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Nat Genet. 2015 Feb;47(2):115-25. doi: 10.1038/ng.3173. Epub 2015 Jan 12.

Gene expression analysis identifies global gene dosage sensitivity in cancer.

Author information

1
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.
2
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
3
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
4
National Center for Advancing Translational Sciences, US National Institutes of Health, Rockville, Maryland, USA.
5
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.
6
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.
7
Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, the Netherlands.
8
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.
9
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

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.

PMID:
25581432
DOI:
10.1038/ng.3173
[Indexed for MEDLINE]

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