRNAs as a non-invasive biomarker in diagnosis and follow-up of high and low-grade gliomas. Clin Neurol Neurosurg 190:105652. https://doi.org/10.1016/j.clineuro.2019.105652

    Article  Google Scholar 

  16. Siegal T, Charbit H, Paldor I, Zelikovitch B, Canello T, Benis A, Wong ML, Morokoff AP, Kaye AH, Lavon I (2016) Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab. J Neurosurg 125:1008–1015. https://doi.org/10.3171/2015.8.JNS15437

    Article  CAS  Google Scholar 

  17. Molania R, Gagnon-Bartsch JA, Dobrovic A, Speed TP (2019) A new normalization for nanostring nCounter gene expression data. Nucleic Acids Res 47:6073–6083. https://doi.org/10.1093/nar/gkz433

    Article  CAS  Google Scholar 

  18. Andersen P, Gill R (1982) Cox's regression model for counting processes: a large sample study. Ann Stat. https://doi.org/10.1214/aos/1176345976

    Article  Google Scholar 

  19. Burgos K, Malenica I, Metpally R, Courtright A, Rakela B, Beach T, Shill H, Adler C, Sabbagh M, Villa S, Tembe W, Craig D, Van Keuren-Jensen K (2014) Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. PLoS ONE 9:e94839. https://doi.org/10.1371/journal.pone.0094839

    Article  CAS  Google Scholar 

  20. Teplyuk NM, Mollenhauer B, Gabriely G, Giese A, Kim E, Smolsky M, Kim RY, Saria MG, Pastorino S, Kesari S, Krichevsky AM (2012) MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 14:689–700. https://doi.org/10.1093/neuonc/nos074

    Article  CAS  Google Scholar 

  21. Stylli SS, Adamides AA, Koldej RM, Luwor RB, Ritchie DS, Ziogas J, Kaye AH (2016) miRNA expression profiling of cerebrospinal fluid in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. https://doi.org/10.3171/2016.1.JNS151454

    Article  Google Scholar 

  22. Akers JC, Hua W, Li H, Ramakrishnan V, Yang Z, Quan K, Zhu W, Li J, Figueroa J, Hirshman BR, Miller B, Piccioni D, Ringel F, Komotar R, Messer K, Galasko DR, Hochberg F, Mao Y, Carter BS, Chen CC (2017) A cerebrospinal fluid microRNA signature as biomarker for glioblastoma. Oncotarget 8:68769–68779. https://doi.org/10.18632/oncotarget.18332

    Article  Google Scholar 

  23. Drusco A, Bottoni A, Lagana A, Acunzo M, Fassan M, Cascione L, Antenucci A, Kumchala P, Vicentini C, Gardiman MP, Alder H, Carosi MA, Ammirati M, Gherardi S, Luscri M, Carapella C, Zanesi N, Croce CM (2015) A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies. Oncotarget 6:20829–20839

    Article  Google Scholar 

  24. Bronisz A, Godlewski J, Wallace JA, Merchant AS, Nowicki MO, Mathsyaraja H, Srinivasan R, Trimboli AJ, Martin CK, Li F, Yu L, Fernandez SA, Pecot T, Rosol TJ, Cory S, Hallett M, Park M, Piper MG, Marsh CB, Yee LD, Jimenez RE, Nuovo G, Lawler SE, Chiocca EA, Leone G, Ostrowski MC (2011) Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol 14:159–167. https://doi.org/10.1038/ncb2396

    Article  CAS  Google Scholar 

  25. Schepeler T, Reinert JT, Ostenfeld MS, Christensen LL, Silahtaroglu AN, Dyrskjot L, Wiuf C, Sorensen FJ, Kruhoffer M, Laurberg S, Kauppinen S, Orntoft TF, Andersen CL (2008) Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer Res 68:6416–6424. https://doi.org/10.1158/0008-5472.CAN-07-6110

    Article  CAS  Google Scholar 

  26. Perez-Carbonell L, Sinicrope FA, Alberts SR, Oberg AL, Balaguer F, Castells A, Boland CR, Goel A (2015) MiR-320e is a novel prognostic biomarker in colorectal cancer. Br J Cancer 113:83–90. https://doi.org/10.1038/bjc.2015.168

    Article  CAS  Google Scholar 

  27. Manterola L, Guruceaga E, Gallego Perez-Larraya J, Gonzalez-Huarriz M, Jauregui P, Tejada S, Diez-Valle R, Segura V, Sampron N, Barrena C, Ruiz I, Agirre A, Ayuso A, Rodriguez J, Gonzalez A, Xipell E, Matheu A, Lopez de Munain A, Tunon T, Zazpe I, Garcia-Foncillas J, Paris S, Delattre JY, Alonso MM (2014) A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 16:520–527. https://doi.org/10.1093/neuonc/not218

    Article  CAS  Google Scholar 

  28. Halle B, Thomassen M, Venkatesan R, Kaimal V, Marcusson EG, Munthe S, Sorensen MD, Aaberg-Jessen C, Jensen SS, Meyer M, Kruse TA, Christiansen H, Schmidt S, Mollenhauer J, Schulz MK, Andersen C, Kristensen BW (2016) Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures. J Neurooncol 128:395–404. https://doi.org/10.1007/s11060-016-2125-x

    Article  CAS  Google Scholar 

  29. Zheng G, Du L, Yang X, Zhang X, Wang L, Yang Y, Li J, Wang C (2014) Serum microRNA panel as biomarkers for early diagnosis of colorectal adenocarcinoma. Br J Cancer 111:1985–1992. https://doi.org/10.1038/bjc.2014.489

    Article  CAS  Google Scholar 

  30. Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H, Watanabe M, Nakagama H, Yokota J, Kohno T, Tsuchiya N (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS ONE 9:e92921. https://doi.org/10.1371/journal.pone.0092921

    Article  CAS  Google Scholar 

  31. Polytarchou C, Oikonomopoulos A, Mahurkar S, Touroutoglou A, Koukos G, Hommes DW, Iliopoulos D (2015) Assessment of circulating microRNAs for the diagnosis and disease activity evaluation in patients with ulcerative colitis by using the nanostring technology. Inflamm Bowel Dis 21:2533–2539. https://doi.org/10.1097/MIB.0000000000000547

    Article  Google Scholar 

  32. Goze C, Reynes C, Forestier L, Sabatier R, Duffau H (2018) Pilot study of whole blood microRNAs as potential tools for diffuse low-grade gliomas detection. Cell Mol Neurobiol 38:715–725. https://doi.org/10.1007/s10571-017-0536-7

    Article  CAS  Google Scholar 

  33. Ding Q, Shen L, Nie X, Lu B, Pan X, Su Z, Yan A, Yan R, Zhou Y, Li L, Xu J (2018) MiR-223-3p overexpression inhibits cell proliferation and migration by regulating inflammation-associated cytokines in glioblastomas. Pathol Res Pract 214:1330–1339. https://doi.org/10.1016/j.prp.2018.05.012

    Article  CAS  Google Scholar 

  34. Huang BS, Luo QZ, Han Y, Huang D, Tang QP, Wu LX (2017) MiR-223/PAX6 axis regulates glioblastoma stem cell proliferation and the chemo resistance to TMZ via regulating PI3K/Akt pathway. J Cell Biochem 118:3452–3461. https://doi.org/10.1002/jcb.26003

    Article  CAS  Google Scholar 

  35. Lan F, Yue X, Xia T (2020) Exosomal microRNA-210 is a potentially non-invasive biomarker for the diagnosis and prognosis of glioma. Oncol Lett 19:1967–1974. https://doi.org/10.3892/ol.2020.11249

    Article  CAS  Google Scholar 

  36. Bernardi D, Padoan A, Ballin A, Sartori M, Manara R, Scienza R, Plebani M, Della Puppa A (2012) Serum YKL-40 following resection for cerebral glioblastoma. J Neurooncol 107:299–305. https://doi.org/10.1007/s11060-011-0762-7

    Article  CAS  Google Scholar 

  37. Vietheer JM, Rieger J, Wagner M, Senft C, Tichy J, Foerch C (2017) Serum concentrations of glial fibrillary acidic protein (GFAP) do not indicate tumor recurrence in patients with glioblastoma. J Neurooncol 135:193–199. https://doi.org/10.1007/s11060-017-2565-y

    Article  CAS  Google Scholar 

  38. Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, Tacey M, Wong R, Singh M, Karapetis CS, Desai J, Tran B, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715–1722. https://doi.org/10.1093/annonc/mdv177

    Article  CAS  Google Scholar 

  39. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209. https://doi.org/10.1056/NEJMoa1213261

    Article  CAS  Google Scholar 

  40. Lavon I, Refael M, Zelikovitch B, Shalom E, Siegal T (2010) Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades. Neuro-oncol 12:173–180. https://doi.org/10.1093/neuonc/nop041

    Article  CAS  Google Scholar 

  41. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih M, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:ra224. https://doi.org/10.1126/scitranslmed.3007094

    Article  CAS  Google Scholar 

  42. Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, Distefano N, Zheng Y, Skakodub A, Mehta SA, Campos C, Hsieh WY, Selcuklu SD, Ling L, Meng F, Jing X, Samoila A, Bale TA, Tsui DWY, Grommes C, Viale A, Souweidane MM, Tabar V, Brennan CW, Reiner AS, Rosenblum M, Panageas KS, DeAngelis LM, Young RJ, Berger MF, Mellinghoff IK (2019) Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 565:654–658. https://doi.org/10.1038/s41586-019-0882-3

    Article  CAS  Google Scholar 

  43. Murray MJ, Watson HL, Ward D, Bailey S, Ferraresso M, Nicholson JC, Gnanapragasam VJ, Thomas B, Scarpini CG, Coleman N (2018) "Future-proofing" blood processing for measurement of circulating miRNAs in samples from biobanks and prospective clinical trials. Cancer Epidemiol Biomark Prev 27:208–218. https://doi.org/10.1158/1055-9965.EPI-17-0657

    Article  CAS  Google Scholar 

  44. Marzi MJ, Montani F, Carletti RM, Dezi F, Dama E, Bonizzi G, Sandri MT, Rampinelli C, Bellomi M, Maisonneuve P, Spaggiari L, Veronesi G, Bianchi F, Di Fiore PP, Nicassio F (2016) Optimization and standardization of circulating microRNA detection for clinical application: the miR-test case. Clin Chem 62:743–754. https://doi.org/10.1373/clinchem.2015.251942

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Professor Mark Rosenthal for helpful discussions and comments regarding this work.

Funding

Cure Brain Cancer Foundation Australia, Brain Foundation Australia, The Royal Melbourne Hospital Neuroscience Foundation.

Author information

Authors and Affiliations

Authors

Contributions

Conception, planning: AM, AK, TS, KD. Writing & editing manuscript: AM, JJ, HN, KD, TS, FG, AK. Experimental work: HN, JJ, IB, RL, SS, RK, IP, LP, CM. Biostatistics: JL, AW, GI, CM, TS, RM, TK, CM. Radiology analysis: FG, AL, JJ.

Corresponding author

Correspondence to Andrew Morokoff.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Ethics approval

Ethics approval for this study was obtained from the Melbourne Health Human Research Ethics Committee (HREC 2009.114), Melbourne, Australia.

Informed consent

All patients provided written informed consent prior to inclusion. The study was performed in accordance with the Declaration of Helsinki.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morokoff, A., Jones, J., Nguyen, H. et al. Serum microRNA is a biomarker for post-operative monitoring in glioma. J Neurooncol 149, 391–400 (2020). https://doi.org/10.1007/s11060-020-03566-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-020-03566-w

Keywords

Navigation