Prognostic relevance of c-Myc and BMI1 expression in patients with glioblastoma.

Although the c-Myc oncogene is frequently deregulated in human cancer, its involvement in the pathogenesis of glioblastoma is not clear. We conducted immunohistochemical analysis of the expression of c-Myc, polycomb ring finger oncogene (BMI1), and acetylation of the lysine 9 (H3K9Ac) of histone 3 in 48 patients with glioblastoma who underwent surgery followed by radiotherapy and temozolomide treatment. The expression of c-Myc, BMI1, and H3K9ac was correlated with clinical characteristics and outcome. We found that overexpression of c-Myc was significantly associated with that of BMI1 (P = .009), and that patients who harbored glioblastomas overexpressing c-Myc and BMI1 showed significantly longer overall survival (P < .0001 and P = .0009, respectively). Our results provide the first evidence of the prognostic value of c-Myc and associated genes in patients with glioblastoma. The favorable effect of c-Myc and BMI1 expression on survival is likely mediated by the sensitization of cancer cells to radiotherapy and temozolomide through the activation of apoptotic pathways.

[1]  B. Turner,et al.  Transcription factors, chromatin and cancer. , 2009, The international journal of biochemistry & cell biology.

[2]  G. Reifenberger,et al.  The WHO Classification of Tumors of the Nervous System , 2002, Journal of neuropathology and experimental neurology.

[3]  E. Markakis,et al.  c-myc oncogene family expression in glioblastoma and survival. , 1999, Surgical neurology.

[4]  J. Štěrba,et al.  Low-level copy number changes of MYC genes have a prognostic impact in medulloblastoma , 2011, Journal of Neuro-Oncology.

[5]  M. Lohuizen,et al.  Stem Cells and Cancer The Polycomb Connection , 2004, Cell.

[6]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[7]  G. Evan,et al.  The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy , 2011, PloS one.

[8]  A. Kaye,et al.  Overexpression of multiple oncogenes related to histological grade of astrocytic glioma. , 1992, British Journal of Cancer.

[9]  L. Soucek,et al.  Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. , 2002, Cancer research.

[10]  C. Faria,et al.  Pediatric brain tumors: genetics and clinical outcome. , 2010, Journal of neurosurgery. Pediatrics.

[11]  L. Ricci-Vitiani,et al.  Cancer Stem Cell Analysis and Clinical Outcome in Patients with Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[12]  B. Seifert,et al.  c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients , 2011, BMC Cancer.

[13]  S. Joos,et al.  Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  R. Pallini,et al.  Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme , 2008, International journal of cancer.

[15]  A. Paetau,et al.  Stem cell protein BMI‐1 is an independent marker for poor prognosis in oligodendroglial tumours , 2008, Neuropathology and applied neurobiology.

[16]  P. Liberski,et al.  Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma , 2010, Child's Nervous System.

[17]  Goberdhan P Dimri,et al.  Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins. , 2006, Molecular biology of the cell.

[18]  Y. Tamaki,et al.  Association between c-myc amplification and pathological complete response to neoadjuvant chemotherapy in breast cancer. , 2011, European journal of cancer.

[19]  M. Lohuizen,et al.  Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas , 2004, Nature.

[20]  Michael D. Cole,et al.  Transcription-independent functions of MYC: regulation of translation and DNA replication , 2008, Nature Reviews Molecular Cell Biology.

[21]  S. Marino,et al.  Bmi1 in development and tumorigenesis of the central nervous system , 2005, Journal of Molecular Medicine.

[22]  Shirley Wu,et al.  Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a). , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  I. D'Agnano,et al.  Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells , 2011, International journal of radiation biology.

[24]  B. Gonçalves,et al.  Expression of Ki‐67, Topoisomerase IIα and c‐MYC in astrocytic tumors: Correlation with the histopathological grade and proliferative status , 2006, Neuropathology : official journal of the Japanese Society of Neuropathology.

[25]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[26]  E. Guccione,et al.  Analysis of Myc-Induced Histone Modifications on Target Chromatin , 2008, PloS one.

[27]  E. Hölttä,et al.  Caspase-8, c-FLIP, and caspase-9 in c-Myc-induced apoptosis of fibroblasts. , 2011, Experimental cell research.

[28]  K Kornfeld,et al.  Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. , 1999, Genes & development.

[29]  M. Lohuizen,et al.  The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression , 2001, British Journal of Cancer.

[30]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[31]  G. Bernier,et al.  BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal , 2009, The Journal of Neuroscience.

[32]  M. Kool,et al.  Molecular Risk Stratification of Medulloblastoma Patients Based on Immunohistochemical Analysis of MYC, LDHB, and CCNB1 Expression , 2008, Clinical Cancer Research.

[33]  Z. Cai,et al.  Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients. , 2012, Cancer epidemiology.

[34]  Chi V. Dang,et al.  c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism , 1999, Molecular and Cellular Biology.

[35]  奈々 佐々木.  Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression , 2013 .

[36]  E. Campo,et al.  BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. , 2001, Cancer research.

[37]  A. Merlo,et al.  GSK3β Regulates Differentiation and Growth Arrest in Glioblastoma , 2009, PloS one.