|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Retrospective Clinical Study |
Department of Neuroscience, University of Turin, 10126 Turin, Italy
2 Address correspondence and reprint requests to Maria Teresa Giordana, Department of Neuroscience, University of Turin, Via Cherasco 15, 10126 Torino, Italy; mariateresa.giordana{at}unito.it.
Abstract
In adult medulloblastoma, postoperative radiotherapy is significantly effective in prolonging time to recurrence and survival time; however, the response of individual cases to radiotherapy, that is the total survival, is different. Apoptosis is an important cellular response to radiation. It can be hypothesized that the individual radiosensitivity of medulloblastomas depends on the individual capability to undergo apoptosis. p53 protein is involved in the apoptotic response to ionizing radiation; loss of function of p53 can be the consequence not only of TP53 mutations, but also of amplification and/or overexpression of the MDM2 gene. We have analyzed cerebellar medulloblastomas from 51 adults (>16 years of age) for MDM2 gene amplification (by differential polymerase chain reaction assay), TP53 gene mutation (by polymerase chain reaction single-strand conformation polymorphism analysis of exons 5-8), and immunohistochemical expression of p53 (clone DO1) and MDM2 (clone IF2). The results have been evaluated in relation to age, tumor location, classic or desmoplastic type, MIB-1 labeling index, and total survival. No tumor had MDM2 amplification. Ten tumors had MDM2-positive tumor cells. One case had a mutated TP53 gene; 16/51 cases had intense p53 immunostaining. Only 2 MDM2 protein-positive tumors were also p53-positive. Both subgroups of MDM2- and p53-positive tumors had a significantly shorter postoperative survival. In conclusion, the overexpression of MDM2 protein and the accumulation of wild-type p53 are unrelated in adult medulloblastoma; they may result in a reduced apoptotic response after radiotherapy and contribute to a shortened survival. Also, MDM2 amplification and TP53 gene mutation are rare events in medulloblastomas of adults.
References
Adesina, A.M., Nalbantoglu, J., and Cavenee, W.K.
(1994) p53 gene mutation and mdm2 gene aqmplification are
uncommon in medulloblastoma. Cancer Res.
54,5649
-5651.
Batra, S.K., McLendon, R.E., Koo, J.S., Castelino-Prabhu, S., Fuchs, H.E., Krisher, J.P., Friedman, H.S., Bigner, D.D., and Bigner, S.H. (1995) Prognostic implications of chromosome 17p deletions in human medulloblastomas. J. Neurooncol. 24, 39-45.[CrossRef][Medline]
Biernat, W., Kleihues, P., Yonekawa, Y., and Ohgaki, H. (1997) Amplification and overexpression of MDM2 in primary (de novo) glioblastomas. J. Neuropathol. Exp. Neurol. 56,180 -185.[Web of Science][Medline]
Bloom, H.J., and Bessel, E.M. (1990) Medulloblastoma in adults: A review of 47 patients treated between 1952 and 1981. Int. J. Radiat. Oncol. Biol. Phys. 18,763 -772.[Web of Science][Medline]
Carrie, C., Lasset, C., Alapetite, C., Haie-Meder, C., Hoffstetter, S., Demaille, M.C., Kerr, C., Wagner, J.P., Lagrange, J.L., Maire, J.P., Seng, S.H., Kong Mao, Y.O.C.T., Muracciole, X., and Pinto, N. (1994) Multivariate analysis of prognostic factors in adult patients with medulloblastoma: Retrospective study of 156 patients. Cancer 74,2352 -2360.[CrossRef][Web of Science][Medline]
Chan, A.W., Tarbell, N.J., Black, P.M., Louis, D.N., Frosch, M.P., Ancukiewicz, M., Chapman, P., and Loeffler, J.S. (2000) Adult medulloblastoma: Prognostic factors and patterns of relapse. Neurosurgery 47,623 -632.[CrossRef][Web of Science][Medline]
Cordon-Cardo, C., Latres, E., Drobnjak, M., Oliva, M.R., Pollack,
D., Woodruff, J.M., Marechal, V., Chen, J.D., Brennan, M.F., and Levine, A.J.
(1994) Molecular abnormalities of mdm2 and p53 genes in adult
soft tissue sarcomas. Cancer Res.
54,794
-799.
Dee, S., Haas-Kogan, D.A., and Israel, M.A. (1995) Inactivation of p53 is associated with decreased levels of radiation-induced apoptosis in medulloblastoma cell lines. Cell Death Differ. 2,267 -275.
Finlay, A.C., Hinds, P.W., and Levine, A.J. (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57,1083 -1093.[CrossRef][Web of Science][Medline]
Giordana, M.T., Cavalla, P., Chiò, A., Marino, S., Soffietti, R., Vigliani, M.C., and Schiffer, D. (1995) Prognostic factors in adult medulloblastoma: A clinico-pathologic study. Tumori 81,338 -346.[Web of Science][Medline]
Giordana, M.T., Cavalla, P., Dutto, A., Borsotti, L., Chiò, A., and Schiffer, D. (1997) Is medulloblastoma the same tumor in children and adults? J. Neurooncol. 35,169 -176.[CrossRef][Medline]
Hartsell, W.F., Montag, A.G., Lydon, J., Galinsky, D.L., and Sarin, P. (1992) Treatment of medulloblastoma in adults. Am. J. Clin. Oncol. 15,207 -211.[Web of Science][Medline]
Haupt, Y., Barak, Y., and Oren, M. (1996) Cell type-specific inhibition of p53-mediated apoptosis by mdm2. EMBO J. 15,1596 -1606.[Web of Science][Medline]
Iggo, R., Gatter, K., Bartek, J., Lane, D., and Harris, A.L. (1990) Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 335,675 -679.[CrossRef][Web of Science][Medline]
Kaplan, E.L., and Meier, P. (1958) Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53,457 -481.[CrossRef][Web of Science]
Korkolopoulou, P., Christodoulou, P., Kouzelis, K., Hadjiyannakis, M., Priftis, A., Stamoulis, G., Seretis, A., and Thomas-Tsagli, E. (1997) MDM2 and p53 expression in gliomas: A multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br. J. Cancer 75,1269 -1278.[Web of Science][Medline]
Kubbutat, M.H.G., Jones, S.N., and Vousden, K.H. (1997) Regulation of p53 stability by Mdm2. Nature 387,299 -303.[CrossRef][Medline]
Kunschner, L.J., Kuttesch, J., Hess, K., and Yung, W.K.A. (2001) Survival and recurrence factors in adult medulloblastoma: The M.D. Anderson Cancer Center experience from 1978 to 1998. Neuro-Oncology [serial online], Doc. 99-058, May 15, 2001. URL http://neuro-oncology.mc.duke.edu. Neuro-Oncology 3,167 -173.[Abstract]
Kyritsis, A.P., and Saya, H. (1993) Epidemiology, cytogenetics, and molecular biology of brain tumors. Curr. Opin. Oncol. 5,474 -480.[Medline]
Landers, J.E., Haines, D.S., Strauss, J.F., III, and George, D.L. (1994) Enhanced translation: A novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene 9,2745 -2750.[Web of Science][Medline]
Lang, F.F., Miller, D.C., Koslow, M., and Newcomb, E.W. (1994) Pathways leading to glioblastoma multiforme: A molecular analysis of genetic alterations in 65 astrocytic tumors. J. Neurosurg. 81,427 -436.[Web of Science][Medline]
Maki, C.G., Huibregtse, J., and Howley, P.M. (1996) In
vivo ubiquitination and proteosome-mediated degradation of p53.
Cancer Res. 56,2649
-2654.
Momand, J., Zambetti, G.P., Olson, D.C., George, D., and Levine, A.J. (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69,1237 -1245.[CrossRef][Web of Science][Medline]
Ohkoudo, M., Sawa, H., Hara, M., Saruta, K., Aiso, T., Ohki, R., Yamamoto, H., Maemura, E., Shiina, Y., Fujii, M., and Saitu, T (1998) Expression of p53, MDM2 protein, and Ki-67 antigen in recurrent meningiomas. J. Neurooncol. 38, 41-49.[CrossRef][Medline]
Packer, R.J., Sutton, L.N., Elterman, R., Lange, B., Goldwein, J., Nicholson, H.S., Mulne, L., Boyett, J., D'Angio, G., Wechsler-Jentzsch, K., Reaman, G., Cohem, B.H., Bruce, D.A., Rorke, L.B., Molloy, P., Ryan, J., LaFond, D., Evans, A.E., and Schut, L. (1994) Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J. Neurosurg. 81,690 -698.[Web of Science][Medline]
Peto, R., Pike, M.G., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., McPherson, K., Peto, J., and Smith, P.G. (1977) Design and analysis of randomized clinical trials requiring prolonged observations of each patient: Analysis and examples. Br. J. Cancer 35,1 -39.[Web of Science][Medline]
Piva, R., Cavalla, P., Bortolotto, S., Cordera, S., Grosso, R., Richiardi, P., Dutto, A., and Schiffer, D. (1998) CDKN2/p16 inactivation and p16 immunohistochemistry in astrocytic gliomas. Int. J. Oncol. 12,55 -58.[Web of Science][Medline]
Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E.E., and
Collins, V.P. (1993) Amplification and overexpression of the MDM2
gene in a subset of human malignant gliomas without p53 mutations.
Cancer. Res. 53,2736
-2739.
Reifenberger, G., Reifenberger, J., Ichimura, K., and Collins, V.P.
(1995) Amplification at 12q13-14 in human malignant gliomas is
frequently accompanied by loss of heterozygosity at loci proximal and distal
to the amplification site. Cancer Res.
55,731
-734.
Riemenschneider, M.J., Buschges, R., Wolter, M., Reifenberger, J.,
Bostrom, J., Kraus, J.A., Schlegel, U., and Reifenberger, G.
(1999) Amplification and overexpression of the MDM4 (MDMX) gene
from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2
amplification. Cancer Res.
59,6091
-6096.
Schiebe, M., Ohneseit, P., Hoffmann, W., Meyermann, R., Rodemann, H.P., and Bamberg, M. (2000) Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. J. Neurooncol. 49,197 -203.[CrossRef][Medline]
Woodburn, R.T., Azzarelli, B., Montebello, J.F., and Goss, I.E. (2001) Intense p53 staining is a valuable prognostic indicator for poor prognosis in medulloblastoma/central nervous system primitive neuroectodermal tumors. J. Neurooncol. 52, 57-62., 832-845.[CrossRef][Medline]
Zeltzer, P.M., Boyett, J.M., Finlay, J.T., Albright, A.L., Rorke,
L.B., Mulstein, J.M., Allen, J.C., Stevens, K.R., Stanley, P., Li, H., Wisoff,
J.H., Geyer, J.R., McGuire-Cullen, P., Stehbens, J.A., Shurin, S.B., and
Packer, R.J. (1999) Metastasis stage, adjuvant therapy, 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
-845.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  P.-O. Frappart, Y. Lee, H. R. Russell, N. Chalhoub, Y.-D. Wang, K. E. Orii, J. Zhao, N. Kondo, S. J. Baker, and P. J. McKinnon Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency PNAS, February 10, 2009; 106(6): 1880 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. de Bont, R. J. Packer, E. M. Michiels, M. L. d. Boer, and R. Pieters Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective Neuro-oncol, January 1, 2008; 10(6): 1040 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Shakhova, C. Leung, E. van Montfort, A. Berns, and S. Marino Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of N-Myc and Ptch2. Cancer Res., May 15, 2006; 66(10): 5190 - 5200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lee, H. L. Miller, P. Jensen, R. Hernan, M. Connelly, C. Wetmore, F. Zindy, M. F. Roussel, T. Curran, R. J. Gilbertson, et al. A Molecular Fingerprint for Medulloblastoma Cancer Res., September 1, 2003; 63(17): 5428 - 5437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Q. Yang, D. Senger, H. Muzik, Z. Q. Shi, D. Johnson, P. M. A. Brasher, N. B. Rewcastle, M. Hamilton, J. Rutka, J. Wolff, et al. Reovirus Prolongs Survival and Reduces the Frequency of Spinal and Leptomeningeal Metastases from Medulloblastoma Cancer Res., June 15, 2003; 63(12): 3162 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Eberhart Medulloblastoma in Mice Lacking p53 and PARP: All Roads Lead To Gli Am. J. Pathol., January 1, 2003; 162(1): 7 - 10. [Full Text] [PDF]
|
|
|
|
|
|
Y. Lee and P. J. McKinnon DNA Ligase IV Suppresses Medulloblastoma Formation Cancer Res., November 15, 2002; 62(22): 6395 - 6399. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
