Research

Gene expression analysis identifies global gene dosage sensitivity in cancer

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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.

biological function DNA copy number global gene dosage sensitivity somatic copy number alteration cancer Neoplasms (MeSH) neoplastic disease Primates Mammalia Vertebrata Chordata Animalia (Animals Chordates Humans Mammals Primates Vertebrates) - Hominidae [86215] human common 03502 Genetics - General 03508 Genetics - Human 24004 Neoplasms - Pathology clinical aspects and systemic effects Biochemistry and Molecular Biophysics array comparative genomic hybridization aCGH laboratory techniques genetic techniques functional genomic mRNA profiling laboratory techniques genetic techniques gene expression profiling laboratory techniques genetic techniques transcriptional analysis laboratory techniques genetic techniques Molecular Genetics Tumor Biology GENETICS HOMOLOGOUS RECOMBINATION MUTATIONS BREAST LANDSCAPE REPAIR CELLS