Candidate glioblastoma development gene identification using concordance between copy number abnormalities and gene expression level changes

Copy number abnormalities (CNAs) in tumor cells are presumed to affect expression levels of genes located in region of abnormality. To investigate this relationship we have surveyed the losses, gains and amplifications in 30 glioblastomas using array comparative genome hybridization and compared these data with gene expression changes in the same tumors using the Affymetrix U133Plus2.0 oligonucleotide arrays. The two datasets were overlaid using our in‐house overlay tool which highlights concordance between CNAs and expression level changes for the same tumors. In this survey we have highlighted genes frequently overexpressed in amplified regions on chromosomes 1, 4, 11, and 12 and have identified novel amplicons on these chromosomes. Deletions of specific regions on chromosomes 9, 10, 11, 14, and 15 have also been correlated with reduced gene expression in the regions of minimal overlap. In addition we describe a novel approach for comparing gene expression levels between tumors based on the presence or absence of chromosome CNAs. This genome wide screen provides an efficient and comprehensive survey of genes which potentially serve as the drivers for the CNAs in GBM. © 2007 Wiley‐Liss, Inc.

[1]  Michael R Rossi,et al.  Identification of consistent novel submegabase deletions in low‐grade oligodendrogliomas using array‐based comparative genomic hybridization , 2005, Genes, chromosomes & cancer.

[2]  Naoki Kagawa,et al.  Genetic analysis of human glioblastomas using a genomic microarray system , 2006, Brain Tumor Pathology.

[3]  T. Furuya,et al.  Genomic alterations detected by comparative genomic hybridization in primary lung adenocarcinomas with special reference to the relationship with DNA ploidy. , 2005, Oncology reports.

[4]  J. Cowell,et al.  Molecular definition of chromosome translocations involving 10q24 and 19q13 in human malignant glioma cells. , 1998, Cancer genetics and cytogenetics.

[5]  Yves Moreau,et al.  Benchmarking the CATMA Microarray. A Novel Tool forArabidopsis Transcriptome Analysis1[w] , 2005, Plant Physiology.

[6]  E Stubblefield,et al.  Analysis of the functional role of chromosome 10 loss in human glioblastomas. , 1993, Cancer research.

[7]  D. Louis,et al.  Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomas. , 1996, Cancer research.

[8]  Charles B. Wilson,et al.  Brain Tumor Working Group Report on the 9th International Conference on Brain Tumor Research and Therapy , 1993, Journal of Neuro-Oncology.

[9]  D. Bigner,et al.  Specific chromosomal abnormalities in malignant human gliomas. , 1988, Cancer research.

[10]  K. Kinzler,et al.  Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[11]  I. Giannopoulou,et al.  Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome. , 2002, Cancer genetics and cytogenetics.

[12]  L. Hawthorn,et al.  Characterization of cell-type specific profiles in tissues and isolated cells from squamous cell carcinomas of the lung. , 2006, Lung cancer.

[13]  R. Gascoyne,et al.  Non‐muscle myosin heavy chain (MYH9): A new partner fused to ALK in anaplastic large cell lymphoma , 2003, Genes, chromosomes & cancer.

[14]  Michael R. Rossi,et al.  Overlay Tool© for aCGHViewer©: An Analysis Module Built for aCGHViewer© used to Perform Comparisons of Data Derived from Different Microarray Platforms , 2007, Cancer informatics.

[15]  B. Feuerstein,et al.  Chromosomal imbalances detected by array comparative genomic hybridization in human oligodendrogliomas and mixed oligoastrocytomas , 2005, Genes, chromosomes & cancer.

[16]  John Quackenbush,et al.  Multiple-laboratory comparison of microarray platforms , 2005, Nature Methods.

[17]  O. Volpert,et al.  Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1. , 2002, Cancer cell.

[18]  S. Wiseman,et al.  TIMP1 and SERPIN‐A overexpression and TFF3 and CRABP1 underexpression as biomarkers for papillary thyroid carcinoma , 2004, Head & neck.

[19]  A. Ligon,et al.  Two tumor suppressive loci on chromosome 10 involved in human glioblastomas , 1995, Genes, chromosomes & cancer.

[20]  Jee-Yin Ahn,et al.  PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Carlos Cordon-Cardo,et al.  Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  S. Horvath,et al.  Gene Expression Profiling of Gliomas Strongly Predicts Survival , 2004, Cancer Research.

[23]  N. Nowak,et al.  Molecular characterization of a consistent 4.5-megabase deletion at 4q28 in prostate cancer cells. , 2005, Cancer genetics and cytogenetics.

[24]  Bryan Frank,et al.  Independence and reproducibility across microarray platforms , 2005, Nature Methods.

[25]  T. Efferth,et al.  Specific patterns of DNA copy number gains and losses in eight new glioblastoma multiforme cell lines. , 2003, International journal of oncology.

[26]  J. Hoheisel.  Microarray technology: beyond transcript profiling and genotype analysis , 2006, Nature Reviews Microbiology.

[27]  G. Amann,et al.  Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical analysis for tissue microarrays. , 2006, American journal of clinical pathology.

[28]  N. Fusenig,et al.  Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[29]  Yan A. Su,et al.  Characterization of a highly conserved gene (OS4) amplified with CDK4 in human sarcomas , 1997, Oncogene.

[30]  L. Hawthorn,et al.  Novel amplicons on the short arm of chromosome 7 identified using high resolution array CGH contain over expressed genes in addition to EGFR in glioblastoma multiforme , 2005, Genes, chromosomes & cancer.

[31]  T. Shiraishi,et al.  Detrended fluctuation analysis of genome-wide copy number profiles of glioblastomas using array-based comparative genomic hybridization. , 2004, Neuro-oncology.

[32]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[33]  N. Nowak,et al.  Application of bacterial artificial chromosome array-based comparative genomic hybridization and spectral karyotyping to the analysis of glioblastoma multiforme. , 2004, Cancer genetics and cytogenetics.

[34]  H. Ng,et al.  Chromosome 14q may harbor multiple tumor suppressor genes in primary glioblastoma multiforme. , 2002, Chinese medical journal.

[35]  R. Natrajan,et al.  High-resolution deletion mapping of 15q13.2-q21.1 in transitional cell carcinoma of the bladder. , 2003, Cancer research.

[36]  L. Guarente,et al.  What Makes Us Tick? , 1997, Science.

[37]  Philip M. Long,et al.  Breast cancer classification and prognosis based on gene expression profiles from a population-based study , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  L. Hawthorn,et al.  LGI1, a Putative Tumor Metastasis Suppressor Gene, Controls in Vitro Invasiveness and Expression of Matrix Metalloproteinases in Glioma Cells through the ERK1/2 Pathway* , 2004, Journal of Biological Chemistry.

[39]  Hermona Soreq,et al.  Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin , 1985, Nature.

[40]  A. Lindahl,et al.  Expression of genes involved in the regulation of p16 in psoriatic involved skin , 2006, Archives of Dermatological Research.

[41]  D. Pinkel,et al.  Analyses of brain tumor cell lines confirm a simple model of relationships among fluorescence in situ hybridization, DNA index, and comparative genomic hybridization , 1997, Genes, chromosomes & cancer.

[42]  K. Ogasawara,et al.  Detection of gene amplification and deletion in high-grade gliomas using a genome DNA microarray (GenoSensor Array 300) , 2006, Brain Tumor Pathology.

[43]  L. Meltesen,et al.  Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4--anaplastic lymphoma kinase gene fusion. , 2001, Blood.

[44]  M. Imagawa,et al.  Crucial Role of TCL/TC10βL, a Subfamily of Rho GTPase, in Adipocyte Differentiation* , 2003, The Journal of Biological Chemistry.

[45]  Ruben Abagyan,et al.  Match-Only Integral Distribution (MOID) Algorithm for high-density oligonucleotide array analysis , 2002, BMC Bioinformatics.

[46]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[47]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[48]  D. Toncheva,et al.  Association of 20q13.2 copy number changes with the advanced stage of ovarian cancer-tissue microarray analysis. , 2005, European journal of obstetrics, gynecology, and reproductive biology.

[49]  T. Poggio,et al.  Prediction of central nervous system embryonal tumour outcome based on gene expression , 2002, Nature.

[50]  Felix Naef,et al.  Empirical characterization of the expression ratio noise structure in high-density oligonucleotide arrays , 2002, Genome Biology.

[51]  S. Seal,et al.  Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. , 1999, Gastroenterology.

[52]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[53]  P. Meltzer,et al.  Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. , 1994, Cancer research.

[54]  P. Fort,et al.  Characterization of TCL, a New GTPase of the Rho Family related to TC10 and Cdc42* 210 , 2000, The Journal of Biological Chemistry.

[55]  R. Mccomb,et al.  Pathology and Genetics of Tumours of the Nervous System , 1998 .

[56]  Bin Tean Teh,et al.  A molecular classification of papillary renal cell carcinoma. , 2005, Cancer research.

[57]  Alec C. Kimmelman,et al.  Loss of heterozygosity of chromosome 10p in human gliomas. , 1996, Genomics.

[58]  B. Scheithauer,et al.  The New WHO Classification of Brain Tumours , 1993, Brain pathology.

[59]  I. Petersen,et al.  Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. , 1996, Oncogene.

[60]  C. Marosi,et al.  Immunohistochemical Analysis of Platelet-derived Growth Factor Receptor-α, -β, c-kit, c-abl, and Arg Proteins in Glioblastoma: Possible Implications for Patient Selection for Imatinib Mesylate Therapy , 2005, Journal of Neuro-Oncology.

[61]  T. Tominaga,et al.  Deletion Mapping of Chromosome 10 in Human Glioma , 1996, Japanese journal of cancer research : Gann.

[62]  G. Reifenberger,et al.  Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target , 2003, International journal of cancer.

[63]  S. Pomeroy,et al.  Overlay analysis of the oligonucleotide array gene expression profiles and copy number abnormalities as determined by array comparative genomic hybridization in medulloblastomas , 2007, Genes, chromosomes & cancer.

[64]  W. Hiddemann,et al.  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Global approach to the diagnosis of leukemia using gene expression profiling , 2022 .

[65]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[66]  Ki-Hyuk Shin,et al.  Heterogeneous Nuclear Ribonucleoprotein G Shows Tumor Suppressive Effect against Oral Squamous Cell Carcinoma Cells , 2006, Clinical Cancer Research.

[67]  K. Hoang-Xuan,et al.  Prognostic impact of molecular markers in a series of 220 primary glioblastomas , 2006, Cancer.

[68]  Rafael A. Irizarry,et al.  A Model-Based Background Adjustment for Oligonucleotide Expression Arrays , 2004 .

[69]  P. O’Connell,et al.  A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution. , 1999, Neuro-oncology.

[70]  U. Fischer,et al.  KUB3 amplification and overexpression in human gliomas , 2001, Glia.

[71]  N. Rahman,et al.  Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B , 2004, Nature Genetics.

[72]  M. Prados,et al.  Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade , 1998, Genes, chromosomes & cancer.

[73]  H. Joensuu,et al.  Amplification of genes encoding KIT, PDGFRα and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme , 2005, The Journal of pathology.

[74]  K. Hoang-Xuan,et al.  Loss of 14q Chromosome in Oligodendroglial and Astrocytic Tumors , 2004, Journal of Neuro-Oncology.

[75]  B. Roe,et al.  A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells , 2001, Oncogene.

[76]  H. Naganuma,et al.  Correlation of thrombospondin‐1 and transforming growth factor‐β expression with malignancy of glioma , 2000, Neuropathology : official journal of the Japanese Society of Neuropathology.

[77]  R. McLendon,et al.  Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. , 1995, Oncogene.

[78]  E. Oldfield,et al.  Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. , 1992, Cancer research.

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

[80]  J. Kere,et al.  A novel low-penetrance locus for familial glioma at 15q23-q26.3. , 2002, Cancer research.

[81]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[82]  F. Waldman,et al.  Prognostic relevance of 20q13 gains in sporadic colorectal cancers: a FISH analysis , 2004, Scandinavian journal of gastroenterology.

[83]  S. Knuutila,et al.  CDK4 is a probable target gene in a novel amplicon at 12q13.3–q14.1 in lung cancer , 2005, Genes, chromosomes & cancer.

[84]  Rafael A. Irizarry,et al.  Comparison of Affymetrix GeneChip expression measures , 2006, Bioinform..

[85]  Guoying Liu,et al.  NetAffx: Affymetrix probesets and annotations , 2003, Nucleic Acids Res..