title: The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.
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.
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pereira
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0310, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0318, Norway.
authors.forename: Hans-Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.|Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Bardwell
authors.affiliation: Inivata, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pugh
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.|Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Jones
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Stephen-John
authors.initials: SJ
authors.lastname: Sammut
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Dana W Y
authors.initials: DW
authors.lastname: Tsui
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Dawson
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.|Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Northen
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Peden
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust, Nottingham NG5 1PB, UK.
authors.forename: Abhik
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University/Kingston General Hospital, 76 Stuart Street, Kingston, Ontario, Canada K7L 2V7.
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust, Nottingham NG5 1PB, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Steve
authors.identifier: 0000-0002-1611-0867
authors.initials: S
authors.lastname: McKinney
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Arusha
authors.initials: A
authors.lastname: Oloumi
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Sohrab
authors.identifier: 0000-0001-6402-523X
authors.initials: S
authors.lastname: Shah
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: Research Institute in Oncology and Hematology, 675 McDermot Avenue, Winnipeg, Mannitoba, Canada R3E 0V9.
authors.forename: Leigh
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Bentley
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust, Nottingham NG5 1PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: NIHR Comprehensive Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and Research Oncology, Cancer Division, King's College London, London SE1 9RT, UK.
authors.forename: Arnie
authors.initials: A
authors.lastname: Purushotham
authors.affiliation: NIHR Comprehensive Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and Research Oncology, Cancer Division, King's College London, London SE1 9RT, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pinder
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0310, Norway.|The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0318, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.|Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Strangeways Research Laboratory, University of Cambridge, 2 Worts' Causeway, Cambridge CB1 8RN, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ross
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|Department of Oncology, University of Cambridge, Cambridge CB2 2QQ, UK.|Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.|Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospitals NHS, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D059467:Transcriptome
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human