title: Subclonal diversification of primary breast cancer revealed by multiregion sequencing.
abstract: The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Oncology, The University of Cambridge, Cambridge, UK.
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Yates
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Moritz
authors.identifier: 000000016709963X
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: 1] Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Department of Surgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Turid
authors.initials: T
authors.lastname: Aas
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Ju
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Haugland
authors.affiliation: 1] Department of Pathology, Haukeland University Hospital, Bergen, Norway. [2] The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Peer Kaare
authors.initials: PK
authors.lastname: Lilleng
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Glodzik
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Keiran
authors.identifier: 0000000256341539
authors.initials: K
authors.lastname: Raine
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hinton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mudie
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vincent
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: April
authors.initials: A
authors.lastname: Greene-Colozzi
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Adnet
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Aquila
authors.initials: A
authors.lastname: Fatima
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Maetens
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: 1] Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: 1] Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002999:Clone Cells; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents