Microbiome signature, immune landscape and global methylation in early onset colorectal cancer.

Abstract

3580 Background: The incidence of colorectal cancer (CRC) in young adults (age at diagnosis < 50 years old) has been rapidly increasing. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as Western diet may be associated with increased incidence of sporadic EO CRC. The gut microbiota decomposes and ferments dietary fibers to produce microbial metabolites, which play important roles in maintaining the intestinal epithelium integrity. A high-fat, low-fiber diet has been associated with intestinal dysbiosis, which disrupts intestinal bacterial homeostasis. An increased inflammation state characterizes dysbiosis and may promote an immunosuppressive tumor microenvironment (TME) and suppress antitumor immune surveillance. In addition, epigenetic modifications are influenced by environmental changes and therefore epigenetics may bridge the knowledge gap in understanding the development of sporadic EOCRC. Methods: We obtained RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Oncology Research Information Exchange Network (ORIEN) from the Ohio State University biospecimen services to characterize intra-tumor microbiota composition, tumor-infiltrating lymphocytes (TILs) and differential pathways in EO CRC. We used Infinium HM450 methylation array in The Cancer Genome Atlas (TCGA) and performed genome-wide analyses using reduced representation bisulfite sequencing (RRBS) method to identify differentially methylated regions (DMRs) in EO CRC. Results: Gene expression analysis is consistent with Fusobacterium promoting inflammation in EO CRC. Intra-tumor microbes are positively correlated with M2 macrophages. Compared to late onset (LO) CRC, EO CRC patients have unique gene signatures of phagosome formation, S100 family signaling pathway and CREB signaling in neurons by using ingenuity pathway analysis (IPA). In addition, we found that methylation ages predicted by epigenetic clocks in EO CRC patients were 15 years older on average than their chronological ages, whereas methylation ages in late onset (LO) CRC patients were comparable with chronological ages. The enriched pathways based on DMRs associated with EO CRC have significant overlap with canonical pathways based on differentially expressed genes (DEGs), including CREB signaling in neurons and S100 family signaling pathways. Conclusions: These data suggest that pathogenic microbes may induce inflammation, which leads to accelerated aging in EO CRC.