Abstract P6-08-10: Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways
Authors: JWM Martens, M Smid, G Rodríguez-González, AM Sieuwerts, WJC Prager-Van der Smissen, M Van Der Vlugt - Daane, A Van Galen, S Nik-Zainal, J Staaf, AB Brinkman, MJ Van de Vijver, AL Richardson, K Berentsen, C Caldas, A Butler, S Martin, HD Davies, R Debets, ME Meijer-Van Gelder, CHM Van Deurzen, MR Ramakrishna, M Ringnér, A Viari, E Birney, A-L Børresen-Dale, HG Stunnenberg, M Stratton, JA Foekens
Journal: Cancer Research (2016)

Abstract A comprehensive whole genome analysis of a large breast cancer cohort of 560 cases (Nik-Zainal et al, submitted 2015) reports novel and existing DNA substitution and rearrangement signatures next a comprehensive list of events driving the breast cancer cell to its malignant potency. In the current study, we linked the observed genetic diversity to the breast cancer transcriptome for 260 cases for which whole genome and whole transcriptome data were both available. Cluster analysis of the global gene expression showed the familiar view of a coherent basal-like and a heterogeneous luminal subgroup. New and previously reported1 subtype-specific aberrations with concordant expression changes were found in TP53, PIK3CA, PTEN, CCND1, CDH1 and GATA3, and mutations in PIK3CA, PTEN, AKT1 and AKT2 were mutually exclusive confirming they are active in the same pathway in breast cancer. Integrating the identified DNA substitutions signatures with the transcriptome, we observed that the total number of substitutions in a cancer, irrespective of substitution type, was positively associated with cell cycle regulated gene expression and with adverse outcome. In addition and more remarkably, we observed that the number substitution of two substitution signatures2 particularly associated with immune-response specific gene expression, with increased amount of tumor infiltrating lymphocytes and with a better outcome. These two signatures comprised 1) mutations of the APOBEC-type (predominant C&amp;gt;G in a TCN context), and 2) mutations which lacks specific features but which are strongly associated with genetic and epigenetic inactivating aberrations in BRCA1 and BRCA2. Thus, while earlier reports3-5 imply that the sheer number of driver events triggers an immune-response, we refine this statement by observing that substitutions of a particular type are much very effective in doing so explaining the superior outcome of cancer having these particular types of substitutions. This result also implies that purposefully augmenting T-cell reactivity against amino-acid substitutions resulting from either of these two DNA substitution types could potentially improve immunotherapies in breast cancer. 1. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012). 2. Alexandrov, L.B., et al. Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013). 3. Rizvi, N.A., et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015). 4. Schumacher, T.N. &amp; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 348, 69-74 (2015). 5. Snyder, A., et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189-2199 (2014). Citation Format: Martens JWM, Smid M, Rodríguez-González G, Sieuwerts AM, Prager-Van der Smissen WJC, Van Der Vlugt - Daane M, Van Galen A, Nik-Zainal S, Staaf J, Brinkman AB, Van de Vijver MJ, Richardson AL, Berentsen K, Caldas C, Butler A, Martin S, Davies HD, Debets R, Meijer-Van Gelder ME, Van Deurzen CHM, Ramakrishna MR, Ringnér M, Viari A, Birney E, Børresen-Dale A-L, Stunnenberg HG, Stratton M, Foekens JA. Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-08-10.