title: Gene expression analysis identifies global gene dosage sensitivity in cancer.
abstract: Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gene expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying this method to 16,172 patient-derived tumor samples, we replicated many loci with aberrant copy numbers and identified recurrently disrupted genes in genomically unstable cancers.
authors.affiliation: 1] Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. [2] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rudolf S N
authors.identifier: 000000027516315X
authors.initials: RS
authors.lastname: Fehrmann
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Juha M
authors.initials: JM
authors.lastname: Karjalainen
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krajewska
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harm-Jan
authors.identifier: 000000017038567X
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: National Center for Advancing Translational Sciences, US National Institutes of Health, Rockville, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Maloney
authors.affiliation: National Center for Advancing Translational Sciences, US National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA. [3] Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, USA. [4] Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA. [3] Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, the Netherlands.
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.affiliation: 1] Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. [2] BioSemantics Group, Leiden Institute of Advanced Computer Science, Leiden University, Leiden, the Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Schultes
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Herman H H B M
authors.initials: HH
authors.lastname: van Haagen
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: te Meerman
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marcel A T M
authors.initials: MA
authors.lastname: van Vugt
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D023281:Genomics; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm