title: Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors.
abstract: Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients.
authors.affiliation: Division of Haematology/Oncology, The Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Walker
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Wes
authors.initials: W
authors.lastname: Wilson
authors.forename: Nataliya
authors.initials: N
authors.lastname: Zhukova
authors.forename: Noa
authors.initials: N
authors.lastname: Alon
authors.forename: Ana
authors.initials: A
authors.lastname: Novokmet
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Peter
authors.initials: P
authors.lastname: Ray
authors.forename: Christiane
authors.initials: C
authors.lastname: Knobbe
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000328:Adult; D000483:Alleles; D001344:Autopsy; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002648:Child; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D019656:Loss of Heterozygosity; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019098:Telomerase