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Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation. Cancer Res; 75(10); 2120–30. ©2015 AACR.

Introduction: Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for tumor subclassification and patient stratification. Methods: Infinium 450k and EPIC data from of non-malignant colorectal adenomas was applied to a consensus clustering algorithm. This defined epigenetic subtypes that were subsequently tested for clinico-pathological features, such as morphology and mutation status. Additionally, the subtypes were compared with Infinium 450k data from colonic crypt sections and also colorectal cancer samples provided by The Cancer Genome Atlas. Finally, clinical significance was addressed by testing for subtype specific overall survival rates. Results: The analysis of the adenoma dataset defined 3 distinct epigenetic subtypes of human premalignant lesions. These 3 subtypes also reflect 3 of 4 epigenetic subtypes identified in colorectal cancer. The fourth, cancer-specific subtype represents the previously known subclass defined by microsatellite instability phenotype and the CpG island methylator phenotype. Comparisons to Crypt section methylomes and to other reference methylomes revealed that the other 3 subtypes represent epigenetic programs reflecting various intestinal crypt cell differentiation stages. Patient survival correlated with the differentiation stages with a particular poor prognosis for patients with stem cell-related epigenetic signatures. Conclusion: Our results establish a novel and clinically relevant approach for colorectal adenoma and cancer classification and illustrate how differences in the cell-type of origin shape the tumor methylome. Citation Format: Felix Bormann, Manuel Rodríguez-Paredes, Felix Lasitschka, Dominic Edelmann, Axel Benner, Yehudit Bergman, Claudia R. Ball, Hanno Glimm, Heinz G. Linhart, Frank Lyko. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3305.