Distinct clinical and genomic profiles of braf mutation subtypes in Chinese colorectal cancer: a retrospective cohort study with cross-population validation

To characterize the clinicogenomic features, prognostic significance and therapeutic implications of BRAF mutation subtypes in Chinese colorectal cancer (CRC) patients. We performed integrated genomic and clinical analyses on 146 BRAF-mutant colorectal cancers identified within a cohort of 2,446 consecutive CRC patients at Fudan University Shanghai Cancer Center (FUSCC) encompassing surgical, neoadjuvant, and advanced disease. Targeted sequencing defined genomic profiles, benchmarking against the western cohorts (TCGA/MSKCC). Clinical outcomes including overall survival (OS), metastasis site, and treatment response were assessed. Isogenic cell line models validated functional impacts of BRAF variants. The FUSCC cohort exhibited a lower overall frequency of BRAF mutations, with V600E accounting for 54.1% of BRAF mutant cases. Compared with the western cohorts, Chinese patients harboring BRAF mutations were younger at diagnosis, presented with fewer metastatic cases, and displayed distinct co-mutation patterns, notably a higher prevalence of BRAFV600E-TP53 co-mutations which predicted poor prognosis. The BRAFV600E subtype was associated with significantly worse OS, an increased risk of peritoneal metastasis, female, advanced disease stage, and poor tumor differentiation compared with BRAFnon−V600E patients. In contrast, non-V600E tumors exhibited a higher tumor mutational burden. In vitro functional assays further confirmed that BRAFV600E mutant cells possessed enhanced proliferative and invasive capacities. Clinically, patients with BRAFV600E mutations demonstrated inferior responses to first-line therapy compared with non-V600E cases (ORR: 21.1% vs. 63.2%; P < 0.01), particularly in those receiving bevacizumab-based regimens. BRAFV600E defines an aggressive CRC subset in Chinese patients with distinct genomic and clinical features, supporting the need for population-tailored precision oncology strategies in Asian populations.