title: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
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.
authors.affiliation: Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.forename: Doug
authors.initials: D
authors.lastname: Speed
authors.forename: Andy G
authors.initials: AG
authors.lastname: Lynch
authors.forename: Shamith
authors.initials: S
authors.lastname: Samarajiwa
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Yuan
authors.forename: Stefan
authors.initials: S
authors.lastname: Gräf
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Haffari
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.forename: Steven
authors.initials: S
authors.lastname: McKinney
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.forename: Gordon
authors.initials: G
authors.lastname: Wishart
authors.forename: Sarah
authors.initials: S
authors.lastname: Pinder
authors.forename: Peter
authors.initials: P
authors.lastname: Watson
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.forename: Leigh
authors.initials: L
authors.lastname: Murphy
authors.forename: Ian
authors.initials: I
authors.lastname: Ellis
authors.forename: Arnie
authors.initials: A
authors.lastname: Purushotham
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D053208:Kaplan-Meier Estimate; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C512974:PPP2R2A protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D054648:Protein Phosphatase 2