Abstract 2630: Integration of tumor microenvironment and molecular subclassification of colorectal cancer identifies patient subsets with poor prognosis

Abstract The patho-molecular diversity of colorectal cancer (CRC) complicates the prediction of patient postoperative prognosis and response to treatment. This calls for methods for CRC stratification beyond clinical features and the few molecular biomarkers currently implemented. Recent studies have highlighted the importance of the tumor microenvironment in CRC. Here we show by integrative transcriptome/methylome analysis of >300 patient samples that CRC generates five arche-typic microenviroments encompassing three molecularly distinct types of cancer cells. The existence of the microenviroments, which we denote “Secretory”, “Stroma”, “Immune”, “ARE”, and “CIN”, could be independently identified in large external CRC datasets and are in concordance with the CRC subtypes recently defined by the CRC Subtyping Consortium (1). Detailed analysis of the five microenvironments reveals striking differences in cell composition and pathway activity. We observe that the microenvironment, particularly immune and stromal cell activity, is closely associated with patient prognosis. In particular, tumors associated with low anti-tumoral immune activity due to poor recruitment of immune cells or immune inhibition by activated stromal cells have poor prognosis. Importantly, we find that microenviroment subtyping is in fact pivotal for molecular prediction of patient prognosis as no single molecular marker carries robust prognostic information in all CRC subtypes and environments. Instead, potent prognostic biomarkers are environment-specific: As an example interferon signaling is deregulated in several microenviroment types, yet the specific interferon response genes deregulated (i.e. biomarker candidates) differ between microenvironments in accordance with their cellular composition. Our approach has allowed us to identify superior, single prognostic biomarkers for each CRC type and, importantly, their prognostic value in external datasets is only observed after environment subtyping. Collectively, these observations may well explain the poor validation rate of prognostic biomarker candidates in the past. In conclusion: we provide a CRC microenvironment framework that has the potential to guide future clinical decision-making primarily in relation to prognosis, but likely also in relation to therapy choice. This work is performed within framework the SYSCOL consortium funded by EU FP7 (1) Guinney, J. et al. “The consensus molecular subtypes of colorectal cancer”, Nature Medicine (2015) doi:10.1038/nm.3967 Citation Format: Jesper B. Bramsen, Mads H. Rasmussen, Halit Ongen, Søren Vang, Philippe Lamy, Manel B. Esteller, Emmanouil T. Dermitzakis, Torben F. Orntoft, Claus L. Andersen. Integration of tumor microenvironment and molecular subclassification of colorectal cancer identifies patient subsets with poor prognosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2630.