Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration.
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.
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Marcel
M
Smid
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
F Germán
FG
Rodríguez-González
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Anieta M
AM
Sieuwerts
Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium.|Department of Pathology/TCRU GZA, 2610 Antwerp, Belgium.
Roberto
R
Salgado
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Wendy J C
WJ
Prager-Van der Smissen
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Michelle van der
MV
Vlugt-Daane
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Anne
A
van Galen
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
Serena
S
Nik-Zainal
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden.
Johan
J
Staaf
Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525GA, Nijmegen, The Netherlands.
Arie B
AB
Brinkman
Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Marc J
MJ
van de Vijver
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Andrea L
AL
Richardson
Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Aquila
A
Fatima
Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525GA, Nijmegen, The Netherlands.
Kim
K
Berentsen
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.
Adam
A
Butler
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.
Sancha
S
Martin
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.
Helen R
HR
Davies
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Reno
R
Debets
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Marion E Meijer-Van
ME
Gelder
Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
Carolien H M
CH
van Deurzen
Département de Biopathologie,Institut Bergonié, CS 61283 33076 Bordeaux, France.
Gaëtan
G
MacGrogan
Department of Pathology/TCRU GZA, 2610 Antwerp, Belgium.|Molecular Immunology Unit, Jules Bordet Institute, B-1000 Brussels, Belgium.
Gert G G M
GG
Van den Eynden
Department of Pathology, Ninewells Hospital &Medical School, Dundee DD1 9SY, UK.
Colin
C
Purdie
Department of Pathology, Ninewells Hospital &Medical School, Dundee DD1 9SY, UK.
Alastair M
AM
Thompson
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Carlos
C
Caldas
Department of Radiation Oncology, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
Paul N
PN
Span
The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane 4029, Australia.
Peter T
PT
Simpson
The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane 4029, Australia.|Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
Sunil R
http://orcid.org/0000-0003-1879-2555
SR
Lakhani
Center for Oncological Research, University of Antwerp &GZA Hospitals Sint-Augustinus, 2610 Wilrijk, Belgium.
Steven
S
Van Laere
Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium.
Christine
C
Desmedt
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden.
Markus
M
Ringnér
IRCCS Istituto Tumori 'Giovanni Paolo II', 70124 Bari, Italy.
Stefania
S
Tommasi
Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
Jorunn
J
Eyford
The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
Annegien
A
Broeks
Department of Pathology and INSERM U934, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Anne
A
Vincent-Salomon
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230, USA.
P Andrew
PA
Futreal
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.|Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway.
Stian
S
Knappskog
Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York 10065, USA.
Tari
T
King
Synergie Lyon Cancer,Centre Léon Bérard, 28 rue Laënnec, Cedex 08 Lyon, France.
Gilles
G
Thomas
Synergie Lyon Cancer,Centre Léon Bérard, 28 rue Laënnec, Cedex 08 Lyon, France.|Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l'Europe, 38330 Montbonnot-Saint Martin, France.
Alain
A
Viari
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital, 0310, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, 0310 Oslo, Norway.
Anita
A
Langerød
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital, 0310, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, 0310 Oslo, Norway.
Anne-Lise
AL
Børresen-Dale
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton CB10 1SD, Cambridgeshire, UK.
Ewan
E
Birney
Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525GA, Nijmegen, The Netherlands.
Hendrik G
HG
Stunnenberg
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridge, UK.
Mike
M
Stratton
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
John A
JA
Foekens
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, 3015CN Rotterdam, The Netherlands.
John W M
JW
Martens
BMC Cancer. 2007 Sep 25;7:182
17894856
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W509-12
18463140
Nature. 2010 Jan 14;463(7278):191-6
20016485
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
10592173
Lancet. 2011 Nov 19;378(9805):1812-23
22098854
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
9843981
Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):E1754-62
25831525
Science. 2015 Apr 3;348(6230):124-8
25765070
J Mol Biol. 1982 May 5;157(1):105-32
7108955
Int J Cancer. 2010 Jul 15;127(2):355-60
19904758
Nature. 2000 Aug 17;406(6797):747-52
10963602
Oncogene. 2004 Oct 7;23(46):7669-78
15361840
BMC Bioinformatics. 2009 Nov 30;10:394
19948066
J Natl Cancer Inst. 2014 Dec 04;107(1):357
25479802
BMC Cancer. 2015 Nov 09;15:877
26553136
Biostatistics. 2010 Apr;11(2):242-53
20097884
Cancer Res. 2008 May 1;68(9):3108-14
18451135
Hum Pathol. 2015 Feb;46(2):182-90
25522926
Genome Biol. 2015 Aug 08;16:160
26253137
Am J Surg Pathol. 2007 Jan;31(1):121-8
17197928
Bioinformatics. 2004 Jan 1;20(1):93-9
14693814
EMBO J. 1995 Dec 15;14(24):6107-15
8557030
Oncogene. 1996 Nov 7;13(9):1919-25
8934538
Biostatistics. 2007 Jan;8(1):118-27
16632515
Clin Cancer Res. 2006 Feb 15;12(4):1157-67
16489069
Nature. 2013 Aug 22;500(7463):415-21
23945592
Cell. 2012 May 25;149(5):979-93
22608084
Endocr Relat Cancer. 2000 Sep;7(3):143-64
11021963
Nature. 2012 Apr 18;486(7403):346-52
22522925
Nature. 2012 Oct 4;490(7418):61-70
23000897
Nature. 2012 May 16;486(7403):400-4
22722201
Nature. 2012 Jun 20;486(7403):405-9
22722202
Science. 2015 Apr 3;348(6230):69-74
25838375
Nature. 2016 May 02;534(7605):47-54
27135926
Breast Cancer Res Treat. 2014 Jul;146(1):211-20
24839032
Cancer Res. 2009 Jan 15;69(2):663-71
19147582
N Engl J Med. 2014 Dec 4;371(23 ):2189-99
25409260
Carcinogenesis. 2012 Nov;33(11):2007-17
22822097
Breast Cancer Res Treat. 2012 Jun;133(2):583-94
22002566
Breast Cancer Res. 2007;9(3):R30
17504517
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
11553815
Cancer Res. 1992 Mar 1;52(5):1107-13
1737370
Protein Sci. 2003 May;12(5):1007-17
12717023