Comprehensive genomic landscape of early-onset colorectal cancer: A comparative analysis with average-onset metastatic colorectal cancer in a next-generation sequencing cohort of 1,892 patients.

Abstract

e15596 Background: The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 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 colorectal cancer (AOCRC) remain incompletely defined, particularly in the metastatic setting. Methods: We conducted a genomic analysis of patients with metastatic colorectal cancer (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. Results: A total of 1,892 patients with metastatic colorectal cancer were analyzed, including 376 (19.9%) with early-onset CRC (EOCRC) and 1,516 with average-onset CRC (AOCRC). EOCRC patients had a median age of 44 years and were mainly aged 40–49 years. While the overall cohort was male predominant, EOCRC showed a higher proportion of female patients. Tumor mutational burden (TMB) was comparable between groups, though TMB-high tumors were more frequent in AOCRC. MSI-H tumors were rare but occurred more often in EOCRC, and all MSI-H tumors were TMB-high. PD-L1 positivity (CPS ≥1) was infrequent and showed no clear association with TMB or MSI. Genomic profiling of EOCRC revealed frequent alterations in TP53, APC, and KRAS, with common TP53–APC co-alterations. DNA damage repair–related genes, including BRCA2 and BARD1, were frequently altered. Comparative analysis demonstrated largely similar genomic landscapes between EOCRC and AOCRC; however, MYC alterations were significantly enriched in EOCRC. MSI-stratified analysis showed distinct genomic patterns, with MSS tumors dominated by chromosomal instability drivers, whereas MSI-H tumors exhibited a heterogeneous mutational landscape. Within EOCRC, several DDR-related genes showed higher alteration frequencies in younger patients, while major CRC drivers were not age-associated. Conclusions: 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 colorectal cancer arising at younger ages may reflect distinct age-associated biological vulnerabilities.