Patterns in genomic mutations among patients with early-onset colorectal cancer: an international, multicohort, observational study

Background The increasing incidence of early-onset colorectal cancer (age <50 years; EOCRC) shows a dramatic growing trend globally, while late-onset colorectal cancer (LOCRC) is gradually decreasing. We aimed to characterise the distinct mutational landscape of EOCRC in an effort to inform age-specific clinical management. Methods In this observational study, we analysed whole-exome sequencing and clinical-grade targeted sequencing data from seven cohorts (the Memorial Sloan Kettering Cancer Center [MSKCC] cohort [the USA], the Leiden University Medical Center cohort [the Netherlands], the Nigerian African Research Group for Oncology [ARGO] cohort [Nigeria], the Genomics Evidence Neoplasia Information Exchange [GENIE] Project [Canada, France, Spain, and the USA], the Sun Yat-sen University Cancer Center (SYSUCC) cohort [China], the Asan Medical Center cohort [South Korea], and the Fudan University Shanghai Cancer Center-Colorectal Cancer [FUSCC-CRC] cohort [China]) across Canada, China, France, Nigeria, South Korea, Spain, the Netherlands, and the USA. Eligible patients were aged 18 years or older with a confirmed diagnosis of colorectal adenocarcinoma or mucinous adenocarcinoma. Samples were categorised into hypermutated (tumour mutational burden [TMB] >15 mutations per megabase) and nonhypermutated (TMB <= 15 mutations per megabase) groups. We evaluated the TMB difference between EOCRC and LOCRC using gamma regression and compared genomic mutation data between EOCRC and LOCRC using multiple logistic regression and pathway enrichment analysis. The primary study objective was to compare genomic mutational patterns between EOCRC and LOCRC, stratified by TMB groups. Findings Between Jan 1 and Dec 31, 2024, 17 133 tumour samples from patients with colorectal cancer in eight countries were analysed (Canada [n=218], China [n=3009], France [n=62], Nigeria [n=64], South Korea [n=44], Spain [n=250], the Netherlands [n=281], and the USA [n=13 205]). Among 17 133 patients, 9452 (55<middle dot>2%) were male, 7681 (44<middle dot>8%) were female, 10 174 (59<middle dot>4%) were White, 3904 (22<middle dot>8%) were Asian or Pacific Islander, 983 (5<middle dot>7%) were Black, and 4983 (29<middle dot>1%) had EOCRC. In hypermutated colorectal cancer, EOCRC exhibited a significantly higher TMB compared with LOCRC (mean ratio 1<middle dot>11 [95% CI 1<middle dot>06-1<middle dot>16]; p<0<middle dot>0001). In non-hypermutated colorectal cancer, EOCRC showed a significantly lower TMB than LOCRC after adjusting for skewness (mean ratio 2<middle dot>92 [95% CI 2<middle dot>88-2<middle dot>96]; p<0<middle dot>0001).In hypermutated colorectal cancer, a total of 23 genes, including APC (EOCRC 464 [75<middle dot>0%] of 619 vs LOCRC 891 [58<middle dot>6%] of 1521; odds ratio [OR] 2<middle dot>00 [95% CI 1<middle dot>59-2<middle dot>51]; adjusted p<0<middle dot>0001), KRAS (EOCRC 331 [53<middle dot>3%] of 621 vs LOCRC 488 [32<middle dot>0%] of 1526; OR 2<middle dot>35 [95% CI 1<middle dot>91-2<middle dot>89]; adjusted p<0<middle dot>0001), and CTNNB1 (EOCRC 196 [31<middle dot>6%] of 621 vs LOCRC 274 [18<middle dot>0%] of 1526; OR 2<middle dot>15 [95% CI 1<middle dot>70-2<middle dot>72]; adjusted p<0<middle dot>0001), and TCF7L2 (EOCRC 294 [51<middle dot>2%] of 574 vs LOCRC 489 [35<middle dot>0%] of 1398; OR 2<middle dot>01 [95% CI 1<middle dot>62-2<middle dot>50]; adjusted p<0<middle dot>0001), displayed elevated mutation frequencies in EOCRC compared with LOCRC, whereas only BRAF (EOCRC 97 [15<middle dot>6%] of 621 vs LOCRC 674 [44<middle dot>2%] of 1526; OR 0<middle dot>27 [95% CI 0<middle dot>21-0<middle dot>35]; adjusted p<0<middle dot>0001) and RNF43 (EOCRC 225 [39<middle dot>3%] of 573 vs LOCRC 778 [53<middle dot>9%] of 1444; OR 0<middle dot>61 [95% CI 0<middle dot>49-0<middle dot>76]; adjusted p=0<middle dot>0015) were less frequently mutated in EOCRC than in LOCRC. In non-hypermutated colorectal cancer, only TP53 (EOCRC 3468 [79<middle dot>5%] of 4362 vs LOCRC 7825 [73<middle dot>7%] of 10 624; OR 1<middle dot>37 [95% CI 1<middle dot>25-1<middle dot>50]; adjusted p<0<middle dot>0001) showed a higher mutation frequency in EOCRC, while nine genes had lower mutation frequencies, including BRAF (EOCRC 274 [6<middle dot>3%] of 4362 vs LOCRC 909 [8<middle dot>6%] of 10 624; OR 0<middle dot>70 [95% CI 0<middle dot>60-0<middle dot>81]; adjusted p=0<middle dot>00024) and KRAS (EOCRC 1794 [41<middle dot>1%] of 4362 vs LOCRC 4840 [45<middle dot>6%] of 10624; OR 0<middle dot>83 [95% CI 0<middle dot>77-0<middle dot>89]; adjusted p=0<middle dot>00019). Interpretation Within hypermutated colorectal cancer, younger patients exhibited a higher mutational burden than older patients. Our study reveals an abnormal accumulation of distinct somatic mutations in hypermutated EOCRC, the pattern of which might be contributing to the alarming rise in the incidence of EOCRC over the past decades. Our results support the need for EOCRC-specific molecular profiling to guide clinical practice. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.