Journal article
Gene expression analysis identifies global gene dosage sensitivity in cancer
University of Groningen1
National Institutes of Health2
Department of Systems Biology, Technical University of Denmark3
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
Massachusetts General Hospital/Harvard Medical School5
Leiden University Medical Center6
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.
Language: | English |
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Publisher: | Nature Publishing Group US |
Year: | 2015 |
Pages: | 115-125 |
ISSN: | 15461718 and 10614036 |
Types: | Journal article |
DOI: | 10.1038/ng.3173 |
ORCIDs: | 0000-0002-7516-315X and 0000-0001-7038-567X |
03502, Genetics - General 03508, Genetics - Human 24004, Neoplasms - Pathology, clinical aspects and systemic effects BREAST Biochemistry and Molecular Biophysics CELLS DNA copy number GENETICS HOMOLOGOUS RECOMBINATION LANDSCAPE MUTATIONS Molecular Genetics Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common REPAIR SDG 3 - Good Health and Well-being Tumor Biology array comparative genomic hybridization aCGH laboratory techniques, genetic techniques biological function cancer Neoplasms (MeSH) neoplastic disease functional genomic mRNA profiling laboratory techniques, genetic techniques gene expression profiling laboratory techniques, genetic techniques global gene dosage sensitivity somatic copy number alteration transcriptional analysis laboratory techniques, genetic techniques