Micro-environmental changes indicate potential for subclinical intestinal tissue damage in early-age-onset colorectal...

While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer (CRC), the incidence of early-age-onset CRC (EAO CRC; age <50 years) has increased. Here, we characterize the genetic alterations and tumor microenvironment (TME) for EAO and later-age-onset (LAO) CRCs to identify relevant biological differences that might point to etiologic factors.

A cohort of EAO (n = 60) and LAO (n = 93) CRC patients were evaluated for mutations by using targeted DNA sequencing and for TME differences by using immunohistochemistry and immunofluorescence. The Cancer Genome Atlas (TCGA) PanCancer Atlas colorectal adenocarcinoma cohort was evaluated for transcriptional changes between EAO (n = 82) and LAO (n = 510) patients.

KRAS and BRAF mutations were less frequent in EAO CRCs. Gene-set enrichment analysis of TCGA data revealed the downregulation of immune-related pathways in EAO CRCs. Both age cohorts had similar numbers of CD8⁺ tumor-infiltrating lymphocytes (TILs), although LAO patients had more CD4⁺ TILs and Th1-polarized CD4s. While significant associations between immune subsets and versican (VCAN), versikine, and alpha-smooth muscle actin (αSMA) were found, none of these trends differed between age cohorts. EAO patients trended towards greater VCAN accumulation in adjacent normal tissue, lower rates of VCAN proteolysis, and decreased αSMA accumulation vs LAO patients.

Overall, established EAO cancers are similar to LAO cancers in mutational profile and key TME features. High VCAN and αSMA expression in adjacent normal colon indicates a presence of factors that are associated with increased intestinal subclinical inflammation. Future mechanistic studies will be conducted to better understand the importance of these findings and related processes should be prioritized as potential etiologic factors for EAO tumorigenesis.