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METABRIC

ABSTRACT: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (CNVs, SNPs) and acquired somatic copy number aberrations (CNAs) were associated with expression in 40% of genes, although the landscape was dominated by cis and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP, and MAP2K4. Unsupervised analysis of paired DNA/RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, ER-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration 0152hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 0152CNA-devoid sub-group and a Basal-specific chromosome 5 deletion-driven mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic copy number aberrations on the transcriptome.

PROVIDER: EGAS00000000083 | EGA |

REPOSITORIES: EGA

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The breast cancer oncogene EMSY represses transcription of antimetastatic microRNA miR-31.

Viré Emmanuelle E Curtis Christina C Davalos Veronica V Git Anna A Robson Samuel S Villanueva Alberto A Vidal August A Barbieri Isaia I Aparicio Samuel S Esteller Manel M Caldas Carlos C Kouzarides Tony T

Molecular cell 20140227 5

Amplification of the EMSY gene in sporadic breast and ovarian cancers is a poor prognostic indicator. Although EMSY has been linked to transcriptional silencing, its mechanism of action is unknown. Here, we report that EMSY acts as an oncogene, causing the transformation of cells in vitro and potentiating tumor formation and metastatic features in vivo. We identify an inverse correlation between EMSY amplification and miR-31 expression, an antimetastatic microRNA, in the METABRIC cohort of human ...[more]

PMID: 24582497

Publication: 1/2

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Project description:Background: Genomic instability is a hallmark of cancer and is frequently reflected in the DNA copy number profile and the expression profile of genes. Methodology is needed to compare array-CGH data and microarray expression data in order to unveil effects of DNA copy number alterations of a gene on the expression of the gene itself (in-cis effects) and on other genes (in-trans effects). Results: We present a method for detection of gene dosage effects on gene expression that first searches for genome-wide in-cis associations between copy number and expression, and then investigates in-trans effects of these genes. A key element of the method is a correction step to eliminate potential confounding effects of in-cis associations when searching for in-trans associations. This facilitates reliable detection of local in-trans associations (i.e. associations within a chromosome) and alleviates the problem of co-occurring copy number aberrations across the genome. Applying the method to data collected from breast carcinomas from 20 women, we found 422 genes with expression levels that are highly correlated to DNA copy number (in-cis) in certain regions of the genome. Of these, 109 (26%) had significant trans-correlation with the expression levels of a large number of genes (20 or more). The strongest trans-regulators were also differentially expressed in subgroups that were found on the basis of expression data by classification of the tumors to previously defined breast cancer subtypes. A study of the most significant in-trans correlated genes yields significant enrichment of certain cancer related pathways and GO terms. Conclusions: We introduce a method for the joint comparative analysis of expression and copy number profiles for the discovery and investigation of in-cis and in-trans regulatory mechanisms. Using data from 20 primary human breast cancers, a number of significant in-trans regulatory genes were found and their biological relevance indicated, calling for the application of the methods on larger data sets. Keywords: Correlations between copy number and gene expression, breast cancer

Dataset Information

METABRIC

Publications

The breast cancer oncogene EMSY represses transcription of antimetastatic microRNA miR-31.

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