Genomic Evolution of Breast Cancer Metastasis and Relapse

Lucy R Yates; Stian Knappskog; David Wedge; James H R Farmery; Santiago Gonzalez; Inigo Martincorena; Ludmil B Alexandrov; Peter Van Loo; Hans Kristian Haugland; Peer Kaare Lilleng; Gunes Gundem; Moritz Gerstung; Elli Pappaemmanuil; Patrycja Gazinska; Shriram G Bhosle; David Jones; Keiran Raine; Laura Mudie; Calli Latimer; Elinor Sawyer; Christine Desmedt; Christos Sotiriou; Michael R Stratton; Anieta M Sieuwerts; Andy G Lynch; John W Martens; Andrea L Richardson; Andrew Tutt; Per Eystein Lønning; Peter J Campbell

doi:10.1016/j.ccell.2017.07.005

Genomic Evolution of Breast Cancer Metastasis and Relapse

Cancer Cell. 2017 Aug 14;32(2):169-184.e7. doi: 10.1016/j.ccell.2017.07.005.

Authors

Lucy R Yates¹, Stian Knappskog², David Wedge³, James H R Farmery⁴, Santiago Gonzalez⁵, Inigo Martincorena⁶, Ludmil B Alexandrov⁷, Peter Van Loo⁸, Hans Kristian Haugland⁹, Peer Kaare Lilleng⁹, Gunes Gundem¹⁰, Moritz Gerstung⁵, Elli Pappaemmanuil¹⁰, Patrycja Gazinska¹¹, Shriram G Bhosle⁶, David Jones⁶, Keiran Raine⁶, Laura Mudie⁶, Calli Latimer⁶, Elinor Sawyer¹², Christine Desmedt¹³, Christos Sotiriou¹³, Michael R Stratton⁶, Anieta M Sieuwerts¹⁴, Andy G Lynch⁴, John W Martens¹⁴, Andrea L Richardson¹⁵, Andrew Tutt¹⁶, Per Eystein Lønning¹⁷, Peter J Campbell¹⁸

Affiliations

¹ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Clinical Oncology, Guys and St Thomas' NHS Trust, London SE1 9RT, UK.
² Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
³ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Big Data Institute, University of Oxford, Oxford OX3 7BN, UK.
⁴ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
⁵ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
⁶ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁷ Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, USA; Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87102, USA.
⁸ The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
⁹ Department of Pathology, Haukeland University Hospital, Bergen, Norway; The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹⁰ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Computational Oncology, Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Institute, New York, NY 10065 USA.
¹¹ Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK.
¹² Department of Clinical Oncology, Guys and St Thomas' NHS Trust, London SE1 9RT, UK; Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK.
¹³ Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, 1000 Brussels, Belgium.
¹⁴ Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, the Netherlands.
¹⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁶ Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK; Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
¹⁷ Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway. Electronic address: [email protected].
¹⁸ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address: [email protected].

Abstract

Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways.

Keywords: breast cancer; genomics; metastasis; relapse; somatic mutation.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / genetics*
Breast Neoplasms / genetics*
Breast Neoplasms / pathology*
Chromosomal Proteins, Non-Histone / antagonists & inhibitors
Chromosomal Proteins, Non-Histone / genetics
Evolution, Molecular*
Female
Humans
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / genetics
Male
Middle Aged
Mutation*
Neoplasm Metastasis / genetics
Neoplasm Recurrence, Local / genetics*
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / genetics
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics

Substances

Biomarkers, Tumor
Chromosomal Proteins, Non-Histone
STAT3 Transcription Factor
STAT3 protein, human
SWI-SNF-B chromatin-remodeling complex
Transcription Factors
JAK2 protein, human
Janus Kinase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding