FBXW7 Gene Mutation and Expression in Colorectal Cancer (CRC): A Systematic Review from Molecular Mechanisms to Clinical Translation

n the context of precision oncology, understanding the molecular drivers of colorectal cancer (CRC) is critical for improving prognosis and guiding targeted therapy. FBXW7 is a tumor suppressor that plays a pivotal role in CRC by regulating the degradation of key oncogenic proteins, influencing tumor initiation, growth, therapeutic response, and metastatic behavior. Mutations in FBXW7 occur in 6–10% of CRC. Despite its biological relevance, the prognostic and predictive role of FBXW7 in CRC remains unclear, with inconsistent findings across studies. This systematic review collects and analyzes current evidence on FBXW7 mutations and expression in CRC, emphasizing its potential role in risk stratification, therapeutic response, and personalized treatment approaches. A total of 113 records were selected on PubMed, SCOPUS, Web of Science and Cochrane Central Register of Controlled Trials from 2015 and January 2025, of which 48 examined the preclinical landscape of FBXW7 in CRC and 65 focused on its clinical role. FBXW7 mutations are associated with different clinicopathological patterns, including early-onset disease, microsatellite instability, and co-occurring driver alterations, all of which shape prognosis and treatment outcomes. While some variants correlate with immune infiltration and better survival, others, especially when co-mutated, predict aggressive disease and poor outcomes. Furthermore, FBXW7 alterations contribute to chemoresistance and anti-EGFR therapy resistance but also reveal potential therapeutic vulnerabilities. These findings underscore FBXW7’s promise as a prognostic biomarker and a potential target for precision oncology strategies in colorectal cancer.