Genomic Landscape of Early-Onset Colorectal Cancer: A Comparative Analysis With Average-Onset Metastatic Colorectal Cancer in a Real-World NGS Cohort.

The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before age 50 years, has been rising globally, in contrast to declining rates in older populations. However, despite its distinct clinical features, the genomic characteristics of EOCRC and its biological relationship to average-onset CRC (AOCRC) remain incompletely defined, particularly in the metastatic setting. We conducted a genomic analysis of patients with metastatic CRC who underwent next-generation sequencing (NGS) as part of routine clinical practice. Using targeted NGS panels (TruSight Oncology 500 and Oncomine Comprehensive Assay), we analyzed the genomic landscape of 1,892 patients, including 376 with EOCRC and 1,516 with AOCRC. Genomic alteration frequencies were compared between age groups, and age-stratified analyses were performed to evaluate associations between patient age and recurrent genomic alterations. The overall genomic landscape was largely similar between EOCRC and AOCRC, with comparable frequencies of canonical CRC drivers, including TP53, APC, and KRAS. MYC alterations were significantly more frequent in EOCRC than in AOCRC. By contrast, age-stratified analyses revealed an inverse association between age at diagnosis and alteration rates in specific DNA damage repair-related genes and tumor suppressor genes, including BRCA2, BARD1, FAT1, HIST1H1C, and LRP1B, whereas canonical drivers showed no significant age-dependent trends. In metastatic disease, EOCRC shares a conserved canonical genomic backbone with AOCRC, indicating that it is not a genomically distinct entity. Nevertheless, limited binary differences involving MYC and broader age-dependent enrichment of specific DNA damage response-related alterations suggest that CRC arising at younger age may reflect distinct age-associated biological vulnerabilities.