title: Gene expression profiling and genetic markers in glioblastoma survival.
abstract: Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.
authors.affiliation: Department of Medicine, W.M. Keck Center for Neuro-Oncogenomics, Institute of Statistics and Decision Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. rich0001@mc.duke.edu
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Christopher
authors.initials: C
authors.lastname: Hans
authors.forename: Beatrix
authors.initials: B
authors.lastname: Jones
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: B K Ahmed
authors.initials: BK
authors.lastname: Rasheed
authors.forename: Adrian
authors.initials: A
authors.lastname: Dobra
authors.forename: Holly K
authors.initials: HK
authors.lastname: Dressman
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Mike
authors.initials: M
authors.lastname: West
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D015676:Osteonectin / Q000096:biosynthesis / Q000235:genetics; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics; D015203:Reproducibility of Results; D039961:Semaphorins; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D000089622:Doublecortin Domain Proteins; D005819:Genetic Markers; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D015676:Osteonectin; C409766:SEMA3B protein, human; D039961:Semaphorins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human