Wu J Y, Li B, Jia Y J, Zhang P H, Xu Z F, Qin T J, Qu S Q, Pan L J, Liu J Q, Yan X, Zhang Y D, Chen J, Gong J Y, 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 Dec 14;41(12):989-995. doi: 10.3760/cma.j.issn.0253-2727.2020.12.004.
To explore the genetic characteristics, clinical features, and prognostic values of RAS mutations in patients with myelofibrosis (MF) . We analyzed 112-gene targeted sequencing data from 226 patients who had a diagnosis of either primary myelofibrosis (PMF) or post-polycythemia vera/post-essential thrombocythemia (post-PV MF and post-ET MF) from December 2011 to December 2019. A retrospective analysis of the genetic characteristics, clinical features, and prognosis of RAS mutations was performed. Among 266 patients diagnosed PMF or post-PV/ET MF, RAS mutations were found in 14 (6.2%) cases, including 9 (4.0%) cases of NRAS mutations, 8 (3.5%) cases of KRAS mutations, and 3 (1.3%) cases of both NRAS and KRAS mutations. All of the NRAS mutations were located in codons 12 and 13. The median VAFs of RAS mutations were significantly lower than those of the driver mutations, confirming that they represent sub-clonal events that are acquired during the disease course. SETBP1, SRSF2, and MPL tended to be clustered with RAS mutations. Patients with RAS mutations had a higher number of additional oncogenic mutations (median, 3.36 1.17, <0.001) . RAS mutations had a statistically significant association with elevated monocyte cell counts (=0.003) , lower platelet counts (=0.026) , higher bone marrow blasts (=0.022) , splenomegaly (=0.005) , and very high-risk (VHR) karyotype abnormality percentage (=0.031) . In univariate analysis, the OS of patients with NRAS mutations were significantly inferior in the entire MF and PMF cohorts (=0.001, =0.008) . In a multivariate model, NRAS retained an independent negative prognostic factor in PMF. RAS gene mutations were constantly related to elevated monocyte cell counts, lower platelet counts, higher bone marrow blasts, and VHR karyotype abnormality percentage that usually defined high-risk disease and often occurred as sub-clonal events. NRAS mutation is an independent poor prognostic factor in PMF.
为探究骨髓纤维化（MF）患者中RAS突变的遗传特征、临床特征及预后价值。我们分析了2011年12月至2019年12月期间226例诊断为原发性骨髓纤维化（PMF）或真性红细胞增多症后/原发性血小板增多症后骨髓纤维化（真性红细胞增多症后MF和原发性血小板增多症后MF）患者的112基因靶向测序数据。对RAS突变的遗传特征、临床特征及预后进行了回顾性分析。在266例诊断为PMF或真性红细胞增多症后/原发性血小板增多症后MF的患者中，14例（6.2%）检测到RAS突变，其中NRAS突变9例（4.0%），KRAS突变8例（3.5%），NRAS和KRAS均突变3例（1.3%）。所有NRAS突变均位于第12和13密码子。RAS突变的中位变异等位基因频率（VAF）显著低于驱动基因突变，证实它们代表疾病过程中获得的亚克隆事件。SETBP1、SRSF2和MPL倾向于与RAS突变聚集。RAS突变患者有更多额外的致癌突变（中位数为3.36±1.17，P<0.001）。RAS突变与单核细胞计数升高（P = 0.003）、血小板计数降低（P = 0.026）、骨髓原始细胞比例升高（P = 0.022）、脾肿大（P = 0.005）以及极高危（VHR）核型异常百分比（P = 0.031）具有统计学显著关联。单因素分析中，NRAS突变患者在整个MF和PMF队列中的总生存期（OS）显著较差（P = 0.001，P = 0.008）。在多变量模型中，NRAS在PMF中仍是独立的负性预后因素。RAS基因突变常与单核细胞计数升高、血小板计数降低、骨髓原始细胞比例升高以及VHR核型异常百分比相关，这些通常定义为高危疾病，且常作为亚克隆事件出现。NRAS突变是PMF中独立的不良预后因素。
