伴环状铁粒幼红细胞增多骨髓增生异常综合征基因突变特征及临床意义

OBJECTIVE: To explore the features and clinical significance of gene mutations in patients with myelodysplastic syndromes with ring sideroblasts（MDS-RS）. METHODS: A total of 255 newly diagnosed primary MDS-RS patients were retrospectively reviewed from our center from January 2001 to June 2019. SF3B1 gene mutations were detected by Sanger sequencing in 129 patients, and next generation sequencing（NGS）was performed in the other 126 patients using a set of selected 112-genes. RESULTS: A total of 193（75.7%）patients presented with SF3B1 mutation, predominantly mutant at amino acid position 700（K700E）（n＝147, 76.2%）. Non-SF3B1 gene mutations were TET2（16.7%）, ASXL1（14.3%）, U2AF1（11.1%）, TP53（7.9%）, SETBP1（6.3%）, and RUNX1（6.3%）. RS 5%–<15%patients had a higher SETBP1 mutation frequency than RS≥15%patients（21.4% vs 4.5%, P＝0.044）. Mutation frequencies of other genes were similar in both groups（all P>0.05）. SF3B1 variant allele frequencies（VAF）had positive correlation with marrow RS percentage but without statistical significance in RS 5%–<15%group（P＝0.078, r＝0.486）. SF3B1 mutant patients presented with higher marrow RS percentage compared with wild-type patients［40.0%（15.0%–80.0%）vs 25.5%（15.0%–82.0%）, P<0.001］, and SF3B1 VAF positively correlated with RS percentage（P＝0.009, rs＝0.261）in RS≥15%group. Age, ANC, PLT, mean RBC corpuscular volume, RS percentage, IPSS-R cytogenetics, and IPSS-R risk score were significantly different between patients with SF3B1 mutations and wild-type SF3B1（all P<0.05）. Multivariable survival analyses adjusted by age and IPSS-R cytogenetics revealed that SF3B1mutation was an independent favorable prognostic factor（HR＝0.265, 95% CI 0.077–0.917, P＝0.036）, and TP53 mutation was an adverse variable independent of SF3B1 mutation（HR＝6.272, 95% CI 1.725–22.809, P＝0.005）. According to the mutant status of SF3B1 and TP53, MDS-RS patients were categorized into 4 groups, namely, with SF3B1 and TP53 mutation, with wild-type SF3B1 and TP53, with wild-type SF3B1 but TP53 mutation, and with SF3B1 mutation but wild-type TP53. There was a significant difference for OS among these 4 groups（P<0.001）. The former 3 groups showed no significant difference in OS in multiple comparisons. However, the SF3B1 mutation but wild-type TP53 group had a better OS than wild-type SF3B1 but TP53 mutation group and wild-type SF3B1 and TP53 group, whereas a similar OS compared with SF3B1 and TP53 mutation group. CONCLUSION: SF3B1 mutations were prevalent in MDS-RS patients with the most common mutation at amino acid position 700（K700E）. SF3B1 mutation was an independent favorable prognostic variable, whereas TP53 mutation was an independent adverse variable. SF3B1 mutation could coordinate with TP53 mutation for more sophisticated prognosis stratification in MDS-RS patients.