The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes

Bernard Pereira, Suet-Feung Chin, Oscar M. Rueda, Hans-Kristian Moen Vollan, Elena Provenzano, Helen A. Bardwell, Michelle Pugh, Linda Jones, Roslin Russell, Stephen-John Sammut, Dana W. Y. Tsui, Bin Liu, Sarah-Jane Dawson, Jean Abraham, Helen Northen, John F. Peden, Abhik Mukherjee, Gulisa Turashvili, Andrew R. Green, Steve McKinney, Arusha Oloumi, Sohrab Shah, Nitzan Rosenfeld, Leigh Murphy, David R. Bentley, Ian O. Ellis, Arnie Purushotham, Sarah E. Pinder, Anne-Lise Børresen-Dale, Helena M. Earl, Paul D. Pharoah, Mark T. Ross, Samuel Aparicio () and Carlos Caldas ()
Additional contact information
Bernard Pereira: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Suet-Feung Chin: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Oscar M. Rueda: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Hans-Kristian Moen Vollan: Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0310, Norway
Elena Provenzano: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre
Helen A. Bardwell: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Michelle Pugh: Inivata, Li Ka Shing Centre, Robinson Way
Linda Jones: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre
Roslin Russell: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Stephen-John Sammut: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Dana W. Y. Tsui: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Bin Liu: University of Cambridge
Sarah-Jane Dawson: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Jean Abraham: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre
Helen Northen: Illumina, Chesterford Research Park, Little Chesterford
John F. Peden: Illumina, Chesterford Research Park, Little Chesterford
Abhik Mukherjee: School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust
Gulisa Turashvili: Queen’s University/Kingston General Hospital
Andrew R. Green: School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust
Steve McKinney: British Columbia Cancer Research Centre
Arusha Oloumi: British Columbia Cancer Research Centre
Sohrab Shah: British Columbia Cancer Research Centre
Nitzan Rosenfeld: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way
Leigh Murphy: Research Institute in Oncology and Hematology
David R. Bentley: Illumina, Chesterford Research Park, Little Chesterford
Ian O. Ellis: School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust
Arnie Purushotham: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and Research Oncology, King’s College London
Sarah E. Pinder: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and Research Oncology, King’s College London
Anne-Lise Børresen-Dale: Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0310, Norway
Helena M. Earl: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre
Paul D. Pharoah: Strangeways Research Laboratory, University of Cambridge
Mark T. Ross: Illumina, Chesterford Research Park, Little Chesterford
Samuel Aparicio: British Columbia Cancer Research Centre
Carlos Caldas: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13–14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13–14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

Date: 2016
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DOI: 10.1038/ncomms11479

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