A microarray-based DNA methylation study of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. The presence of epigenetic lesions, like hypermethylation of known tumor suppressor genes such as MGMT, has been widely described in GBM, but to our knowledge, a genome-wide profile of DNA methylation changes in these lethal tumors is not yet available. In the present analysis, we have quantified the DNA methylation level of 1,505 CpG dinucleotides (807 genes) in 87 consecutive GBMs using universal BeadArrays. Supervised cluster analyses identified 25 and seven genes that were respectively hypermethylated and hypomethylated in more than 20% of the cases studied. The most frequently hypermethylated genes were HOXA11, CD81, PRKCDBP, TES, MEST, TNFRSF10A and FZD9, being involved in more than half of the cases. Studying the biological features of hypermethylated genes, we found that the group of genes hypermethylated in GBM was highly enriched (41%, P

[1]  P. Laird,et al.  Epigenetic stem cell signature in cancer , 2007, Nature Genetics.

[2]  J. Vonesch,et al.  Disruption of the interaction between transcriptional intermediary factor 1{beta} and heterochromatin protein 1 leads to a switch from DNA hyper- to hypomethylation and H3K9 to H3K27 trimethylation on the MEST promoter correlating with gene reactivation. , 2009, Molecular biology of the cell.

[3]  Y. Tomizawa,et al.  Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors , 2003, Oncogene.

[4]  Gabriele Schackert,et al.  CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. , 2007, Carcinogenesis.

[5]  I. Simon,et al.  Evidence for an instructive mechanism of de novo methylation in cancer cells , 2006, Nature Genetics.

[6]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[7]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[8]  Bekim Sadikovic,et al.  Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. , 2009, Human molecular genetics.

[9]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[10]  K Walsh,et al.  The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals. , 1996, Genomics.

[11]  C. Caslini,et al.  Histone modifications silence the GATA transcription factor genes in ovarian cancer , 2006, Oncogene.

[12]  Stephan Sauer,et al.  Chromatin signatures of pluripotent cell lines , 2006, Nature Cell Biology.

[13]  Reto Meuli,et al.  Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D Bentley,et al.  Highly parallel SNP genotyping. , 2003, Cold Spring Harbor symposia on quantitative biology.

[15]  C. O'keefe,et al.  Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. , 2009, Blood.

[16]  T. Roszman,et al.  Immune defects observed in patients with primary malignant brain tumors , 1999, Journal of Neuroimmunology.

[17]  E. Budinská,et al.  Screening of genomic imbalances in glioblastoma multiforme using high-resolution comparative genomic hybridization. , 2007, Oncology reports.

[18]  Wei Jiang,et al.  High-throughput DNA methylation profiling using universal bead arrays. , 2006, Genome research.

[19]  M. Lishner,et al.  Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  Vitaly L. Galinsky,et al.  Automatic registration of microarray images. II. Hexagonal grid , 2003, Bioinform..

[21]  K. Schuebel,et al.  CIMPle origin for promoter hypermethylation in colorectal cancer? , 2006, Nature Genetics.

[22]  C. Hawkins,et al.  GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model , 2007, Proceedings of the National Academy of Sciences.

[23]  A. Bowcock,et al.  Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers. , 2001, Cancer research.

[24]  R. Spang,et al.  New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. , 2009, Blood.

[25]  Martin Widschwendter,et al.  HOXA11 DNA methylation—A novel prognostic biomarker in ovarian cancer , 2008, International journal of cancer.

[26]  Jae Hyuk Lee,et al.  Lack of death receptor 4 (DR4) expression through gene promoter methylation in gastric carcinoma , 2009, Langenbeck's Archives of Surgery.

[27]  Elizabeth Eisenhauer,et al.  Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. , 2008, The Lancet. Oncology.

[28]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[29]  D. Louis,et al.  Downregulation of RUNX3 and TES by hypermethylation in glioblastoma , 2007, Oncogene.

[30]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[31]  D P Byar,et al.  Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. , 1980, The New England journal of medicine.

[32]  Matty P. Weijenberg,et al.  A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer , 2002, Nature Genetics.

[33]  Kelly M. McGarvey,et al.  A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing , 2007, Nature Genetics.

[34]  J. Squire,et al.  Molecular cytogenetic analysis in the study of brain tumors: findings and applications. , 2005, Neurosurgical focus.

[35]  J. McNamara.  Cancer Stem Cells , 2007, Methods in Molecular Biology.

[36]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[37]  A. Guha,et al.  Expression of GATA6 in the human and mouse central nervous system. , 2005, Brain research. Developmental brain research.

[38]  M. Esteller.  CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future , 2002, Oncogene.

[39]  Erwin G. Van Meir,et al.  Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma. , 2004, The American journal of pathology.

[40]  Agnieszka Bronisz,et al.  Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. , 2008, Cancer research.

[41]  M. Lishner,et al.  Promoter hypermethylation of tetraspanin members contributes to their silencing in myeloma cell lines. , 2005, Carcinogenesis.

[42]  S. Chi,et al.  Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses , 2007, International journal of cancer.

[43]  Y. Yonekawa,et al.  p14ARF Deletion and Methylation in Genetic Pathways to Glioblastomas , 2001, Brain pathology.

[44]  E. Tobias,et al.  The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein , 2001, Oncogene.

[45]  Gang Meng,et al.  Changes in genomic imprinting and gene expression associated with transformation in a model of human osteosarcoma. , 2008, Experimental and molecular pathology.

[46]  Vitaly L. Galinsky,et al.  Automatic registration of microarray images. I. Rectangular grid , 2003, Bioinform..

[47]  Y. Yuasa,et al.  Involvement of GATA-4/-5 transcription factors in ovarian carcinogenesis. , 2006, Cancer letters.

[48]  C. Abate-Shen.  Homeobox genes and cancer: new OCTaves for an old tune. , 2003, Cancer cell.

[49]  Jo Handelsman,et al.  EPIGENETIC REGULATION OF CELLULAR MEMORY BY THE POLYCOMB AND TRITHORAX GROUP PROTEINS , 2008 .

[50]  Zohar Yakhini,et al.  Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer , 2007, Nature Genetics.

[51]  M. Katoh,et al.  WNT Signaling Pathway and Stem Cell Signaling Network , 2007, Clinical Cancer Research.

[52]  O. Wiestler,et al.  Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. , 2005, Neoplasia.

[53]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[54]  Edward Gabrielson,et al.  Hypermethylation of the GATA Genes in Lung Cancer , 2004, Clinical Cancer Research.