Huang H J, Li B, Qin T J, Xu Z F, Hu N B, Pan L J, Qu S Q, Liu D, Zhang Y D, Xiao Z J
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
Zhonghua Xue Ye Xue Za Zhi. 2020 Sep 14;41(9):723-730. doi: 10.3760/cma.j.issn.0253-2727.2020.09.004.
To explore the molecular features and prognostic value of RAS mutations in patients with myelodysplastic syndromes (MDS) . 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. 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 (<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% . 35.2% , <0.001) and had higher levels of white blood cell count (4.33×10(9)/L . 2.71×10(9)/L, <0.001) , neutrophil absolute count (2.13×10(9)/L . 1.12×10(9)/L, <0.001) , and bone marrow blast percentage (7% . 2% , <0.001) but lower levels of platelet count (48×10(9)/L . 62×10(9)/L, =0.048) . RAS mutations were correlated with higher-risk categories in the Revised International Prognostic Scoring System (IPSS-R) (71.1% . 37.9% , <0.001) . The median overall survival of patients with NRAS mutations was shorter than the others (=0.011) , while the significance was lost in the multivariable model. 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.
为探究骨髓增生异常综合征（MDS）患者中RAS突变的分子特征及预后价值。对2011年12月至2018年12月期间776例新诊断的原发性MDS患者进行112基因靶向测序以检测RAS突变。探究基因突变和克隆结构中的相互排斥性和共现性。此外，分析MDS中RAS突变的预后意义。52例（6.7%）患者发现RAS基因突变，其中38例（4.9%）携带NRAS突变，18例（2.3%）携带KRAS突变，4例（0.5%）同时携带NRAS和KRAS突变。所有NRAS突变及65%的KRAS突变位于密码子12、13和61。PTPN11、FLT3、U2AF1、RUNX1、WT1、ETV6和NPM1突变在RAS突变患者中富集（<0.05）。在携带至少两种不同突变的患者中，约80%的RAS突变代表亚克隆病变。RAS突变患者更常被诊断为伴有过多原始细胞的MDS（MDS-EB）（82.7%对35.2%，<0.001），且白细胞计数（4.33×10⁹/L对2.71×10⁹/L，<0.001）、中性粒细胞绝对计数（2.13×10⁹/L对1.12×10⁹/L，<0.001）和骨髓原始细胞百分比（7%对2%，<0.001）更高，但血小板计数更低（48×10⁹/L对62×10⁹/L，=0.048）。RAS突变与修订的国际预后评分系统（IPSS-R）中的高危类别相关（71.1%对37.9%，<0.001）。NRAS突变患者的中位总生存期短于其他患者（=0.011），而在多变量模型中该意义消失。RAS基因突变总是发生在晚期MDS中，并与其他信号转导和转录因子相关基因突变共同出现。PTPN11，一种RAS通路相关基因，是MDS患者独立的不良预后因素。
