Molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes

Objective: To explore the molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing was conducted to detect RAS mutations in 776 patients with newly diagnosed primary MDS from December 2011 to December 2018. The mutual exclusivity and co-occurrence in gene mutations and clonal architecture were explored. Moreover, the prognostic significance of RAS mutations in MDS was analyzed. Results: RAS gene mutations were found in 52 (6.7% ) cases, 38 (4.9% ) of whom harbored NRAS mutation, 18 (2.3% ) KRAS mutation, and 4 (0.5% ) both NRAS and KRAS mutations. All the NRAS mutations and 65% of the KRAS mutations were located in codons 12, 13, and 61. PTPN11, FLT3, U2AF1, RUNX1, WT1, ETV6, and NPM1 mutations were enriched in patients with RAS mutations (Q<0.05) . Around 80% of RAS mutations represented subclonal lesions in patients who harbored at least two different mutations. Patients with RAS mutations were more frequently diagnosed with MDS with excess blast (MDS-EB) (82.7% vs. 35.2% , P<0.001) and had higher levels of white blood cell count (4.33×10(9)/L vs. 2.71×10(9)/L, P<0.001) , neutrophil absolute count (2.13×10(9)/L vs. 1.12×10(9)/L, P<0.001) , and bone marrow blast percentage (7% vs. 2% , P<0.001) but lower levels of platelet count (48×10(9)/L vs. 62×10(9)/L, P=0.048) . RAS mutations were correlated with higher-risk categories in the Revised International Prognostic Scoring System (IPSS-R) (71.1% vs. 37.9% , P<0.001) . The median overall survival of patients with NRAS mutations was shorter than the others (P=0.011) , while the significance was lost in the multivariable model. Conclusion: RAS gene mutations always occurred in the late-stage MDS and co-occurred with other signal transduction- and transcription factor-related gene mutations. PTPN11, a RAS pathway-related gene, is an independent poor prognostic factor in MDS patients.