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FOXG1 dysregulation is a frequent event in medulloblastoma

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Abstract

Medulloblastomas represent 20% of malignant brain tumors of childhood. Although, they show multiple, non-random genomic alterations, no common, early genetic event involving all histologic types of medulloblastomas have been described. Nineteen medulloblastomas were analyzed using chromosomal comparative genomic hybridization (cCGH). Nine tumors with the most frequent number of genetic changes were further analyzed using bacterial artificial chromosome array CGH (aCGH). With aCGH, the frequency of gains and losses were higher than with cCGH. Chromosome 2p gains spanning 2p11–2p25 including N-myc locus, 2p24.1 were detected in 5/9 (55%) tumors while 14q12 gains were detected in 6/9 (67%) tumors. The 14q12 locus overlapped with the FOXGI gene locus. Quantitative real time PCR showed a 2–7-fold copy gain for FOXG1 in all the nine tumors. Protein expression was demonstrated by immunohistochemistry in all histologic types. The expression of FOXG1 and p21cip1 showed an inverse relationship. FOXG1 copy gain (>2 to 21 folds) was seen in 93% (55/59) of a validating set of tumors and showed a positive correlation with protein expression (Spearman’s rank order correlation coefficient = 0.276; P = 0.038) representing the first report of FOXG1 dysregulation in medulloblastoma. Modulation of FOXG1 expression in DAOY cell line using siRNA showed a modest decrease in proliferation with a 2-fold upregulation of p21cip1. Current reports indicate that FOXG1 represses TGF-β induced expression of p21cip1 and cytostasis, and forms a transcriptional repressor complex with Notch signaling induced hes1. Our findings are consistent with a role for FOXG1 in the inhibition of TGF-β induced cytostasis in medulloblastoma.

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References

  1. Giangaspero F, Bigner SH, Kleihues P, Pietsch T, Trojanowski JQ (2000) Medulloblastoma. In: Kleihues P, Cavenee WK (eds) Pathology & genetics: tumours of the nervous system. Publisher, IARC, Lyon

    Google Scholar 

  2. Raffel C, Jenkins RB, Frederick L et al (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845

    PubMed  CAS  Google Scholar 

  3. Zurawel RH, Chiappa SA, Allen C, Raffel C (1998) Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res 58:896–899

    PubMed  CAS  Google Scholar 

  4. Adesina AM, Dunn ST, Nalbantoglu J (2000) Expression of p27kip1 and p53 gene in medulloblastoma; relationship with cell proliferation and survival. Pathol Res Pract 196:243–250

    PubMed  CAS  Google Scholar 

  5. Ray A, Ho M, Ma J et al (2004) A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10:7613–7620

    Article  PubMed  CAS  Google Scholar 

  6. Adesina AM, Nalbantoglu J, Cavenee WK (1994) p53 gene mutation and mdm2 gene amplification are uncommon in medulloblastoma. Cancer Res 54:5649–5651

    PubMed  CAS  Google Scholar 

  7. Saylors RL 3rd, Sidransky D, Friedman HS et al (1991): Infrequent p53 gene mutations in medulloblastomas. Cancer Res 51:4721–4723

    PubMed  Google Scholar 

  8. Gilbertson R, Wickramasinghe C, Hernan R et al (2001): Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712

    Article  PubMed  CAS  Google Scholar 

  9. Bigner SH, Friedman HS, Vogelstein B, Oakes WJ, Bigner DD (1990) Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res 50:2347–2350

    PubMed  CAS  Google Scholar 

  10. Aldosari N, Bigner SH, Burger PC et al (2002) MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med 26:540–544

    Google Scholar 

  11. Brown HG, Kepner JL, Perlman EJ et al (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865

    PubMed  CAS  Google Scholar 

  12. Herms J, Neidt I, Luscher B et al (2000) C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 89:395–402

    Article  PubMed  CAS  Google Scholar 

  13. Oliver TG, Grasfeder LL, Carroll AL et al (2003): Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA 100:7331–7336

    Article  PubMed  CAS  Google Scholar 

  14. Thompson MC, Fuller C, Hogg TL et al (2006): Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931

    Article  PubMed  CAS  Google Scholar 

  15. Tong C, Hui A, Yin XL et al (2004) Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization. J Neurosurg Spine 100:187–193

    CAS  Google Scholar 

  16. Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28:257–282

    Article  PubMed  CAS  Google Scholar 

  17. Hernan R, Fasheh R, Calabrese C et al (2003) ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma. Cancer Res 63:140–148

    PubMed  CAS  Google Scholar 

  18. Eberhart CG, Kratz J, Wang Y et al (2004) Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63:441–449

    PubMed  CAS  Google Scholar 

  19. Korshunov A, Savostikova M, Ozerov S (2002) Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression. J Neurooncol 58:271–279

    Article  PubMed  Google Scholar 

  20. Boon K, Eberhart CG, Riggins GJ (2005) Genomic Amplification of Orthodenticle Homologue 2 in Medulloblastomas. Cancer Res 65:703–707

    PubMed  CAS  Google Scholar 

  21. Di C, Liao S, Adamson DC et al (2005) Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res 65:919–924

    PubMed  CAS  Google Scholar 

  22. Bale AE (1997) The nevoid basal carcinoma syndrome: Genetics and mechanisms of carcinogenesis. Cancer Invest 15:180–186

    PubMed  CAS  Google Scholar 

  23. Hamilton SR, Liu B, Parsons RE et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–849

    Article  PubMed  CAS  Google Scholar 

  24. Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351:453–456

    Article  PubMed  CAS  Google Scholar 

  25. Arden K (2004) FoxO: linking new signaling pathways. Mol Cell 14:416–418

    Article  PubMed  CAS  Google Scholar 

  26. Yang YH, Dudoit S, Luu P, Peng V, Ngai J, Speed TP (2002): Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nuclei Acid Res 30:e15

    Article  Google Scholar 

  27. Draghici S (2003) Data pre-processing and normalization; In: Draghici S (eds) Data analysis tools for microarrays, Publisher, Chapman Hall/CRC, pp 309–340

    Google Scholar 

  28. Siegenthaler JA, Miller MW (2005): Transforming growth factor beta 1 promotes cell cycle exit through the cyclin-dependent kinase inhibitor p21 in the developing cerebral cortex. J Neurosci 25(38):8627–8636

    Article  PubMed  CAS  Google Scholar 

  29. Kasai M, Satoh K, Akiyama T (2005): Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs. Genes Cells 10:777–783

    Article  PubMed  CAS  Google Scholar 

  30. Lu J, Wu Y, Sousa N, Almeida OF (2005) SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. Development 132:3231–3242

    Article  PubMed  CAS  Google Scholar 

  31. Ellison DW, Onilude OE, Lindsey JC et al (2005) United Kingdom Children’s Cancer Study Group Brain Tumour Committee: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951–7957

    Article  PubMed  CAS  Google Scholar 

  32. Martynoga B, Morrison H, Price DJ, Mason JO (2005) FOXG1 is required for specification of ventral telencephalon and region-specific regulation of dorsal telencephalic precursor proliferation and apoptosis. Dev Biol 283:113–127

    Article  PubMed  CAS  Google Scholar 

  33. Muzio L, Mallamaci A (2005) FOXG1 Confines Cajal–Retzius Neuronogenesis and Hippocampal Morphogenesis to the Dorsomedial Pallium. J Neurosci 25:4435–4441

    Article  PubMed  CAS  Google Scholar 

  34. Hanachima C, Li SC, Shen L, Lai E, Fishell G (2004) FOXG1 suppresses early cortical cell fate. Science 303:56–59

    Article  Google Scholar 

  35. Dou C, Lee J, Liu B et al (2000) BF-1 Interferes with Transforming Growth Factor β Signaling by Associating with Smad Partners. Mol Cell Biol 20:6201–6211

    Article  PubMed  CAS  Google Scholar 

  36. Seoane J, Le H-V, Shen L, Anderson SA, Massague J (2004): Integration of Smad and Forkhead Pathways in the Control of Neuroepithelial and Glioblastoma Cell Proliferation. Cell 117:211–223

    Article  PubMed  CAS  Google Scholar 

  37. Bourguignon C, Li J, Papalopulu N (1998) XBF-1, a winged helix transcription factor with dual activity has a role in positioning neurogenesis in Xenopus competent ectoderm. Development 125:4889–4900

    PubMed  CAS  Google Scholar 

  38. Hanashima C, Shen L, Li SC, Lai E (2002) : Brain factor-1 controls the proliferation and differentiation of neocortical progenitor cells through independent mechanisms. J Neurosci 22:6526–6536

    PubMed  CAS  Google Scholar 

  39. Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E (1995) Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 14:1141–1152

    Article  PubMed  CAS  Google Scholar 

  40. Tao W, Lai E (1992): Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family in the developing rat brain. Neuron 8:957–966

    Article  PubMed  CAS  Google Scholar 

  41. Ahlgren S, Vogt P, Bronner-Fraser M (2003) Excess FOXG1 Causes Overgrowth of the Neural Tube. J Neurobiol 57:337–349

    Article  PubMed  CAS  Google Scholar 

  42. Del Valle L, Enam S, Lassak A et al (2002) Insulin-like growth factor I receptor activity in human medulloblastomas. Clin Cancer Res 8:1822–1830

    PubMed  Google Scholar 

  43. Rao G, Pedone CA, Del Valle L et al (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice Oncogene 23:6156–6162

    Google Scholar 

  44. Fan X, Mikolaenko I, Elhassan I et al (2004) Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 64:7787–7793

    Article  PubMed  CAS  Google Scholar 

  45. Hallahan AR, Pritchard JI, Hansen S et al (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas Cancer Res 64:7794–7800

    Google Scholar 

  46. Dakubo GD, Mazerolle CJ, Wallace VA (2006): Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice. J Neurooncol 79:221–227

    Article  PubMed  CAS  Google Scholar 

  47. Yao J, Lai E, StifanI S (2001) The Winged-Helix Protein Brain Factor 1 Interacts with Groucho and Hes Proteins To Repress Transcription. Mol Cell Biol 21:1962–1972

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The supports of the Oklahoma Center for the Advancement of Science and Technology, the Moran Foundation and an equipment grant from the Presbyterian Health Foundation (AMA) are acknowledged.

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Correspondence to Adekunle M. Adesina.

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Adesina, A.M., Nguyen, Y., Mehta, V. et al. FOXG1 dysregulation is a frequent event in medulloblastoma. J Neurooncol 85, 111–122 (2007). https://doi.org/10.1007/s11060-007-9394-3

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  • DOI: https://doi.org/10.1007/s11060-007-9394-3

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