domingo, 29 de abril de 2012

The genomic and transcriptomic architecture of 2,000 ... [Nature. 2012] - PubMed - NCBI

The genomic and transcriptomic architecture of 2,000 ... [Nature. 2012] - PubMed - NCBI

Nature. 2012 Apr 18. doi: 10.1038/nature10983. [Epub ahead of print]

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

Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S; METABRIC Group; Co-chairs, Caldas C, Aparicio S; Writing committee, Curtis C, Shah SP, Caldas C, Aparicio S; Steering committee, Brenton JD, Ellis I, Huntsman D, Pinder S, Purushotham A, Murphy L, Caldas C, Aparicio S; Tissue and clinical data source sites:; University of Cambridge/Cancer Research UK Cambridge Research Institute, Caldas C, Bardwell H, Chin SF, Curtis C, Ding Z, Gräf S, Jones L, Liu B, Lynch AG, Papatheodorou I, Sammut SJ, Wishart G; British Columbia Cancer Agency, Aparicio S, Chia S, Gelmon K, Huntsman D, McKinney S, Speers C, Turashvili G, Watson P; University of Nottingham, Ellis I, Blamey R, Green A, Macmillan D, Rakha E; King’s College London, Purushotham A, Gillett C, Grigoriadis A, Pinder S, di Rinaldis E, Tutt A; Manitoba Institute of Cell Biology, Murphy L, Parisien M, Troup S; Cancer genome/transcriptome characterization centres:; University of Cambridge/Cancer Research UK Cambridge Research Institute, Caldas C, Chin SF, Chan D, Fielding C, Maia AT, McGuire S, Osborne M, Sayalero SM, Spiteri I, Hadfield J; British Columbia Cancer Agency, Aparicio S, Turashvili G, Bell L, Chow K, Gale N, Huntsman D, Kovalik M, Ng Y, Prentice L; Data analysis subgroup:; University of Cambridge/Cancer Research UK Cambridge Research Institute, Caldas C, Tavaré S, Curtis C, Dunning MJ, Gräf S, Lynch AG, Rueda OM, Russell R, Samarajiwa S, Speed D, Markowetz F, Yuan Y, Brenton JD; British Columbia Cancer Agency, Aparicio S, Shah SP, Bashashati A, Ha G, Haffari G, McKinney S, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Børresen-Dale AL, Brenton JD, Tavaré S, Caldas C, Aparicio S.

Source

1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [3] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA (Ch.C.); University College London, Genetics Institute, WC1E 6BT, UK (D.S.). [4].

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.
PMID:
22522925
[PubMed - as supplied by publisher]

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