Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ
Abstract
Abstract Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.
Authors 47
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Genetics, MD Anderson Cancer Center, Houston, USA
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, USA
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Affiliation as printed
Biodesign Center for Biocomputing, Security and Society, Arizona State University, USA
School of Life Sciences, Arizona State University, Tempe, AZ
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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The Netherlands Cancer Institute
Affiliation as printed
Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Genetics, MD Anderson Cancer Center, Houston, USA
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Affiliation as printed
Biodesign Center for Biocomputing, Security and Society, Arizona State University, USA
School of Life Sciences, Arizona State University, Tempe, AZ
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, USA
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The Netherlands Cancer Institute
Affiliation as printed
Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Affiliation as printed
Screening Quality Assurance Service, Public Health England, UK
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University of Cambridge · MRC Cancer Unit · Hutchison/MRC Research Centre
Affiliation as printed
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre and Academic Department of Medical Genetics, Cambridge Biomedical Research Campus, Cambridge, UK
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Duke University · Duke Medical Center
Affiliation as printed
Department of Surgery, Duke University School of Medicine, Durham, NC
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Duke University · Duke Medical Center
Affiliation as printed
Department of Surgery, Duke University School of Medicine, Durham, NC
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The Netherlands Cancer Institute
Affiliation as printed
Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Affiliation as printed
Biodesign Center for Biocomputing, Security and Society, Arizona State University, USA
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Duke University · Duke Medical Center
Affiliation as printed
Department of Surgery, Duke University School of Medicine, Durham, NC
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Baylor College of Medicine · Dan L Duncan Comprehensive Cancer Center
Affiliation as printed
Department of Surgical Oncology, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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The Netherlands Cancer Institute
Affiliation as printed
Division of Psychosocial research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Queen Elizabeth Hospital Birmingham · University of Birmingham
Affiliation as printed
Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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Affiliation as printed
Independent Cancer Patients’ Voice, UK
Independent Cancer Patients' Voice, UK
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Affiliation as printed
Patient Advocates in Research, USA
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University of Cambridge · MRC Cancer Unit · Hutchison/MRC Research Centre
Affiliation as printed
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre and Academic Department of Medical Genetics, Cambridge Biomedical Research Campus, Cambridge, UK
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The Netherlands Cancer Institute · Delft University of Technology
Affiliation as printed
Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, the Netherlands
Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Duke University · Duke Medical Center
Affiliation as printed
Department of Surgery, Duke University School of Medicine, Durham, NC
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Genetics, MD Anderson Cancer Center, Houston, USA
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, USA
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Baylor College of Medicine · Dan L Duncan Comprehensive Cancer Center
Affiliation as printed
Department of Surgical Oncology, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Leiden University Medical Center, the Netherlands
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Divisions of Diagnostic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Elinor J. Sawyer corresponding
Affiliation as printed
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK
School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Cancer Centre, King's College London, London, UK
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