Global Mapping of KRAS, NRAS, and BRAF V600E Prevalence and Co-mutation Patterns in Colorectal Cancer: A Systematic Review and Meta-analysis

Abstract Colorectal cancer (CRC) is a major global health challenge, yet reliable molecular epidemiology remains unevenly distributed across regions, particularly in low- and middle-income settings. Mutations in KRAS, NRAS, and BRAF define biologically distinct subgroups that influence prognosis and guide anti-EGFR therapy, but reported prevalence varies widely across studies and platforms. We conducted a systematic review and meta-analysis to generate updated, region-stratified prevalence estimates for these MAPK pathway mutations, evaluate methodological determinants of variability, and summarize clinically relevant co-mutation patterns. Following PRISMA 2020 guidelines, PubMed, Google Scholar, and ScienceDirect were searched for studies published from January 1, 2009 to December 1, 2023. Studies were eligible if they reported primary CRC cohorts tested with validated molecular assays. Two reviewers independently screened articles, extracted data on mutation frequency, assay type, geography, and co-mutations, and assessed quality using the Hoy risk-of-bias tool. Pooled mutation prevalence was calculated using random-effects logit models. Subgroup analyses and meta-regression explored the effects of geographic region, assay methodology, publication year, and sample size. Between-study heterogeneity, prediction intervals, and small-study effects were evaluated. A total of 47 studies encompassing 40,496 patients were included. Pooled prevalence was 42.7% (95% CI 39.7–45.8%; prediction interval 26.8–60.4%) for KRAS, 5.2% (95% CI 4.0–6.6%; prediction interval 1.3–18.5%) for NRAS, and 6.7% (95% CI 5.5–8.0%; prediction interval 2.3–17.6%) for BRAF V600E. KRAS was most frequent in East Asia and least prevalent in Middle East/South Asia (p < 0.001), while BRAF showed marked enrichment in Western populations (p < 0.001). Next-generation sequencing detected approximately 5 to 6% more KRAS mutations than PCR-based platforms (p = 0.018), highlighting a methodological contributor to prevalence variability. Analysis of co-mutation reporting demonstrated that MAPK–non-MAPK overlaps (e.g., KRAS + PIK3CA, KRAS + TP53, KRAS + APC) occurred more commonly than dual MAPK events (KRAS–BRAF, KRAS–NRAS, NRAS–BRAF). These subsets frequently co-segregated with high-risk histologic features and have emerging therapeutic implications. This systematic review provides robust, region-specific prevalence estimates, quantifies methodological influences, and underscores understudied co-mutation landscapes. These findings support region-tailored molecular testing algorithms and justify prospective evaluation of targeted combination approaches in precision oncology.