Cell Reports (May 2019)
The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer
- Leticia De Mattos-Arruda,
- Stephen-John Sammut,
- Edith M. Ross,
- Rachael Bashford-Rogers,
- Erez Greenstein,
- Havell Markus,
- Sandro Morganella,
- Yvonne Teng,
- Yosef Maruvka,
- Bernard Pereira,
- Oscar M. Rueda,
- Suet-Feung Chin,
- Tania Contente-Cuomo,
- Regina Mayor,
- Alexandra Arias,
- H. Raza Ali,
- Wei Cope,
- Daniel Tiezzi,
- Aliakbar Dariush,
- Tauanne Dias Amarante,
- Dan Reshef,
- Nikaoly Ciriaco,
- Elena Martinez-Saez,
- Vicente Peg,
- Santiago Ramon y Cajal,
- Javier Cortes,
- George Vassiliou,
- Gad Getz,
- Serena Nik-Zainal,
- Muhammed Murtaza,
- Nir Friedman,
- Florian Markowetz,
- Joan Seoane,
- Carlos Caldas
Affiliations
- Leticia De Mattos-Arruda
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK; Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona 08035, Spain
- Stephen-John Sammut
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Edith M. Ross
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Rachael Bashford-Rogers
- Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
- Erez Greenstein
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
- Havell Markus
- Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; Mayo Clinic Center for Individualized Medicine, Scottsdale, AZ, USA
- Sandro Morganella
- Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge CB2 0QQ, UK
- Yvonne Teng
- Cancer Molecular Diagnosis Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Yosef Maruvka
- The Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA 02129, USA
- Bernard Pereira
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Oscar M. Rueda
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Suet-Feung Chin
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Tania Contente-Cuomo
- Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; Mayo Clinic Center for Individualized Medicine, Scottsdale, AZ, USA
- Regina Mayor
- Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona 08035, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain
- Alexandra Arias
- Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona 08035, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain
- H. Raza Ali
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Wei Cope
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Daniel Tiezzi
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Aliakbar Dariush
- Institute of Astronomy, University of Cambridge, Cambridge CB3 0HA, UK
- Tauanne Dias Amarante
- Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge CB2 0QQ, UK
- Dan Reshef
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
- Nikaoly Ciriaco
- Department of Pathology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Elena Martinez-Saez
- Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain; Department of Pathology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Vicente Peg
- Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain; Department of Pathology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; Translational Molecular Pathology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Santiago Ramon y Cajal
- Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain; Department of Pathology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; Translational Molecular Pathology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Javier Cortes
- Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona 08035, Spain; Ramon y Cajal Hospital, 28034 Madrid, Spain
- George Vassiliou
- Cancer Molecular Diagnosis Laboratory, NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust/MRC Cambridge Stem Cell Institute, Cambridge, UK
- Gad Getz
- The Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA 02129, USA
- Serena Nik-Zainal
- Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge CB2 0QQ, UK
- Muhammed Murtaza
- Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; Mayo Clinic Center for Individualized Medicine, Scottsdale, AZ, USA
- Nir Friedman
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
- Florian Markowetz
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
- Joan Seoane
- Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona 08035, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain; Corresponding author
- Carlos Caldas
- Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK; Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge CB2 2QQ, UK; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 9
pp. 2690 – 2708.e10
Abstract
Summary: The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer. : De Mattos-Arruda et al. profiled multiple metastases from autopsies of patients with therapy-resistant breast cancer, showing that multi-clonal spreading occurs in a small number of founder events. The analysis characterizes predicted neo-antigen landscapes, tumor microenvironments, and accumulation of HLA LOH. T cell immune responses appear to co-evolve with metastatic cancer genomes. Keywords: breast cancer, metastases, stem mutations, clade mutations, private mutations, genomic landscapes, immune landscapes, metastatic phylogenies, immunoediting, TCR repertoire
