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

doi:10.1038/ng.3173

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 journal › Journal article › Research › peer-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 language	English
Journal	Nature Genetics
Volume	47
Issue number	2
Pages (from-to)	115-125
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3173
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Fehrmann, R. S. N., Karjalainen, J. M., Krajewska, M., Westra, H-J., Maloney, D., Simeonov, A., Pers, T. H., Hirschhorn, J. N., Jansen, R. C., Schultes, E. A., van Haagenl, H. H. H. B. M., de Vries, E. G. E., Meerman, G. J. T., Wijmenga, C., van Vugt, M. A. T. M., & Franke, L. (2015). Gene expression analysis identifies global gene dosage sensitivity in cancer. Nature Genetics, 47(2), 115-125. https://doi.org/10.1038/ng.3173

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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.",

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Fehrmann, RSN, Karjalainen, JM, Krajewska, M, Westra, H-J, Maloney, D, Simeonov, A, Pers, TH, Hirschhorn, JN, Jansen, RC, Schultes, EA, van Haagenl, HHHBM, de Vries, EGE, Meerman, GJT, Wijmenga, C, van Vugt, MATM & Franke, L 2015, 'Gene expression analysis identifies global gene dosage sensitivity in cancer', Nature Genetics, vol. 47, no. 2, pp. 115-125. https://doi.org/10.1038/ng.3173

TY - JOUR

T1 - Gene expression analysis identifies global gene dosage sensitivity in cancer

AU - Fehrmann, Rudolf S. N.

AU - Karjalainen, Juha M.

AU - Krajewska, Malgorzata

AU - Westra, Harm-Jan

AU - Maloney, David

AU - Simeonov, Anton

AU - Pers, Tune Hannes

AU - Hirschhorn, Joel N.

AU - Jansen, Ritsert C.

AU - Schultes, Erik A.

AU - van Haagenl, Herman H. H. B. M.

AU - de Vries, Elisabeth G. E.

AU - Meerman, Gerard J. te

AU - Wijmenga, Cisca

AU - van Vugt, Marcel A. T. M.

AU - Franke, Lude

PY - 2015

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N2 - 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.

AB - 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.

KW - biological function

KW - DNA copy number

KW - global gene dosage sensitivity

KW - somatic copy number alteration

KW - cancer Neoplasms (MeSH) neoplastic disease

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common

KW - 03502, Genetics - General

KW - 03508, Genetics - Human

KW - 24004, Neoplasms - Pathology, clinical aspects and systemic effects

KW - Biochemistry and Molecular Biophysics

KW - array comparative genomic hybridization aCGH laboratory techniques, genetic techniques

KW - functional genomic mRNA profiling laboratory techniques, genetic techniques

KW - gene expression profiling laboratory techniques, genetic techniques

KW - transcriptional analysis laboratory techniques, genetic techniques

KW - Molecular Genetics

KW - Tumor Biology

KW - GENETICS

KW - HOMOLOGOUS RECOMBINATION

KW - MUTATIONS

KW - BREAST

KW - LANDSCAPE

KW - REPAIR

KW - CELLS

U2 - 10.1038/ng.3173

DO - 10.1038/ng.3173

M3 - Journal article

C2 - 25581432

SN - 1061-4036

VL - 47

SP - 115

EP - 125

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Gene expression analysis identifies global gene dosage sensitivity in cancer

Abstract

Keywords

UN SDGs

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