**Nomenclature**

pathway restoration. It was observed that the therapeutic efficacy of p53 pathway restoration was greatly influenced by both the initial mechanism of p53 pathway-inactivating mutation and the temporal manner in which the selective pressure elicited by p53 pathway restoration was applied. Their results suggested that intermittent dosing regimens of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more

This topic focused on GBM because of its poor prognosis and the target for most clinical trials. However, it is important to recognize that there are many other brain tumors which are also targets for gene therapy. Recently, Kunkele *et al.* [227] observed that targeting the p53-MDM2 complex using nutlin-3 significantly reduced cell viability and induced either apoptosis or cell cycle arrest and expression of the p53 target gene p21 in 4 of 6 human medulloblastomas cell lines. However, UW-228 and DAOY cells harboring *TP53* mutations were almost unaffected by nutlin-3, showing that the mutational status of the gene interfere in the efficacy of the treatment. MDM2 knockdown in medulloblastoma cells by siRNA mimicked nutlin-3 treat‐ ment, whereas expression of dominant negative p53 abrogated nutlin-3 effects. Oral nutlin-3 treatment of mice with established medulloblastoma xenografts inhibited tumor growth and significantly increased survival. Hence, the authors suggested that inhibition of the MDM2 p53 interaction with nutlin-3 is a promising therapeutic option for medulloblastomas with

After a detailed review of the literature about the role of the *TP53* gene in the genesis and development of CNS tumors we can conclude that both genetic and epigenetic alterations that inactivate this gene are directly related to these phenomena in specific histopathological tumors. In addition, several studies have investigated the predictive value of *TP53* mutation status and have shown that specific types of genetic mutations can alter the function and expression of p53, influencing tumor response to treatment and patient outcome, revealing thus to be a useful prognostic tool. Genetic alterations in the p53 pathway are early events in the molecular pathogenesis of diffuse astrocytoma and the highest frequencies of allelic loss and/or mutation of *TP53* gene are mostly seen in gliomas, and are a genetic hallmark of: lowgrade diffuse astrocytomas (> 60%), mainly in gemistocytic astrocytomas that carry *TP53* mutations in up to 80% of the cases; anaplastic astrocytomas (40-70%); secondary glioblastoma (>65%); oligoastrocytomas (~40%). Genetic *TP53* mutations are rarely found or seen less frequently in other CNS tumors, however, some studies have shown that some changes have found important prognostic value. Recently, our group investigated the presence of numerical aberrations of chromosome 17 and *TP53* in 5 subjects with brain metastasis from breast cancer using dual-color fluorescence in situ hybridization experiments. Deletion of *TP53* was the most frequent alteration observed, suggesting that if this alteration is present in the primary tumors, breast tumors with loss of *TP53* copies have a poorer prognosis and a higher chance for

efficacious than traditional chronic dosing by similarly reducing adaptive resistance.

functional p53 that should be further evaluated in clinical trials.

150 Tumors of the Central Nervous System – Primary and Secondary

**6. Conclusion**

metastasis [237].



*TP53* Tumor protein p53 TSC1 Tuberous Sclerosis 1 WHO World Health Organization

PXA Xanthoastrocytoma pleomorphic

Authors would like to thank PPGGBM-UFPA, IFPA and IEC for support. We also would like to thank the staffs at Francisco Mauro Salzano Laboratory (UFPA) and Laboratory of Tissue Culture and Cytogenetics (SAMAM, IEC). We are especially grateful to Dr. Cynthia Hawkins (Dept. of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada)

Alterations in *TP53* gene – Implications in Tumorigenesis Process and Prognosis in Central Nervous System Cancer

, Fabio P. Estumano da Silva1,2, Nilson Praia Anselmo3

1 Programa de Pós Graduação em Genética e Biologia Molecular, ICB, Universidade Federal

2 Laboratório de Biociências e Comportamento, Instituto Federal do Pará, Tucuruí, PA, Brazil

3 Laboratório de Biologia Molecular Francisco Mauro Salzano, ICB, Universidade Federal do

4 Faculdade de Ciências Naturais, ICEN, Universidade Federal do Pará, Belém, PA, Brazil

5 Laboratório de Cultura de Tecidos e Citogenética, SAMAM, Instituto Evandro Chagas,

[1] Olivier M, Taniere P. Somatic mutations in cancer prognosis and prediction: lessons from TP53 and EGFR genes. Current Opinion in Oncology 2011; 23(1):88-92.

and

http://dx.doi.org/10.5772/58334

153

WT Wild-type WNT Wingless

**Acknowledgements**

for her important contribution.

Edivaldo Herculano C. de Oliveira1,4,5

**Author details**

Igor Andrade Pessôa1

do Pará, Belém, PA, Brazil

Pará, Belém, PA, Brazil

Ananindeua, PA, Brazil

**References**

