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The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

Accepted version
Peer-reviewed

Type

Article

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Authors

Curtis, Christina 
Shah, Sohrab P 
Turashvili, Gulisa 
Rueda, Oscar M 

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 (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape 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, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

Description

Keywords

Breast Neoplasms, DNA Copy Number Variations, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genes, Neoplasm, Genome, Human, Genomics, Humans, Kaplan-Meier Estimate, MAP Kinase Kinase 4, Polymorphism, Single Nucleotide, Prognosis, Protein Phosphatase 2, Treatment Outcome

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

486

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (A7199)