Worse outcome in primary glioblastoma multiforme with concurrent epidermal growth factor receptor and p53 alteration.

Primary glioblastoma multiforme (GBM), in contrast with secondary GBM, has been associated with the presence of EGFR amplification and absence of p53 mutation. In this study, we analyzed relevant molecular and clinical variables in 194 primary GBMs and tested them for survival analysis. Although most of the tumors showed a mutually exclusive pattern, concurrent alterations of EGFR and p53 were detected. Survival analysis of CDK4 amplification revealed a highly significant association with a worse clinical outcome (P = .01), whereas MDM2, CDK6, PTEN, and p21 were not associated with patient survival. Multivariate analysis including the significant clinical and molecular variables revealed CDK4 amplification, age, and radiotherapy to be markers with independent prognostic value. In addition, the primary GBM tumors showing simultaneous EGFR and p53 alterations were significantly associated with worse survival (P < .01). These results highlight the prognostic value of CDK4 amplification and of simultaneous EGFR-p53 alterations in the clinical outcome of patients with primary GBM.

[1]  Pedro Martínez,et al.  Identification of survival‐related genes of the phosphatidylinositol 3′‐kinase signaling pathway in glioblastoma multiforme , 2008, Cancer.

[2]  D. Caldiroli,et al.  Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. , 2008, Neuro-oncology.

[3]  G. Kapoor,et al.  EGFR inhibition in glioblastoma cells induces G2/M arrest and is independent of p53 , 2007, Cancer Biology & Therapy.

[4]  K. Nishio,et al.  Identification of expressed genes characterizing long-term survival in malignant glioma patients , 2006, Oncogene.

[5]  Pedro Martínez,et al.  Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling , 2006, Molecular Cancer.

[6]  F. Yamasaki,et al.  Prognosis of cerebellar glioblastomas: correlation between prognosis and immunoreactivity for epidermal growth factor receptor compared with supratentorial glioblastomas. , 2006, Anticancer research.

[7]  M. Berger,et al.  Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. , 2005, Journal of the National Cancer Institute.

[8]  J. Schlegel,et al.  Expression of p53 and p21 in Primary Glioblastomas , 2005, Strahlentherapie und Onkologie.

[9]  Alona Muzikansky,et al.  The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Daniel J Brat,et al.  Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma , 2004, Laboratory Investigation.

[11]  Chan Zeng,et al.  Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Catherine L Nutt,et al.  Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas. , 2003, Cancer research.

[13]  Motoo Nagane,et al.  Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. , 2002, Cancer research.

[14]  C. Marosi,et al.  Prognostic relevance of p53 protein expression in glioblastoma. , 2002, Oncology reports.

[15]  M. C. Lee,et al.  p53 mutation and epidermal growth factor receptor overexpression in glioblastoma. , 2001, Journal of Korean medical science.

[16]  Anne Jedlicka,et al.  Glioblastoma-related gene mutations and over-expression of functional epidermal growth factor receptors in SKMG-3 glioma cells , 2001, Acta Neuropathologica.

[17]  Susan M. Chang,et al.  Glioblastoma Patients Epidermal Growth Factor Receptor , and Survival in Analysis of Complex Relationships between Age , p 53 , Updated , 2001 .

[18]  P. Ohneseit,et al.  Analysis of mdm2 and p53 Gene Alterations in Glioblastomas and its Correlation with Clinical Factors , 2000, Journal of Neuro-Oncology.

[19]  K. Ichimura,et al.  Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. , 2000, Cancer research.

[20]  Linet,et al.  RESPONSE: re: brain and other central nervous system cancers: recent trends in incidence and mortality , 1999, Journal of the National Cancer Institute.

[21]  B. Scheithauer,et al.  Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas. , 1999, American journal of clinical pathology.

[22]  H. Moch,et al.  Tissue microarrays for gene amplification surveys in many different tumor types. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  Douglas C. Miller,et al.  Survival of Patients with Glioblastoma Multiforme is not Influenced by Altered Expression of P16, P53, EGFR, MDM2 or Bcl‐2 Genes , 1998, Brain pathology.

[24]  P. Forsyth,et al.  Long-term Glioblastoma Multiforme Survivors: a Population-based Study , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[25]  Yasuhiro Yonekawa,et al.  Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas , 1997, Acta Neuropathologica.

[26]  B. Iacopetta,et al.  A rapid and nonisotopic method for the screening and sequencing of p53 gene mutations in formalin-fixed, paraffin-embedded tumors. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[27]  G. Reifenberger,et al.  Analysis of p53 Mutation and Epidermal Growth Factor Receptor Amplification in Recurrent Gliomas with Malignant Progression , 1996, Journal of neuropathology and experimental neurology.

[28]  Y. Yonekawa,et al.  Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. , 1996, Brain pathology.

[29]  D. Louis,et al.  A tiger behind many doors: multiple genetic pathways to malignant glioma. , 1995, Trends in genetics : TIG.

[30]  Y. Soini,et al.  p53 immunohistochemical positivity as a prognostic marker in intracranial tumours , 1994, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[31]  M. Piris,et al.  The expression of p53 protein in non-Hodgkin's lymphomas is not always dependent on p53 gene mutations. , 1993, Blood.

[32]  R. Perry,et al.  Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. , 1992, British Journal of Cancer.

[33]  E. B. Jackson,et al.  Effects of Colchicine and Radiation on Growth of Normal Tissues and Tumors , 1940 .

[34]  D. Louis WHO classification of tumours of the central nervous system , 2007 .

[35]  M. Hirata,et al.  Whole-genome analysis of human astrocytic tumors by comparative genomic hybridization , 2006, Brain Tumor Pathology.

[36]  H. Mehdorn,et al.  Age-related Expression of p53, Mdm2, EGFR and Msh2 in Glioblastoma Multiforme , 2003, Zentralblatt fur Neurochirurgie.

[37]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[38]  E F Heineman,et al.  Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality. , 1999, Journal of the National Cancer Institute.

[39]  P. Kleihues,et al.  Primary and secondary glioblastomas: from concept to clinical diagnosis. , 1999, Neuro-oncology.

[40]  P. Korkolopoulou,et al.  MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. , 1997, British Journal of Cancer.