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 H. Pers; Joel N. Hirschhorn; Ritsert C. Jansen; Erik A. Schultes; Herman H. H. B. M. van Haagenl; Elisabeth G. E. de Vries; Gerhardus 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 H. Pers, Joel N. Hirschhorn, Ritsert C. Jansen, Erik A. Schultes, Herman H. H. B. M. van Haagenl, Elisabeth G. E. de Vries, Gerhardus te Meerman, Cisca Wijmenga, Marcel A. T. M. van Vugt, Lude Franke

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	115-125
Number of pages	11
Journal	Nature Genetics
Volume	47
Issue number	2
DOIs	https://doi.org/10.1038/ng.3173
Publication status	Published - Feb-2015

Keywords

HOMOLOGOUS RECOMBINATION
MUTATIONS
BREAST
LANDSCAPE
REPAIR
CELLS

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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., te Meerman, G., 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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title = "Gene expression analysis identifies global gene dosage sensitivity in cancer",

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.",

keywords = "HOMOLOGOUS RECOMBINATION, MUTATIONS, BREAST, LANDSCAPE, REPAIR, CELLS",

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

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doi = "10.1038/ng.3173",

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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 , te Meerman, G , 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 H.

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 - te Meerman, Gerhardus

AU - Wijmenga, Cisca

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

AU - Franke, Lude

PY - 2015/2

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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 - HOMOLOGOUS RECOMBINATION

KW - MUTATIONS

KW - BREAST

KW - LANDSCAPE

KW - REPAIR

KW - CELLS

U2 - 10.1038/ng.3173

DO - 10.1038/ng.3173

M3 - Article

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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

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