Effect of RAS Pathway Gene Mutations on Survival in Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

IntroductionMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenia, and risk of progression to acute myeloid leukemia. Somatic mutations in RAS pathway, including NRAS, KRAS, and PTPN11, are known contributors to leukemogenesis, yet their prognostic significance in MDS remains incompletely defined. This systematic review and meta-analysis assesses the impact of RAS pathway genes mutation on survival outcomes in adult patients with MDS.MethodsPubMed, Embase, Scopus, Web of Science, and Gene Expression Omnibus were systematically searched on January 2025. This review included English-language studies involving adults with MDS that examined the impact of RAS pathway mutations on survival, including either hazard ratios or Kaplan-Meier data. Studies were excluded if they included only specific treatments, narrow subgroups, secondary MDS, or were not original research. Sixteen papers eventually met the inclusion criteria. Data extraction and quality assessment were independently performed by multiple reviewers. The methodological quality of each study was assessed using the MASTER scale. Hazard ratios were pooled using a random-effects model.ResultsSixteen retrospective cohort studies involving 7969 patients tested for RAS pathway mutations were included. KRAS mutations were associated with poorer overall survival when compared to patients without the mutation (HR 1.66, 95% CI 1.32-2.08, P < 0.001). NRAS mutations were linked to worse overall survival (HR 1.73, 95% CI 1.46-2.04, P < 0.001) and leukemia-free survival (HR 2.48, 95% CI 1.47-4.18, P < 0.001) in comparison to those without the mutation. PTPN11 mutations were also associated with decreased overall survival (HR 1.36, 95% CI 1.01-1.85, P = 0.046) compared to individuals without the mutation.ConclusionMutations in the RAS pathway, particularly NRAS, KRAS, and PTPN11, are associated with inferior survival outcomes in adult patients with MDS. These findings underscore the prognostic relevance of RAS mutations and highlight their potential utility in refining current risk stratification models such as IPSS-M, WPSS, and MDAS.