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Nat Commun. 2016 Sep 26;7:12910. doi: 10.1038/ncomms12910.

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

Author information

1
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
2
Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium.
3
Department of Pathology/TCRU GZA, 2610 Antwerp, Belgium.
4
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.
5
East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
6
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden.
7
Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525GA, Nijmegen, The Netherlands.
8
Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
9
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
10
Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
11
Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
12
Département de Biopathologie,Institut Bergonié, CS 61283 33076 Bordeaux, France.
13
Molecular Immunology Unit, Jules Bordet Institute, B-1000 Brussels, Belgium.
14
Department of Pathology, Ninewells Hospital &Medical School, Dundee DD1 9SY, UK.
15
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
16
Department of Radiation Oncology, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
17
Department of Laboratory Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
18
The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane 4029, Australia.
19
Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
20
Center for Oncological Research, University of Antwerp &GZA Hospitals Sint-Augustinus, 2610 Wilrijk, Belgium.
21
IRCCS Istituto Tumori 'Giovanni Paolo II', 70124 Bari, Italy.
22
Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
23
The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
24
Department of Pathology and INSERM U934, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
25
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230, USA.
26
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
27
Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway.
28
Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York 10065, USA.
29
Synergie Lyon Cancer,Centre Léon Bérard, 28 rue Laënnec, Cedex 08 Lyon, France.
30
Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l'Europe, 38330 Montbonnot-Saint Martin, France.
31
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital, 0310, Oslo, Norway.
32
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, 0310 Oslo, Norway.
33
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton CB10 1SD, Cambridgeshire, UK.

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.

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