Gene expression analysis identifies global gene dosage sensitivity in cancer

被引：249

作者：

Fehrmann, Rudolf S. N. ^{[1
,2
]}

Karjalainen, Juha M. ^{[2
]}

Krajewska, Malgorzata ^{[1
]}

Westra, Harm-Jan ^{[2
]}

Maloney, David ^{[3
]}

Simeonov, Anton ^{[3
]}

Pers, Tune H. ^{[4
,5
,6
,7
]}

Hirschhorn, Joel N. ^{[4
,5
,6
,8
]}

Jansen, Ritsert C. ^{[9
]}

Schultes, Erik A. ^{[10
,11
]}

van Haagenl, Herman H. H. B. M. ^{[10
]}

de Vries, Elisabeth G. E. ^{[1
]}

Meerman, Gerard J. te ^{[2
]}

Wijmenga, Cisca ^{[2
]}

van Vugt, Marcel A. T. M. ^{[1
]}

Franke, Lude

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[3] US Natl Inst Hlth, Natl Ctr Adv Translat Sci, Rockville, MD USA

[4] Broad Inst MIT & Harvard, Cambridge, MA USA

[5] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[6] Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

[7] Tech Univ Denmark, Dept Syst Biol, DK-2800 Lyngby, Denmark

[8] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[9] Univ Groningen, Groningen Biomol Sci & Biotechnol Inst, Groningen Bioinformat Ctr, Haren, Netherlands

[10] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[11] Leiden Univ, Leiden Inst Adv Comp Sci, BioSemant Grp, Leiden, Netherlands

来源：

NATURE GENETICS | 2015年 / 47卷 / 02期

关键词：

HOMOLOGOUS RECOMBINATION; HUMAN-BREAST; MUTATIONS; LANDSCAPE; REPAIR;

D O I：

10.1038/ng.3173

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：115 / 125

页数：11

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