Journal of Neuro-Oncology

, Volume 110, Issue 1, pp 49–57 | Cite as

Prognostic value of the TP53 Arg72Pro single-nucleotide polymorphism and susceptibility to medulloblastoma in a cohort of Brazilian patients

  • Raimundo M. Carvalho
  • Giovanny R. PintoEmail author
  • France K. N. Yoshioka
  • Patrícia D. L. Lima
  • Carolina R. T. Souza
  • Adriana C. Guimarães
  • Letícia M. Lamarão
  • Juan A. Rey
  • Rommel R. Burbano
Laboratory Investigation


Medulloblastoma is a highly cellular malignant embryonal neoplasm, being the most common malignant pediatric brain tumor, accounting for 20–25 % of pediatric central nervous system tumors. To investigate the effect of the TP53 Arg72Pro single-nucleotide polymorphism (SNP) on clinicopathological and phenotypic parameters, we performed a case-controlled study of 122 patients and 122 healthy controls from Brazil. No significant associations were found between the TP53 Arg72Pro genotypes and the clinicopathological parameters studied. Compared with Arg/Arg, which is the most common genotype in the study population, both the Arg/Pro and Pro/Pro genotypes did not influence the medulloblastoma development risk [odds ratio (OR) = 1.36 and P = 0.339 for the Arg/Pro genotype; OR = 1.50 and P = 0.389 for the Pro/Pro genotype]. With regard to prognosis, disease-free survival was not significantly different among the TP53 Arg72Pro SNP genotypes (P > 0.05), but the less frequent genotype (Pro/Pro) was associated with shorter overall survival of medulloblastoma patients (P = 0.021). These data suggest that, although there is no association between the TP53 Arg72Pro SNP and medulloblastoma risk, the Pro/Pro genotype is associated with shorter overall survival of patients submitted to adjuvant therapy. Nevertheless, due to the interethnic composition of the Brazilian population, future studies on larger populations from other parts of the world are essential for a definitive conclusion on the function of the TP53 Arg72Pro SNP.


Medulloblastomas TP53 Arg72Pro SNP Risk Prognosis Adjuvant therapy 



This study was supported by the National Counsel of Technological and Scientific Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq; grant nos. 302774/2009-2 and 484282/2010-7) and by the Coordination of Improvement of Higher Education (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; CAPES). G.R.P. and R.R.B. have received fellowships granted by CNPq.


  1. 1.
    Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A (2008) Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res 14(4):971–976. doi: 10.1158/1078-0432.CCR-07-2072 PubMedCrossRefGoogle Scholar
  2. 2.
    Brandes AA, Franceschi E, Tosoni A, Reni M, Gatta G, Vecht C, Kortmann RD (2009) Adult neuroectodermal tumors of posterior fossa (medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol/Hematol 71(2):165–179. doi: 10.1016/j.critrevonc.2009.02.002 CrossRefGoogle Scholar
  3. 3.
    Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VM, Trojanowski JQ (2000) TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18(5):1027–1035PubMedGoogle Scholar
  4. 4.
    Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A (2009) Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27(10):1627–1636. doi: 10.1200/JCO.2008.17.9432 PubMedCrossRefGoogle Scholar
  5. 5.
    Pizem J, Cort A, Zadravec-Zaletel L, Popovic M (2005) Survivin is a negative prognostic marker in medulloblastoma. Neuropathol Appl Neurobiol 31(4):422–428. doi: 10.1111/j.1365-2990.2005.00664.x PubMedCrossRefGoogle Scholar
  6. 6.
    Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S, McLaughlin J, Bouffet E, Rutka JT, Hawkins CE (2004) A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10(22):7613–7620. doi: 10.1158/1078-0432.CCR-04-0499 PubMedCrossRefGoogle Scholar
  7. 7.
    Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28(8):1345–1350. doi: 10.1200/JCO.2009.23.5952 PubMedCrossRefGoogle Scholar
  8. 8.
    Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24(12):1924–1931. doi: 10.1200/JCO.2005.04.4974 PubMedCrossRefGoogle Scholar
  9. 9.
    Benard J, Douc-Rasy S, Ahomadegbe JC (2003) TP53 family members and human cancers. Hum Mutat 21(3):182–191. doi: 10.1002/humu.10172 PubMedCrossRefGoogle Scholar
  10. 10.
    Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28(6):622–629. doi: 10.1002/humu.20495 PubMedCrossRefGoogle Scholar
  11. 11.
    Pfaff E, Remke M, Sturm D, Benner A, Witt H, Milde T, von Bueren AO, Wittmann A, Schöttler A, Jorch N, Graf N, Kulozik AE, Witt O, Scheurlen W, von Deimling A, Rutkowski S, Taylor MD, Tabori U, Lichter P, Korshunov A, Pfister SM (2010) TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma. J Clin Oncol 28(35):5188–5196. doi: 10.1200/JCO.2010.31.1670 PubMedCrossRefGoogle Scholar
  12. 12.
    Lindsey JC, Hill RM, Megahed H, Lusher ME, Schwalbe EC, Cole M, Hogg TL, Gilbertson RJ, Ellison DW, Bailey S, Clifford SC (2011) TP53 mutations in favorable-risk Wnt/wingless-subtype medulloblastomas. J Clin Oncol 29(12):e344–e346. doi: 10.1200/JCO.2010.33.8590 PubMedCrossRefGoogle Scholar
  13. 13.
    Gessi M, von Bueren AO, Rutkowski S, Pietsch T (2012) p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol 106(1):135–141. doi: 10.1007/s11060-011-0648-8 PubMedCrossRefGoogle Scholar
  14. 14.
    Efeyan A, Serrano M (2007) p53: guardian of the genome and policeman of the oncogenes. Cell Cycle 6(9):1006–1010PubMedCrossRefGoogle Scholar
  15. 15.
    Dumont P, Leu JI, Della Pietra AC, 3rd, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nature Genet 33(3):357–365. doi: 10.1038/ng1093 Google Scholar
  16. 16.
    Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nat Cell Biol 6(5):443–450. doi: 10.1038/ncb1123 PubMedCrossRefGoogle Scholar
  17. 17.
    Almeida LO, Custodio AC, Pinto GR, Santos MJ, Almeida JR, Clara CA, Rey JA, Casartelli C (2009) Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors. Genet Mol Res 8(1):8–18PubMedCrossRefGoogle Scholar
  18. 18.
    El Hallani S, Ducray F, Idbaih A, Marie Y, Boisselier B, Colin C, Laigle-Donadey F, Rodero M, Chinot O, Thillet J, Hoang-Xuan K, Delattre JY, Sanson M (2009) TP53 codon 72 polymorphism is associated with age at onset of glioblastoma. Neurology 72(4):332–336. doi: 10.1212/ PubMedCrossRefGoogle Scholar
  19. 19.
    Jha P, Jha P, Pathak P, Chosdol K, Suri V, Sharma MC, Kumar G, Singh M, Mahapatra AK, Sarkar C (2011) TP53 polymorphisms in gliomas from Indian patients: study of codon 72 genotype, rs1642785, rs1800370 and 16 base pair insertion in intron-3. Exp Mol Pathol 90(2):167–172. doi: 10.1016/j.yexmp.2010.11.002 PubMedCrossRefGoogle Scholar
  20. 20.
    Zawlik I, Kita D, Vaccarella S, Mittelbronn M, Franceschi S, Ohgaki H (2009) Common polymorphisms in the MDM2 and TP53 genes and the relationship between TP53 mutations and patient outcomes in glioblastomas. Brain Pathol 19(2):188–194. doi: 10.1111/j.1750-3639.2008.00170.x PubMedCrossRefGoogle Scholar
  21. 21.
    Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group Study. Cancer 94(2):552–560. doi: 10.1002/cncr.10189 PubMedCrossRefGoogle Scholar
  22. 22.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. doi: 10.1007/s00401-007-0243-4 PubMedCrossRefGoogle Scholar
  23. 23.
    Pinto GR, Yoshioka FK, Silva RL, Clara CA, Santos MJ, Almeida JR, Burbano RR, Rey JA, Casartelli C (2008) Prognostic value of TP53 Pro47Ser and Arg72Pro single nucleotide polymorphisms and the susceptibility to gliomas in individuals from Southeast Brazil. Genet Mol Res 7(1):207–216PubMedCrossRefGoogle Scholar
  24. 24.
    Feng Z, Levine AJ (2010) The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20(7):427–434. doi: 10.1016/j.tcb.2010.03.004 PubMedCrossRefGoogle Scholar
  25. 25.
    Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SD (2003) Color and genomic ancestry in Brazilians. Proc Natl Acad Sci USA 100(1):177–182. doi: 10.1073/pnas.0126614100 PubMedCrossRefGoogle Scholar
  26. 26.
    Biros E, Kalina I, Kohut A, Bogyiova E, Salagovic J, Sulla I (2002) Allelic and haplotype frequencies of the p53 polymorphisms in brain tumor patients. Physiol Res/Acad Sci Bohemoslov 51(1):59–64Google Scholar
  27. 27.
    Parhar P, Ezer R, Shao Y, Allen JC, Miller DC, Newcomb EW (2005) Possible association of p53 codon 72 polymorphism with susceptibility to adult and pediatric high-grade astrocytomas. Brain Res Mol Brain Res 137(1–2):98–103. doi: 10.1016/j.molbrainres.2005.02.016 PubMedCrossRefGoogle Scholar
  28. 28.
    Lima-Ramos V, Pacheco-Figueiredo L, Costa S, Pardal F, Silva A, Amorim J, Lopes JM, Reis RM (2008) TP53 codon 72 polymorphism in susceptibility, overall survival, and adjuvant therapy response of gliomas. Cancer Genet Cytogenet 180(1):14–19. doi: 10.1016/j.cancergencyto.2007.08.019 PubMedCrossRefGoogle Scholar
  29. 29.
    Wang Y, Kringen P, Kristensen GB, Holm R, Baekelandt MM, Olivier M, Skomedal H, Hainaut P, Tropé CG, Abeler VM, Nesland JM, Børresen-Dale AL, Helland A (2004) Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma. Hum Mutat 24(1):21–34. doi: 10.1002/humu.20055 PubMedCrossRefGoogle Scholar
  30. 30.
    Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S, McLaughlin J, Bouffet E, Rutka JT, Hawkins CE (2004) A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 22:7613–7620. doi: 10.1158/1078-0432.CCR-04-0499 CrossRefGoogle Scholar
  31. 31.
    Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29(11):1408–1414. doi: 10.1200/JCO.2009.27.4324 PubMedCrossRefGoogle Scholar
  32. 32.
    Ellison DW (2010) Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease. Acta Neuropathol 3:305–316. doi: 10.1007/s00401-010-0726-6 CrossRefGoogle Scholar
  33. 33.
    von Hoff K, Hartmann W, von Bueren AO, Gerber NU, Grotzer MA, Pietsch T, Rutkowski S (2010) Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer 3:369–376. doi: 10.1002/pbc.22339 CrossRefGoogle Scholar
  34. 34.
    Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, Giangaspero F, Ellison DW, Garre ML, Biassoni V, Grundy RG, Finlay JL, Dhall G, Raquin MA, Grill J (2010) Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 33:4961–4968. doi: 10.1200/JCO.2010.30.2299 CrossRefGoogle Scholar
  35. 35.
    de Haas T, Hasselt N, Troost D, Caron H, Popovic M, Zadravec-Zaletel L, Grajkowska W, Perek M, Osterheld MC, Ellison D, Baas F, Versteeg R, Kool M (2008) Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression. Clin Cancer Res 13:4154–4160. doi: 10.1158/1078-0432.CCR-07-4159 CrossRefGoogle Scholar
  36. 36.
    Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845PubMedGoogle Scholar
  37. 37.
    Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS (2005) Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727–734. doi: 10.1016/j.ejca.2004.12.017 PubMedCrossRefGoogle Scholar
  38. 38.
    Pizer BL, Clifford SC (2009) The potential impact of tumor biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg 23:364–375. doi: 10.1080/02688690903121807 PubMedCrossRefGoogle Scholar
  39. 39.
    Kweekel DM, Van der Straaten T, Koopman M, Meijer GA, Nortier JW, Cornelis JA, Gelderblom H, Guchelaar HJ (2010) Comparison of genetic polymorphisms in DNA isolated from blood and paraffin embedded colorectal cancer tissue. Accessed 10 Feb 2012
  40. 40.
    Cerne JZ, Pohar-Perme M, Novakovic S, Frkovic-Grazio S, Stegel V, Gersak K (2011) Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer. J Gynecol Oncol 22(2):110–119. doi: 10.3802/jgo.2011.22.2.110 PubMedCrossRefGoogle Scholar
  41. 41.
    Rae JM, Cordero KE, Scheys JO, Lippman ME, Flockhart DA, Johnson MD (2003) Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics 13(8):501–507. doi: 10.1097/00008571-200308000-00008 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Raimundo M. Carvalho
    • 1
    • 2
  • Giovanny R. Pinto
    • 3
    Email author
  • France K. N. Yoshioka
    • 3
  • Patrícia D. L. Lima
    • 2
  • Carolina R. T. Souza
    • 2
  • Adriana C. Guimarães
    • 2
  • Letícia M. Lamarão
    • 2
  • Juan A. Rey
    • 4
  • Rommel R. Burbano
    • 2
  1. 1.Department of NeurosurgeryOphir Loyola HospitalBelémBrazil
  2. 2.Human Cytogenetics LaboratoryFederal University of ParáBelémBrazil
  3. 3.Genetics and Molecular Biology LaboratoryFederal University of PiauíParnaíbaBrazil
  4. 4.Research Unit, Unidad de InvestigaciónHospital Universiatrio La PazMadridSpain

Personalised recommendations