Differences in Somatic Mutations Between Early-Onset and Late-Onset Colorectal Cancer: A Systematic Review and...

Early-onset colorectal cancer (EOCRC, diagnosed <50 years) is increasing globally and presents with advanced clinicopathological features, yet its mutational landscape compared to late-onset CRC (LOCRC) remains poorly defined.

We systematically searched PubMed and Embase (January 2016-December 2025) for studies comparing somatic mutations between EOCRC and LOCRC. Two reviewers independently screened 1880 records; 43 studies met inclusion criteria. Two public datasets (TCGA, China PanCancer) were also included. Meta-analyses were conducted using random-effects models with Review Manager. Subgroup analysis was restricted to microsatellite-stable (MSS) tumors. Meta-regression evaluated study-level differences in tumor sidedness and stage distribution as sources of heterogeneity. The primary outcome was odds ratios (OR) for mutations in 10 driver genes.

Among 154,982 participants, 33,937 (21.9%) had EOCRC. In the overall analysis, EOCRC showed higher frequencies of TP53 (OR 1.13), SMAD4 (OR 1.15), and PTEN mutations (OR 1.77), and lower frequencies of APC (OR 0.73), KRAS (OR 0.94), and BRAF mutations (OR 0.69). In MSS-restricted analysis, differences persisted for TP53, SMAD4, APC, and KRAS, whereas PTEN and BRAF differences became non-significant. Additionally, NRAS (OR 0.74) and PIK3CA mutations (OR 0.89) were less frequent in MSS-EOCRC. Meta-regression showed that study-level differences in left-sided tumor distribution were associated with lower relative BRAF mutation frequency in EOCRC (β = -5.08, 95% CI -7.66 to -2.49, p < 0.001).

EOCRC exhibits a different mutational profile with higher TP53 and SMAD4 and lower APC and KRAS mutations. These findings highlight the need for further research into alternative mechanisms of CRC carcinogenesis among younger adults.