Data mining of pediatric medulloblastoma microarray expression reveals a novel potential subdivision of the Group 4 molecular subgroup

Castillo‑Rodríguez,Rosa Angélica; Dávila‑Borja,Víctor Manuel; Juárez‑Méndez,Sergio

doi:10.3892/ol.2018.8094

Data mining of pediatric medulloblastoma microarray expression reveals a novel potential subdivision of the Group 4 molecular subgroup

Authors:
- Rosa Angélica Castillo‑Rodríguez
- Víctor Manuel Dávila‑Borja
- Sergio Juárez‑Méndez
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Affiliations: Laboratory of Experimental Oncology, National Institute of Pediatrics, Mexico City 04530, Mexico
Published online on: February 21, 2018 https://doi.org/10.3892/ol.2018.8094
Pages: 6241-6250
Copyright: © Castillo‑Rodríguez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Medulloblastoma is the most common type of solid brain tumor in children. This type of embryonic tumor is highly heterogeneous and has been classified into 4 molecular subgroups based on their gene expression profiles: WNT, SHH, Group 3 (G3) and Group 4 (G4). WNT and SHH tumors exhibit the specific dysregulation of genes and pathways, whereas G3 and G4 tumors, two of the more frequent subtypes, are the least characterized. Thus, novel markers to aid in the diagnosis, prognosis and management of medulloblastoma are required. In the present study, microarray gene expression data was downloaded from the Gene Expression Omnibus database, including data from the 4 subgroups of medulloblastoma and healthy cerebellum tissue (CT). The data was utilized in an in silico analysis to characterize each subgroup at a transcriptomic level. Using Partek Genomics Suite software, the data were visualized via hierarchical clustering and principal component analysis. The differentially expressed genes were uploaded to the MetaCore portal to perform enrichment analysis using CT gene expression as baseline, with fold change thresholds of <‑5 and >5 for differential expression. The data mining analysis of microarray gene expression data enabled the identification of a range of dysregulated molecules associated with each subgroup of medulloblastoma. G4 is the most heterogeneous subgroup, as no definitive pathway defines its pathogenesis; analysis of the gene expression profiles were associated with the G4α and G4β subcategories. TOX high mobility group box family member 3, synuclein α interacting protein and, potassium voltage‑gated channel interacting protein 4 were identified as three novel potential markers for distinguishing the α and β subcategories of G4. These genes may be associated with medulloblastoma pathogenesis, and thus may provide a basis for researching novel targeted treatment strategies for G4 medulloblastoma.

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1	Smoll NR: Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs). Cancer. 118:1313–1322. 2012. View Article : Google Scholar : PubMed/NCBI
2	Smoll NR and Drummond KJ: The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci. 19:1541–1544. 2012. View Article : Google Scholar : PubMed/NCBI
3	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
4	Scotting PJ, Walker DA and Perilongo G: Childhood solid tumours: A developmental disorder. Nat Rev Cancer. 5:481–488. 2005. View Article : Google Scholar : PubMed/NCBI
5	Gilbertson RJ and Ellison DW: The origins of medulloblastoma subtypes. Annu Rev Pathol. 3:341–365. 2008. View Article : Google Scholar : PubMed/NCBI
6	Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®), . Health Professional Version: PDQ pediatric treatment editorial boardPDQ Cancer Information Summaries[Internet]. Bethesda (MD): National Cancer Institute (US); 2002
7	Crawford JR, MacDonald TJ and Packer RJ: Medulloblastoma in childhood: New biological advances. Lancet Neurol. 6:1073–1085. 2007. View Article : Google Scholar : PubMed/NCBI
8	Paulino AC, Lobo M, Teh BS, Okcu MF, South M, Butler EB, Su J and Chintagumpala M: Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys. 78:1445–1450. 2010. View Article : Google Scholar : PubMed/NCBI
9	Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, et al: Molecular subgroups of medulloblastoma: An international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 123:473–484. 2012. View Article : Google Scholar : PubMed/NCBI
10	Kijima N and Kanemura Y: Molecular classification of medulloblastoma. Neurol Med Chir (Tokyo). 56:687–697. 2016. View Article : Google Scholar : PubMed/NCBI
11	Skowron P, Ramaswamy V and Taylor MD: Genetic and molecular alterations across medulloblastoma subgroups. J Mol Med (Berl). 93:1075–1084. 2015. View Article : Google Scholar : PubMed/NCBI
12	Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P and Ohgaki H: APC mutations in sporadic medulloblastomas. Am J Pathol. 156:433–437. 2000. View Article : Google Scholar : PubMed/NCBI
13	Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sörensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD and Pietsch T: Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 61:7039–7043. 2001.PubMed/NCBI
14	Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D and Ellison DW: Wnt/wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell cycle. 5:2666–2670. 2006. View Article : Google Scholar : PubMed/NCBI
15	Evans DG, Farndon PA, Burnell LD, Gattamaneni HR and Birch JM: The incidence of gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer. 64:959–961. 1991. View Article : Google Scholar : PubMed/NCBI
16	Fujii K and Miyashita T: Gorlin syndrome (nevoid basal cell carcinoma syndrome): Update and literature review. Pediatr Int. 56:667–674. 2014. View Article : Google Scholar : PubMed/NCBI
17	He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, et al: The G protein α subunit Gαs is a tumor suppressor in sonic hedgehog-driven medulloblastoma. Nat Med. 20:1035–1042. 2014. View Article : Google Scholar : PubMed/NCBI
18	Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, Kenney AM, Brat DJ, Perry A, Yong WH, et al: Medulloblastoma: Clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 121:381–396. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J, et al: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One. 3:e30882008. View Article : Google Scholar : PubMed/NCBI
20	Pöschl J, Stark S, Neumann P, Gröbner S, Kawauchi D, Jones DT, Northcott PA, Lichter P, Pfister SM, Kool M and Schüller U: Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts. Acta Neuropathol. 128:123–136. 2014. View Article : Google Scholar : PubMed/NCBI
21	Rack PG, Ni J, Payumo AY, Nguyen V, Crapster JA, Hovestadt V, Kool M, Jones DT, Mich JK, Firestone AJ, et al: Arhgap36-dependent activation of Gli transcription factors. Proc Natl Acad Sci USA. 111:pp. 11061–11066. 2014; View Article : Google Scholar : PubMed/NCBI
22	Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, et al: Novel mutations target distinct subgroups of medulloblastoma. Nature. 488:43–48. 2012. View Article : Google Scholar : PubMed/NCBI
23	Lambert SR, Witt H, Hovestadt V, Zucknick M, Kool M, Pearson DM, Korshunov A, Ryzhova M, Ichimura K, Jabado N, et al: Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma. Acta Neuropathol. 126:291–301. 2013. View Article : Google Scholar : PubMed/NCBI
24	Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, et al: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 25:393–405. 2014. View Article : Google Scholar : PubMed/NCBI
25	Villegas-Ruiz V, Moreno J, Jacome-Lopez K, Zentella-Dehesa A and Juarez-Mendez S: Quality control usage in high-density microarrays reveals differential gene expression profiles in ovarian cancer. Asian Pac J Cancer Prev. 17:2519–2525. 2016.PubMed/NCBI
26	Villegas-Ruiz V and Juarez-Mendez S: Data mining for identification of molecular targets in ovarian cancer. Asian Pac J Cancer Prev. 17:1691–1699. 2016. View Article : Google Scholar : PubMed/NCBI
27	McCall MN, Murakami PN, Lukk M, Huber W and Irizarry RA: Assessing affymetrix Genechip microarray quality. BMC Bioinformatics. 12:1372011. View Article : Google Scholar : PubMed/NCBI
28	Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, et al: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 29:1408–1414. 2011. View Article : Google Scholar : PubMed/NCBI
29	Li KK, Lau KM and Ng HK: Signaling pathway and molecular subgroups of medulloblastoma. Int J Clin Exp Pathol. 6:1211–1222. 2013.PubMed/NCBI
30	Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, et al: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol. 24:1924–1931. 2006. View Article : Google Scholar : PubMed/NCBI
31	Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, et al: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol. 29:1424–1430. 2011. View Article : Google Scholar : PubMed/NCBI
32	Hooper CM, Hawes SM, Kees UR, Gottardo NG and Dallas PB: Gene expression analyses of the spatio-temporal relationships of human medulloblastoma subgroups during early human neurogenesis. PLoS One. 9:e1129092014. View Article : Google Scholar : PubMed/NCBI
33	Dittmer S, Kovacs Z, Yuan SH, Siszler G, Kögl M, Summer H, Geerts A, Golz S, Shioda T and Methner A: TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. J Cell Sci. 124(Pt 2): 1–260. 2011.PubMed/NCBI
34	Yuan SH, Qiu Z and Ghosh A: TOX3 regulates calcium-dependent transcription in neurons. Proc Natl Acad Sci USA. 106:pp. 2909–2914. 2009; View Article : Google Scholar : PubMed/NCBI
35	Tessema M, Yingling CM, Grimes MJ, Thomas CL, Liu Y, Leng S, Joste N and Belinsky SA: Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers. PLoS One. 7:e348502012. View Article : Google Scholar : PubMed/NCBI
36	Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T and Iwatsubo T: Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4. J Biol Chem. 277:14965–14975. 2002. View Article : Google Scholar : PubMed/NCBI
37	Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, et al: Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 488:49–56. 2012. View Article : Google Scholar : PubMed/NCBI
38	Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, et al: Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet. 22:110–114. 1999. View Article : Google Scholar : PubMed/NCBI
39	Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, et al: Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 361:1173–1178. 2009. View Article : Google Scholar : PubMed/NCBI