Distinct genetic alterations in pediatric glioblastomas
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Pediatric high-grade tumors, especially glioblastomas (GBs), can be clinically devastating but are under-studied in comparison with adult GBs (aGBs). Molecular features of pediatric GBs (pGBs) are poorly understood and novel-targeted therapies have not been routinely used in pediatric patients with GBs.
Twenty-four non-brainstem pGBs were studied. To compare pGBs with aGBs, immunohistochemical staining and fluorescent in situ hybridization were performed in paraffin-embedded tissues. Microarray gene expression analyses were performed in snap-frozen tissues of four primary pGBs, six primary aGBs, and one non-neoplastic brain.
Immunohistochemial p16 loss was more frequent in pGBs, whereas p53, epidermal growth factor receptor, and phosphatase and tensin homolog loss were similar to that of aGBs. No case was isocitrate dehydrogenase (IDH)1 immunopositive or showed the IDH1 R132/IDH2 R172 mutation, suggesting primary GB. Microarray analysis revealed two pGB subtypes (A and B). Type B pGBs and aGBs had similar gene expression profiles; however, the profiles of type A pGBs differed from those of aGBs. In type A pGBs, we identified 90 up- and 63 down-regulated genes; platelet-derived growth factor receptor α polypeptide and CCND2 expression were significantly reduced, whereas they were up-regulated in aGBs.
Our study found two distinct pGB gene expression profiles: one similar to that of aGBs and the other different. We identified significantly up- and down-regulated genes in pGBs that may provide better targets for diagnostic, prognostic, and therapeutic uses; however, more studies are required to determine the classification and optimal treatment of pediatric patients with GBs.
KeywordGlioblastoma Pediatrics Molecular pathology Gene expression profile
This research was supported by Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0003666).
Conflict of interest
We have no conflicts of interest to declare.
- 5.Bax DA, Little SE, Gaspar N, Perryman L, Marshall L, Viana-Pereira M, Jones TA, Williams RD, Grigoriadis A, Vassal G, Workman P, Sheer D, Reis RM, Pearson AD, Hargrave D, Jones C (2009) Molecular and phenotypic characterisation of paediatric glioma cell lines as models for preclinical drug development. PLoS One 4:e5209PubMedCrossRefGoogle Scholar
- 10.Yin D, Ogawa S, Kawamata N, Tunici P, Finocchiaro G, Eoli M, Ruckert C, Huynh T, Liu G, Kato M, Sanada M, Jauch A, Dugas M, Black KL, Koeffler HP (2009) High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. Mol Cancer Res 7:665–677PubMedCrossRefGoogle Scholar
- 12.Bax DA, Gaspar N, Little SE, Marshall L, Perryman L, Regairaz M, Viana-Pereira M, Vuononvirta R, Sharp SY, Reis-Filho JS, Stavale JN, Al-Sarraj S, Reis RM, Vassal G, Pearson AD, Hargrave D, Ellison DW, Workman P, Jones C (2009) EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines. Clin Cancer Res 15:5753–5761PubMedCrossRefGoogle Scholar
- 13.Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28:1337–1344PubMedCrossRefGoogle Scholar
- 14.Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061–3068PubMedCrossRefGoogle Scholar
- 16.Gaspar N, Marshall L, Perryman L, Bax DA, Little SE, Viana-Pereira M, Sharp SY, Vassal G, Pearson AD, Reis RM, Hargrave D, Workman P, Jones C (2010) MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature. Cancer Res 70:9243–9252PubMedCrossRefGoogle Scholar
- 17.Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PA Jr, Varella-Garcia M (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643–655PubMedCrossRefGoogle Scholar
- 20.Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognar L, Hanzely Z, Liberski PP, Lopez-Aguilar E, Valera ET, Tone LG, Carret AS, Del Maestro RF, Gleave M, Montes JL, Pietsch T, Albrecht S, Jabado N (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25:1196–1208PubMedCrossRefGoogle Scholar