Advertisement

MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter

  • Luiz Guilherme Darrigo Júnior
  • Regia Caroline Peixoto Lira
  • Paola Fernanda Fedatto
  • David Santos Marco Antonio
  • Elvis Terci Valera
  • Simone Aguiar
  • José Andres Yunes
  • Silvia Regina Brandalise
  • Luciano Neder
  • Fabiano Pinto Saggioro
  • Aline Paixão Becker
  • Ricardo Santos de Oliveira
  • Hélio Rubens Machado
  • Rodrigo Alexandre Panepucci
  • Luiz Gonzaga Tone
  • Carlos Alberto ScrideliEmail author
Clinical Study

Abstract

Purposes

Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs.

Methods

In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data.

Results

Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway.

Conclusions

In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

Keywords

Pilocytic astrocitoma Neurofibromatosis type 1 miRNA Global expression 

Notes

Acknowledgements

This work was supported by the Brazilian Public Research Agencies: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Grant Number: 2010/07020-9; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Grant Number: 471885/2013-4.

Compliance with ethical standards

Conflict of interest

All authors declare that they had no conflict of interest that could be perceived to impair the impartiality of the research reported.

Supplementary material

11060_2018_3042_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 17 KB)

References

  1. 1.
    Gutmann DH, Hedrick NM, Li J et al (2002) Comparative gene expression profile analysis of neurofibromatosis 1-associated and sporadic pilocytic astrocytomas. Cancer Res 62:2085–2091Google Scholar
  2. 2.
    Fernandez C, Figarella-Branger D, Girard N et al (2003) Pilocytic astrocytomas in children: prognostic factors—a retrospective study of 80 cases. Neurosurgery 53:544–555.  https://doi.org/10.1227/01.NEU.0000079330.01541.6E CrossRefGoogle Scholar
  3. 3.
    Louis D, Carvenee W (2007) WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109CrossRefGoogle Scholar
  4. 4.
    Burkhard C, Di Patre P-L, Schüler D et al (2003) A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 98:1170–1174.  https://doi.org/10.3171/jns.2003.98.6.1170 CrossRefGoogle Scholar
  5. 5.
    Ronghe M, Hargrave D, Bartels U et al (2010) Vincristine and carboplatin chemotherapy for unresectable and/or recurrent low-grade astrocytoma of the brainstem. Pediatr Blood Cancer 55:471–477.  https://doi.org/10.1002/pbc.22557 CrossRefGoogle Scholar
  6. 6.
    Sawamura Y, Kamoshima Y, Kato T et al (2009) Chemotherapy with cisplatin and vincristine for optic pathway/hypothalamic astrocytoma in young children. Jpn J Clin Oncol 39:277–283.  https://doi.org/10.1093/jjco/hyp012 CrossRefGoogle Scholar
  7. 7.
    Bornhorst M, Frappaz D, Packer RJ (2016) Pilocytic astrocytomas. In: Handbook of clinical neurology. Elsevier, Amsterdam, pp 329–344Google Scholar
  8. 8.
    Bergthold G, Bandopadhayay P, Bi WL et al (2014) Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 1845:294–307.  https://doi.org/10.1016/j.bbcan.2014.02.004 Google Scholar
  9. 9.
    Jones DTW, Gronych J, Lichter P et al (2012) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69:1799–1811.  https://doi.org/10.1007/s00018-011-0898-9 CrossRefGoogle Scholar
  10. 10.
    Ho C, Bar E, Giannini C et al (2013) MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2. Neuro Oncol 15:69–82CrossRefGoogle Scholar
  11. 11.
    Dahiya S, Yu J, Kaul A et al (2012) Novel BRAF alteration in a sporadic pilocytic astrocytoma. Case Rep Med 2012:418672.  https://doi.org/10.1155/2012/418672 CrossRefGoogle Scholar
  12. 12.
    Kluwe L, Hagel C, Tatagiba M et al (2001) Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas. J Neuropathol Exp Neurol 60:917–920CrossRefGoogle Scholar
  13. 13.
    Pfister S, Hartmann C, Korshunov A (2009) Histology and molecular pathology of pediatric brain tumors. J Child Neurol 24:1375–1386.  https://doi.org/10.1177/0883073809339213 CrossRefGoogle Scholar
  14. 14.
    Catania A, Maira F, Skarmoutsou E et al (2012) Insight into the role of microRNAs in brain tumors (review). Int J Oncol 40:605–624.  https://doi.org/10.3892/ijo.2011.1305 Google Scholar
  15. 15.
    Hummel R, Maurer J, Haier J (2011) MicroRNAs in brain tumors: a new diagnostic and therapeutic perspective? Mol Neurobiol 44:223–234.  https://doi.org/10.1007/s12035-011-8197-x CrossRefGoogle Scholar
  16. 16.
    Zhang B, Pan X, Cobb GP, Anderson T (2007) microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12.  https://doi.org/10.1016/j.ydbio.2006.08.028 CrossRefGoogle Scholar
  17. 17.
    Louis DN, Perry A, Reifenberger G et al (2016) The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820CrossRefGoogle Scholar
  18. 18.
    Becker AP, Scapulatempo-Neto C, Carloni AC et al (2015) KIAA1549: BRAF gene fusion and FGFR1 hotspot mutations are prognostic factors in pilocytic astrocytomas. J Neuropathol Exp Neurol 74:743–754.  https://doi.org/10.1097/NEN.0000000000000213 CrossRefGoogle Scholar
  19. 19.
    Meyer SU, Kaiser S, Wagner C et al (2012) Profound effect of profiling platform and normalization strategy on detection of differentially expressed microRNAs—a comparative study. PLoS ONE.  https://doi.org/10.1371/journal.pone.0038946 Google Scholar
  20. 20.
    Vlachos IS, Zagganas K, Paraskevopoulou MD et al (2015) DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res 43:W460–W466.  https://doi.org/10.1093/nar/gkv403 CrossRefGoogle Scholar
  21. 21.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408.  https://doi.org/10.1006/meth.2001.1262 CrossRefGoogle Scholar
  22. 22.
    Cowland JB, Hother C, Gronbaek K (2008) MicroRNAs and cancer. J Intern Med 263:366–375.  https://doi.org/10.1111/j.1365-2796.2008.01926.x CrossRefGoogle Scholar
  23. 23.
    Ambros V (2003) MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113:673–676CrossRefGoogle Scholar
  24. 24.
    Diwanji TP, Engelman A, Snider JW, Mohindra P (2017) Epidemiology, diagnosis, and optimal management of glioma in adolescents and young adults. Adolesc Health Med Ther 8:99–113.  https://doi.org/10.2147/AHMT.S53391 CrossRefGoogle Scholar
  25. 25.
    Birks DK, Barton VN, Donson AM et al (2011) Survey of MicroRNA expression in pediatric brain tumors. Pediatr Blood Cancer.  https://doi.org/10.1002/pbc Google Scholar
  26. 26.
    Jeyapalan JN, Doctor GT, Jones TA et al (2016) DNA methylation analysis of paediatric low-grade astrocytomas identifies a tumour-specific hypomethylation signature in pilocytic astrocytomas. Acta Neuropathol Commun 4:54.  https://doi.org/10.1186/s40478-016-0323-6 CrossRefGoogle Scholar
  27. 27.
    Jones TA, Jeyapalan JN, Forshew T et al (2015) Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-κB pathways. Acta Neuropathol Commun 3:86.  https://doi.org/10.1186/s40478-015-0266-3 CrossRefGoogle Scholar
  28. 28.
    Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199.  https://doi.org/10.1038/cdd.2009.56 CrossRefGoogle Scholar
  29. 29.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307CrossRefGoogle Scholar
  30. 30.
    Ishii N, Sawamura Y, Tada M et al (1998) Absence of p53 gene mutations in a tumor panel representative of pilocytic astrocytoma diversity using a p53 functional assay. Int J Cancer 800:797–800CrossRefGoogle Scholar
  31. 31.
    Gao H, Zhao H, Xiang W (2013) Expression level of human miR-34a correlates with glioma grade and prognosis. J Neurooncol 113:221–228.  https://doi.org/10.1007/s11060-013-1119-1 CrossRefGoogle Scholar
  32. 32.
    Sadighi Z, Slopis J (2013) Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. J Child Neurol 28:625–632.  https://doi.org/10.1177/0883073813476141 CrossRefGoogle Scholar
  33. 33.
    Zha W, Cao L, Shen Y, Huang M (2013) Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer. PLoS ONE.  https://doi.org/10.1371/journal.pone.0074175 Google Scholar
  34. 34.
    Katayama Y, Maeda M, Miyaguchi K et al (2012) Identification of pathogenesis-related microRNAs in hepatocellular carcinoma by expression profiling. Oncol Lett 4:817–823.  https://doi.org/10.3892/ol.2012.810 CrossRefGoogle Scholar
  35. 35.
    Lin L, Zheng Y, Tu Y et al (2015) MicroRNA-144 suppresses tumorigenesis and tumor progression of astrocytoma by targeting EZH2. Hum Pathol 46:971–980.  https://doi.org/10.1016/j.humpath.2015.01.023 CrossRefGoogle Scholar
  36. 36.
    Schmitz KJ, Helwig J, Bertram S et al (2011) Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours. J Clin Pathol 64:529–535.  https://doi.org/10.1136/jcp.2010.085621 CrossRefGoogle Scholar
  37. 37.
    Li R-Y, Chen L-C, Zhang H-Y et al (2013) MiR-139 inhibits Mcl-1 expression and potentiates TMZ-induced apoptosis in glioma. CNS Neurosci Ther 19:477–483.  https://doi.org/10.1111/cns.12089 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Ribeirão Preto Medical SchoolUniversity of Sao Paulo - USPRibeirão PretoBrazil
  2. 2.Centro Universitário CESMACMaceióBrazil
  3. 3.Department of Research and DevelopmentFleury GroupSão PauloBrazil
  4. 4.State University of CampinasCampinasBrazil
  5. 5.Boldrini´s Children CenterCampinasBrazil
  6. 6.Department of Pathology, Ribeirão Preto Medical SchoolUniversity of Sao PauloRibeirão PretoBrazil
  7. 7.Department of Surgery, Ribeirão Preto Medical SchoolUniversity of Sao PauloRibeirão PretoBrazil
  8. 8.Hemocentro Foundation, Ribeirão Preto Medical SchoolUniversity of Sao PauloRibeirão PretoBrazil

Personalised recommendations