Molecular differences between early- and later-onset colorectal cancer in a Chilean cohort: A retrospective MSI and NGS-based analysis.

3670 Background: The incidence of early-onset colorectal cancer (EOC) is increasing worldwide; however, molecular data from Latin American populations remain scarce. We compared molecular alterations, including microsatellite instability (MSI) status and selected next-generation sequencing (NGS)–derived gene alterations, between EOC and later-onset colorectal cancer (LOC) in a Chilean cohort. Methods: We conducted a retrospective analysis of patients diagnosed with colorectal cancer with MSI assessment and/or NGS testing available between March 2017 and September 2025 at a private hospital in Chile. MSI status was determined by immunohistochemistry and/or PCR. In-house NGS panels were analyzed. Clinical variables included age at diagnosis, sex, and tumor location. EOC was defined as diagnosis <50 years and LOC as ≥50 years. Molecular alterations were compared using Fisher exact test, reporting odds ratios (OR) with Benjamini–Hochberg false discovery rate (FDR) correction. Results: A total of 324 patients were included (EOC n=66; LOC n=258). Median age was 42.6 years in EOC and 66.5 years in LOC. Tumor sidedness was comparable between groups, with a predominance of left-sided tumors in both EOC (54.5%) and LOC (61.2%). MSI status was available in 310 patients; MSI-H prevalence was 10.8% in EOC and 15.1% in LOC (OR 0.68, 95% CI 0.29–1.59; p=0.43). NGS denominators varied by gene according to panel coverage. No individual gene showed statistically significant differences after FDR correction. Pathway-level trends were observed (Table 1). In the WNT pathway, APC alterations were more frequent in EOC (83.3% vs 52.2%; OR 4.60; p=0.059). In the MAPK pathway, KRAS alterations were numerically higher in LOC (55.2% vs 37.5%; OR 0.49; p=0.13), while BRAF alterations were more frequent in EOC (16.7% vs 8.3%; OR 2.20; p=0.29). In the PI3K pathway, PIK3CA (29.2% vs 15.6%; OR 2.22; p=0.12) and PTEN (8.3% vs 2.1%; OR 4.27; p=0.15) alterations trended higher in EOC. TP53 alterations were highly prevalent and similar across groups. Conclusions: In this Chilean cohort, EOC and LOC showed similar MSI prevalence and largely overlapping molecular profiles. Although no gene-level differences remained significant after multiple-testing correction, pathway-specific trends suggest increased WNT and PI3K alterations in EOC and higher MAPK signaling in LOC. These findings highlight the need for larger, uniformly sequenced studies in Latin American populations. Selected pathway-specific molecular alterations. Category Gene EOC n/N (%) LOC n/N (%) OR p WNT APC 10/12 (83,3) 36/69 (52,2) 4,60 0,059 MAPK KRAS 9/24 (37,5) 53/96 (55,2) 0,49 0,13 BRAF 4/24 (16,7) 8/96 (8,3) 2,20 0,29 PI3K PIK3CA 7/24 (29,2) 15/96 (15,6) 2,22 0,12 PTEN 2/24 (8,3) 2/96 (2,1) 4,27 0,15 DDR ATM 1/24 (4,2) 5/96 (5,2) 0,80 1,00 TGF-β SMAD4 3/24 (12,5) 7/96 (7,3) 1,81 0,47 Cell cycle TP53 15/24 (62,5) 62/96 (64,6) 0,91 1,00