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; John W. M. Martens

doi:10.1038/ncomms12910

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 DeurzenGaëtan 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, John W. M. Martens (Lead / Corresponding author)

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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.

Original language	English
Article number	12910
Pages (from-to)	1-9
Number of pages	9
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12910
Publication status	Published - 26 Sept 2016

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Smid, M., Rodríguez-González, F. G., Sieuwerts, A. M., Salgado, R., Prager-Van der Smissen, W. J. C., Vlugt-Daane, M. V. D., van Galen, A., Nik-Zainal, S., Staaf, J., Brinkman, A. B., van de Vijver, M. J., Richardson, A. L., Fatima, A., Berentsen, K., Butler, A., Martin, S., Davies, H. R., Debets, R., Gelder, M. E. M.-V., ... Martens, J. W. M. (2016). Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration. Nature Communications, 7, 1-9. Article 12910. https://doi.org/10.1038/ncomms12910

@article{68d52ae054cf49408a17ba28e286e0c6,

title = "Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration",

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.",

author = "Marcel Smid and Rodr{\'i}guez-Gonz{\'a}lez, {F. Germ{\'a}n} and Sieuwerts, {Anieta M.} and Roberto Salgado and {Prager-Van der Smissen}, {Wendy J. C.} and Vlugt-Daane, {Michelle van der} and {van Galen}, Anne and Serena Nik-Zainal and Johan Staaf and Brinkman, {Arie B.} and {van de Vijver}, {Marc J.} and Richardson, {Andrea L.} and Aquila Fatima and Kim Berentsen and Adam Butler and Sancha Martin and Davies, {Helen R.} and Reno Debets and Gelder, {Marion E. Meijer-Van} and {van Deurzen}, {Carolien H. M.} and Ga{\"e}tan MacGrogan and {Van den Eynden}, {Gert G. G. M.} and Colin Purdie and Thompson, {Alastair M.} and Carlos Caldas and Span, {Paul N.} and Simpson, {Peter T.} and Lakhani, {Sunil R.} and {Van Laere}, Steven and Christine Desmedt and Markus Ringn{\'e}r and Stefania Tommasi and Jorunn Eyford and Annegien Broeks and Anne Vincent-Salomon and Futreal, {P. Andrew} and Stian Knappskog and Tari King and Gilles Thomas and Alain Viari and Anita Langer{\o}d and Anne-Lise B{\o}rresen-Dale and Ewan Birney and Stunnenberg, {Hendrik G.} and Mike Stratton and Foekens, {John A.} and Martens, {John W. M.}",

note = "This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project funded by the European Community{\textquoteright}s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006); the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z).",

year = "2016",

month = sep,

day = "26",

doi = "10.1038/ncomms12910",

language = "English",

volume = "7",

pages = "1--9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Smid, M, Rodríguez-González, FG, Sieuwerts, AM, Salgado, R, Prager-Van der Smissen, WJC, Vlugt-Daane, MVD, van Galen, A, Nik-Zainal, S, Staaf, J, Brinkman, AB, van de Vijver, MJ, Richardson, AL, Fatima, A, Berentsen, K, Butler, A, Martin, S, Davies, HR, Debets, R, Gelder, MEM-V, van Deurzen, CHM, MacGrogan, G, Van den Eynden, GGGM, Purdie, C, Thompson, AM, Caldas, C, Span, PN, Simpson, PT, Lakhani, SR, Van Laere, S, Desmedt, C, Ringnér, M, Tommasi, S, Eyford, J, Broeks, A, Vincent-Salomon, A, Futreal, PA, Knappskog, S, King, T, Thomas, G, Viari, A, Langerød, A, Børresen-Dale, A-L, Birney, E, Stunnenberg, HG, Stratton, M, Foekens, JA & Martens, JWM 2016, 'Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration', Nature Communications, vol. 7, 12910, pp. 1-9. https://doi.org/10.1038/ncomms12910

TY - JOUR

T1 - Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

AU - Smid, Marcel

AU - Rodríguez-González, F. Germán

AU - Sieuwerts, Anieta M.

AU - Salgado, Roberto

AU - Prager-Van der Smissen, Wendy J. C.

AU - Vlugt-Daane, Michelle van der

AU - van Galen, Anne

AU - Nik-Zainal, Serena

AU - Staaf, Johan

AU - Brinkman, Arie B.

AU - van de Vijver, Marc J.

AU - Richardson, Andrea L.

AU - Fatima, Aquila

AU - Berentsen, Kim

AU - Butler, Adam

AU - Martin, Sancha

AU - Davies, Helen R.

AU - Debets, Reno

AU - Gelder, Marion E. Meijer-Van

AU - van Deurzen, Carolien H. M.

AU - MacGrogan, Gaëtan

AU - Van den Eynden, Gert G. G. M.

AU - Purdie, Colin

AU - Thompson, Alastair M.

AU - Caldas, Carlos

AU - Span, Paul N.

AU - Simpson, Peter T.

AU - Lakhani, Sunil R.

AU - Van Laere, Steven

AU - Desmedt, Christine

AU - Ringnér, Markus

AU - Tommasi, Stefania

AU - Eyford, Jorunn

AU - Broeks, Annegien

AU - Vincent-Salomon, Anne

AU - Futreal, P. Andrew

AU - Knappskog, Stian

AU - King, Tari

AU - Thomas, Gilles

AU - Viari, Alain

AU - Langerød, Anita

AU - Børresen-Dale, Anne-Lise

AU - Birney, Ewan

AU - Stunnenberg, Hendrik G.

AU - Stratton, Mike

AU - Foekens, John A.

AU - Martens, John W. M.

N1 - This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006); the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z).

PY - 2016/9/26

Y1 - 2016/9/26

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms12910

DO - 10.1038/ncomms12910

M3 - Article

C2 - 27666519

SN - 2041-1723

VL - 7

SP - 1

EP - 9

JO - Nature Communications

JF - Nature Communications

M1 - 12910

ER -

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

Abstract

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