骨髓增生异常综合征RAS基因突变的分子学特征及预后意义

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.