真性红细胞增多症的突变图谱：表型、基因型及预后相关性
The Mutational Landscape in Polycythemia Vera: Phenotype, Genotype, and Prognostic Correlates.
作者信息
Rana Masooma S, Iftikhar Moazah, Jadoon Yamna, Abdelmagid Maymona, Viswanatha David S, He Rong, Reichard Kaaren K, Pardanani Animesh D, Gangat Naseema, Tefferi Ayalew
机构信息
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Division of Hematology and Oncology; Department of Medicine, University of California San Francisco, San Francisco, California, USA.
出版信息
Am J Hematol. 2025 Aug;100(8):1343-1353. doi: 10.1002/ajh.27717. Epub 2025 May 15.
Polycythemia vera (PV) is invariably associated with a JAK2 mutation, with over 50% of patients harboring additional non-JAK2 mutations. In the current study, 319 patients with PV underwent NGS at diagnosis or in chronic phase PV (Group A: N = 270, 85%) or at the time of fibrotic (Group B; N = 37, 12%) or leukemic (Group C; N = 12, 4%) transformation. Mutational frequencies involving TP53/SRSF2/IDH1/U2AF1 were significantly (p < 0.05) different between patients in the mutually exclusive Groups A (2%/4%/2%/0.4%), B (8%/0%/0%/5%), and C (50%/25%/17%/8%). Analyses on phenotype/genotype associations and prognostic impact on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival were limited to Group A patients. ASXL1 was associated with younger age (p < 0.01), SRSF2 with older age and leukocytosis (p < 0.01), and TP53 with leukocytosis (p < 0.01). Mutation co-segregation was apparent between ASXL1 and IDH2 (p < 0.01) or SRSF2 (p < 0.01), SRSF2 and IDH2 (p < 0.01), and TP53 and NRAS (p = 0.01). Multivariable analysis identified SRSF2 (p < 0.01; HR, 4.2, 1.9-9.5), IDH2 (p = 0.01; HR, 5.3, 1.8-15.3), ASXL1 (p = 0.04; HR, 2.0, 1.1-3.7), leukocyte count ≥ 15 × 10/L (p < 0.01; HR 2.0, 1.3-3.1), and advanced age (p < 0.01) as risk factors for OS. Median OS in the presence (N = 235; 87%) or absence (N = 35; 13%) of any adverse mutation (i.e., SRSF2, ASXL1, or IDH2) was 8.8 versus 17.8 years (p = 0.01; HR 1.8, 1.1-2.9). In addition, ASXL1 (p = 0.02; HR, 1.6-24.9), SRSF2 (p = 0.06; HR, 11.9, 1.1-126.2), and advanced age (p = 0.04) were associated with inferior LFS, and SRSF2 (p < 0.01; HR, 24.0, 5.5-103.8) and abnormal karyotype (p < 0.01; HR 3.8, 1.6-8.9) with inferior MFFS. The number of non-JAK2 mutations was significant in predicting outcome in univariate but not multivariable analysis. The observations from the current study highlight the prognostic significance of non-JAK2 mutations in PV and the prospect of their inclusion in future prognostic models.
真性红细胞增多症（PV）总是与JAK2突变相关，超过50%的患者还存在其他非JAK2突变。在本研究中，319例PV患者在诊断时、慢性期PV（A组：N = 270，85%）、纤维化期（B组；N = 37，12%）或白血病转化期（C组；N = 12，4%）接受了二代测序（NGS）。在相互排斥的A组（2%/4%/2%/0.4%）、B组（8%/0%/0%/5%）和C组（50%/25%/17%/8%）患者中，涉及TP53/SRSF2/IDH1/U2AF1的突变频率存在显著差异（p < 0.05）。对表型/基因型关联以及对总生存期（OS）、无白血病生存期（LFS）和无骨髓纤维化生存期（MFFS）的预后影响的分析仅限于A组患者。ASXL1与较年轻的年龄相关（p < 0.01），SRSF2与较年长的年龄和白细胞增多相关（p < 0.01），TP53与白细胞增多相关（p < 0.01）。ASXL1与IDH2（p < 0.01）或SRSF2（p < 0.01）、SRSF2与IDH2（p < 0.01）以及TP53与NRAS（p = 0.01）之间存在明显的突变共分离现象。多变量分析确定SRSF2（p < 0.01；HR，4.2，1.9 - 9.5）、IDH2（p = 0.01；HR，5.3，1.8 - 15.3）、ASXL1（p = 0.04；HR，2.0，1.1 - 3.7）、白细胞计数≥15×10⁹/L（p < 0.01；HR 2.0，1.3 - 3.1）和高龄（p < 0.01）是OS的危险因素。存在（N = 235；87%）或不存在（N = 35；13%）任何不良突变（即SRSF2、ASXL1或IDH2）时的中位OS分别为8.8年和17.8年（p = 0.01；HR 1.8，1.1 - 2.9）。此外，ASXL1（p = 0.02；HR，1.6 - 24.9）、SRSF2（p = 0.06；HR，11.9，1.1 - 126.2）和高龄（p = 0.04）与较差的LFS相关，SRSF2（p < 0.01；HR，24.0，5.5 - 103.8）和异常核型（p < 0.01；HR 3.8，1.6 - 8.9）与较差的MFFS相关。在单变量分析中，非JAK2突变的数量对预后有显著预测价值，但在多变量分析中并非如此。本研究的观察结果突出了非JAK2突变在PV中的预后意义以及将其纳入未来预后模型的前景。
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