Gene expression analysis identifies global gene dosage sensitivity in cancer

Rudolf S. N. Fehrmann, Juha M. Karjalainen, Malgorzata Krajewska, Harm-Jan Westra, David Maloney, Anton Simeonov, Tune Hannes Pers, Joel N. Hirschhorn, Ritsert C. Jansen, Erik A. Schultes, Herman H. H. B. M. van Haagenl, Elisabeth G. E. de Vries, Gerard J. te Meerman, Cisca Wijmenga, Marcel A. T. M. van Vugt, Lude Franke

    Research output: Contribution to journalJournal articleResearchpeer-review

    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.
    Original languageEnglish
    JournalNature Genetics
    Volume47
    Issue number2
    Pages (from-to)115-125
    ISSN1061-4036
    DOIs
    Publication statusPublished - 2015

    Keywords

    • 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

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