This large international study reveals that early-onset colorectal cancer (EOCRC, age <50) has distinct mutational patterns compared to late-onset disease, with hypermutated EOCRC showing higher mutational burden and unique gene mutation frequencies. These findings support the need for age-specific molecular profiling to guide clinical management of younger colorectal cancer patients.
Study Design & Population
- Study Type: International, multicohort, observational genomic analysis
- Sample Size: 17,133 tumor samples from 8 countries (Canada, China, France, Nigeria, South Korea, Spain, Netherlands, USA)
- Patient Demographics: 55.2% male, 44.8% female; 59.4% White, 22.8% Asian/Pacific Islander, 5.7% Black
- Study Population: 29.1% (4,983) had EOCRC, 70.9% had late-onset colorectal cancer (LOCRC)
- Analysis Methods: Whole-exome sequencing and targeted sequencing, stratified by tumor mutational burden (TMB)
Key Findings
- Hypermutated EOCRC: Significantly higher TMB than LOCRC (mean ratio 1.11, 95% CI 1.06-1.16, p<0.0001)
- Non-hypermutated EOCRC: Significantly lower TMB than LOCRC (mean ratio 2.92, 95% CI 2.88-2.96, p<0.0001)
- Gene-specific differences in hypermutated tumors: APC (75.0% vs 58.6%, OR 2.00), KRAS (53.3% vs 32.0%, OR 2.35), and CTNNB1 (31.6% vs 18.0%, OR 2.15) more frequently mutated in EOCRC
- BRAF mutations: Less frequent in EOCRC across both hypermutated (15.6% vs 44.2%, OR 0.27) and non-hypermutated (6.3% vs 8.6%, OR 0.70) groups
- TP53 mutations: Higher frequency in non-hypermutated EOCRC (79.5% vs 73.7%, OR 1.37)
Clinical Implications
- Age-specific molecular profiling may be warranted for colorectal cancer patients under 50 years
- Different mutational patterns suggest potentially different therapeutic targets between EOCRC and LOCRC
- Higher mutational burden in hypermutated EOCRC may indicate different immunotherapy responsiveness
- Findings may partly explain the alarming global increase in early-onset colorectal cancer incidence
Limitations
- Observational design cannot establish causality between mutations and disease onset
- Potential selection bias across different international cohorts and sequencing platforms
- Limited functional validation of identified mutational differences
- Therapeutic implications remain speculative pending clinical correlation studies
Source: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00239-6/abstract
