{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T13:56:27Z","timestamp":1793368587981,"version":"4.5.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The prognostic significance of <jats:italic>KRAS<\/jats:italic> and <jats:italic>BRAF<\/jats:italic> mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II\/III CRC patients undergoing curative surgery to assess the association of mutations in <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, and <jats:italic>PIK3CA<\/jats:italic> with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II\/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, and <jats:italic>PIK3CA<\/jats:italic> were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P\u2009&lt;\u20090.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that <jats:italic>KRAS<\/jats:italic> and <jats:italic>BRAF<\/jats:italic> mutations were significantly linked to poor OS (<jats:italic>KRAS<\/jats:italic>: HR\u2009= 1.25, 95%CI: 1.06-1.47, P\u2009=\u20090.008; <jats:italic>BRAF<\/jats:italic>: HR\u2009=\u20091.43, 95%CI: 1.26-1.63, P\u2009&lt;\u20090.001) and DFS (<jats:italic>KRAS<\/jats:italic>: HR\u2009=\u20091.36, 95%CI: 1.21-1.53, P\u2009&lt;\u20090.001; <jats:italic>BRAF<\/jats:italic>: HR\u2009=\u20091.21, 95%CI: 1.02-1.44, P\u2009=\u20090.032). The prognostic impact of <jats:italic>BRAF<\/jats:italic> mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, <jats:italic>KRAS<\/jats:italic>-mutant patients demonstrated significantly shorter DFS (HR\u2009=\u20091.63, 95%CI: 1.25-2.13, P\u2009&lt;\u20090.001), while <jats:italic>BRAF<\/jats:italic>-mutant patients exhibited reduced OS (HR\u2009=\u20091.53, 95%CI: 1.24-1.89, P\u2009&lt;\u20090.001) and DFS (HR\u2009=\u20091.72, 95%CI: 1.20-2.46, P\u2009=\u20090.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although <jats:italic>PIK3CA<\/jats:italic> mutation was nominally associated with OS (HR\u2009=\u20090.86, 95%CI: 0.75-1.00, P\u2009=\u20090.046), the pooled result lacked robustness. In conclusion, <jats:italic>KRAS<\/jats:italic> and <jats:italic>BRAF<\/jats:italic> mutations had a negative prognostic impact on MSS stage II\/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.<\/jats:p>","DOI":"10.1371\/journal.pone.0320783","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T17:20:56Z","timestamp":1745601656000},"page":"e0320783","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II\/III colorectal cancer: A retrospective study and 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