Epigenetic Modulation, Intratumoral Microbiome, and Immunity in Early-Onset Colorectal Cancer.

[UNLABELLED] The incidence of colorectal cancer in young adults (age of diagnosis <50 years) has been rapidly increasing. Although ∼20% of early-onset colorectal cancer (EOCRC) cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. Nongenetic factors such as environmental exposure and lifestyle changes are likely to have a direct link to the increased incidence of sporadic EOCRC. We hypothesize that such factors may be observable as alterations in the epigenome, microbiome, and immunome. We characterized the DNA methylation (DNAm) signature and measured DNAm age in EOCRC by using The Cancer Genome Atlas (TCGA). Furthermore, we carefully identified intratumoral microbes from TCGA and the Oncology Research Information Exchange Network datasets and then related the microbes to deconvolved immune cell abundances in EOCRC. We observed that the DNAm age in the EOCRC cohort was 12 years older when compared with the average-onset colorectal cancer (AOCRC) cohort, using three different epigenetic clocks. Differentially methylated sites associated with gene expression include cAMP-responsive element binding protein signaling in neurons, G protein-coupled receptor signaling, phagosome formation, and S100 family signaling. These differences were validated in the gene expression data from TCGA and the Oncology Research Information Exchange Network. When comparing the intratumoral microbes between EOCRC and AOCRC, no consistent differences were observed. Interestingly, the most abundant microbes interacted with the immune systems differently between the EOCRC and AOCRC tumors, characterized by more and larger positive correlations in EOCRC. These data suggest that epigenetic modulation and accelerated aging may play a key role in the development of EOCRC.

[SIGNIFICANCE] We investigated whether environmentally driven factors contribute to EOCRC. We observed accelerated epigenetic aging in EOCRC and epigenetic changes associated with chronic inflammation. Tumor immune cell abundances correlated more strongly with microbes in EOCRC than in AOCRC. These data suggest a dysregulation of the immune response in EOCRC, driving chronic inflammation and tissue aging.