The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
Christina Curtis, Sohrab P Shah, Suet-Feung Chin, Gulisa Turashvili, Oscar M Rueda, Mark J Dunning, Doug Speed, Andy G Lynch, Shamith Samarajiwa, Yinyin Yuan, Stefan Gräf, Gavin Ha, Gholamreza Haffari, Ali Bashashati, Roslin Russell, Steven McKinney, METABRIC Group, Anita Langerød, Andrew Green, Elena Provenzano, Gordon Wishart, Sarah Pinder, Peter Watson, Florian Markowetz, Leigh Murphy, Ian Ellis, Arnie Purushotham, Anne-Lise Børresen-Dale, James D Brenton, Simon Tavaré, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Samuel Aparicio, Christina Curtis, Sohrab P Shah, Carlos Caldas, Samuel Aparicio, James D Brenton, Ian Ellis, David Huntsman, Sarah Pinder, Arnie Purushotham, Leigh Murphy, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Helen Bardwell, Suet-Feung Chin, Christina Curtis, Zhihao Ding, Stefan Gräf, Linda Jones, Bin Liu, Andy G Lynch, Irene Papatheodorou, Stephen J Sammut, Gordon Wishart, Samuel Aparicio, Steven Chia, Karen Gelmon, David Huntsman, Steven McKinney, Caroline Speers, Gulisa Turashvili, Peter Watson, Ian Ellis, Roger Blamey, Andrew Green, Douglas Macmillan, Emad Rakha, Arnie Purushotham, Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Emanuele de Rinaldis, Andy Tutt, Leigh Murphy, Michelle Parisien, Sandra Troup, Carlos Caldas, Suet-Feung Chin, Derek Chan, Claire Fielding, Ana-Teresa Maia, Sarah McGuire, Michelle Osborne, Sara M Sayalero, Inmaculada Spiteri, James Hadfield, Samuel Aparicio, Gulisa Turashvili, Lynda Bell, Katie Chow, Nadia Gale, David Huntsman, Maria Kovalik, Ying Ng, Leah Prentice, Carlos Caldas, Simon Tavaré, Christina Curtis, Mark J Dunning, Stefan Gräf, Andy G Lynch, Oscar M Rueda, Roslin Russell, Shamith Samarajiwa, Doug Speed, Florian Markowetz, Yinyin Yuan, James D Brenton, Samuel Aparicio, Sohrab P Shah, Ali Bashashati, Gavin Ha, Gholamreza Haffari, Steven McKinney, Christina Curtis, Sohrab P Shah, Suet-Feung Chin, Gulisa Turashvili, Oscar M Rueda, Mark J Dunning, Doug Speed, Andy G Lynch, Shamith Samarajiwa, Yinyin Yuan, Stefan Gräf, Gavin Ha, Gholamreza Haffari, Ali Bashashati, Roslin Russell, Steven McKinney, METABRIC Group, Anita Langerød, Andrew Green, Elena Provenzano, Gordon Wishart, Sarah Pinder, Peter Watson, Florian Markowetz, Leigh Murphy, Ian Ellis, Arnie Purushotham, Anne-Lise Børresen-Dale, James D Brenton, Simon Tavaré, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Samuel Aparicio, Christina Curtis, Sohrab P Shah, Carlos Caldas, Samuel Aparicio, James D Brenton, Ian Ellis, David Huntsman, Sarah Pinder, Arnie Purushotham, Leigh Murphy, Carlos Caldas, Samuel Aparicio, Carlos Caldas, Helen Bardwell, Suet-Feung Chin, Christina Curtis, Zhihao Ding, Stefan Gräf, Linda Jones, Bin Liu, Andy G Lynch, Irene Papatheodorou, Stephen J Sammut, Gordon Wishart, Samuel Aparicio, Steven Chia, Karen Gelmon, David Huntsman, Steven McKinney, Caroline Speers, Gulisa Turashvili, Peter Watson, Ian Ellis, Roger Blamey, Andrew Green, Douglas Macmillan, Emad Rakha, Arnie Purushotham, Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Emanuele de Rinaldis, Andy Tutt, Leigh Murphy, Michelle Parisien, Sandra Troup, Carlos Caldas, Suet-Feung Chin, Derek Chan, Claire Fielding, Ana-Teresa Maia, Sarah McGuire, Michelle Osborne, Sara M Sayalero, Inmaculada Spiteri, James Hadfield, Samuel Aparicio, Gulisa Turashvili, Lynda Bell, Katie Chow, Nadia Gale, David Huntsman, Maria Kovalik, Ying Ng, Leah Prentice, Carlos Caldas, Simon Tavaré, Christina Curtis, Mark J Dunning, Stefan Gräf, Andy G Lynch, Oscar M Rueda, Roslin Russell, Shamith Samarajiwa, Doug Speed, Florian Markowetz, Yinyin Yuan, James D Brenton, Samuel Aparicio, Sohrab P Shah, Ali Bashashati, Gavin Ha, Gholamreza Haffari, Steven McKinney
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.
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Source: PubMed