Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

Marcel Smid, F. Germán Rodríguez-González, Anieta M. Sieuwerts, Roberto Salgado, Wendy J. C. Prager- Van der Smissen, Michelle van der Vlugt-Daane, Anne van Galen, Serena Nik-Zainal, Johan Staaf, Arie B. Brinkman, Marc J. van de Vijver, Andrea L. Richardson, Aquila Fatima, Kim Berentsen, Adam Butler, Sancha Martin, Helen R. Davies, Reno Debets, Marion E. Meijer- Van Gelder, Carolien H. M. van Deurzen, Gaëtan MacGrogan, Gert G. G. M. Van den Eynden, Colin Purdie, Alastair M. Thompson, Carlos Caldas, Paul N. Span, Peter T. Simpson, Sunil R. Lakhani, Steven Van Laere, Christine Desmedt, Markus Ringnér, Stefania Tommasi, Jorunn Eyford, Annegien Broeks, Anne Vincent-Salomon, P. Andrew Futreal, Stian Knappskog, Tari King, Gilles Thomas, Alain Viari, Anita Langerød, Anne-Lise Børresen-Dale, Ewan Birney, Hendrik G. Stunnenberg, Mike Stratton, John A. Foekens and John W. M. Martens ()
Additional contact information
Marcel Smid: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
F. Germán Rodríguez-González: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Anieta M. Sieuwerts: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Roberto Salgado: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles
Wendy J. C. Prager- Van der Smissen: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Michelle van der Vlugt-Daane: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Anne van Galen: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Serena Nik-Zainal: Wellcome Trust Sanger Institute
Johan Staaf: Lund University
Arie B. Brinkman: Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen
Marc J. van de Vijver: Academic Medical Center
Andrea L. Richardson: Brigham and Women's Hospital
Aquila Fatima: Erasmus MC Cancer Institute, Erasmus University Medical Center
Kim Berentsen: Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen
Adam Butler: Wellcome Trust Sanger Institute
Sancha Martin: Wellcome Trust Sanger Institute
Helen R. Davies: Wellcome Trust Sanger Institute
Reno Debets: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Marion E. Meijer- Van Gelder: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Carolien H. M. van Deurzen: Erasmus MC Cancer Institute, Erasmus University Medical Center
Gaëtan MacGrogan: Département de Biopathologie,
Gert G. G. M. Van den Eynden: Department of Pathology/TCRU GZA
Colin Purdie: Ninewells Hospital & Medical School
Alastair M. Thompson: Ninewells Hospital & Medical School
Carlos Caldas: Cancer Research UK Cambridge Institute, University of Cambridge
Paul N. Span: Radboud University Medical Center
Peter T. Simpson: The University of Queensland: UQ Centre for Clinical Research and School of Medicine
Sunil R. Lakhani: The University of Queensland: UQ Centre for Clinical Research and School of Medicine
Steven Van Laere: Center for Oncological Research, University of Antwerp & GZA Hospitals Sint-Augustinus
Christine Desmedt: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles
Markus Ringnér: Lund University
Stefania Tommasi: IRCCS Istituto Tumori ‘Giovanni Paolo II’
Jorunn Eyford: Cancer Research Laboratory, Faculty of Medicine, University of Iceland
Annegien Broeks: The Netherlands Cancer Institute
Anne Vincent-Salomon: Institut Curie
P. Andrew Futreal: UT MD Anderson Cancer Center
Stian Knappskog: University of Bergen
Tari King: Memorial Sloan Kettering Cancer Center
Gilles Thomas: Synergie Lyon Cancer,Centre Léon Bérard
Alain Viari: Synergie Lyon Cancer,Centre Léon Bérard
Anita Langerød: Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital
Anne-Lise Børresen-Dale: Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital
Ewan Birney: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
Hendrik G. Stunnenberg: Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen
Mike Stratton: Wellcome Trust Sanger Institute
John A. Foekens: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
John W. M. Martens: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.

Date: 2016
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DOI: 10.1038/ncomms12910

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