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

Marcel Smid 1 F. Germán Rodríguez-González 1 Anieta M. Sieuwerts 1 Roberto Salgado 2 Wendy J. C. Prager-van der Smissen 1 Michelle van Der Vlugt-Daane 1 Anne van Galen 1 Serena Nik-Zainal 3 Johan Staaf 4 Arie B. Brinkman 5 Marc J. van de Vijver 6 Andrea L. Richardson 7 Aquila Fatima 1 Kim Berentsen 5 Adam Butler 3 Sancha Martin 3 Helen R. Davies 3 Reno Debets 1 Marion E. Meijer-Van Gelder 1, 8 Carolien H. M. van Deurzen 1 Gaëtan Macgrogan 9 Gert G. G. M. van den Eynden 10 Colin Purdie 11 Alastair M. Thompson 11 Carlos Caldas 12 Paul N. Span 13, 14 Peter T. Simpson 15 Sunil R. Lakhani 15 Steven van Laere 16, 17 Christine Desmedt 2 Markus Ringnér 4 Stefania Tommasi 18 Jorunn Eyford 19 Anne Broeks 20 Anne Vincent-Salomon 21, 22 P. Andrew Futreal 23 Stian Knappskog 24 Tari A King 25 Gilles Thomas 26 Alain Viari 27, 28 Anita Langerød 29 Anne-Lise Børresen-Dale 29 Ewan Birney 3 Hendrik G. Stunnenberg 30 Mike Stratton 3 John A. Foekens 1 John W. M. Martens 1
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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Marcel Smid, F. Germán Rodríguez-González, Anieta M. Sieuwerts, Roberto Salgado, Wendy J. C. Prager-van der Smissen, et al.. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration. Nature Communications, Nature Publishing Group, 2016, 7, ⟨10.1038/ncomms12910⟩. ⟨hal-01388445⟩

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