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INTRODUCTION:Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management.

METHODS:Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases.

RESULTS:The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated) (all Ptrend<0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors (P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend<0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend.

DISCUSSION:Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.