并发高分子风险突变和较低 JAK2 突变体等位基因频率对骨髓纤维化患者预后的协同作用——来自多中心研究的见解。
Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.
发表日期：2024 Oct 04
作者：
Yu-Hung Wang, Chao-Hung Wei, Chien-Chin Lin, Carmelo Gurnari, Hussein Awada, Lina Benajiba, Rafael Daltro de Oliveira, Juliette Soret-Dulphy, Bruno Cassinat, Andrius Zucenka, Adrián Mosquera Orgueira, Chang-Tsu Yuan, Sze-Hwei Lee, Chi-Yuan Yao, Kristian Gurashi, Hsin-An Hou, Kiran Batta, Manuel Mateo Pérez Encinas, Wen-Chien Chou, Jaroslaw P Maciejewski, Daniel H Wiseman, Jean-Jacques Kiladjian, Hwei-Fang Tien
来源：
LEUKEMIA
摘要：
除了高分子风险 (HMR) 突变（ASXL1、EZH2、SRSF2、IDH 和 U2AF1Q157）之外，较低的 JAK2V617F 变异等位基因频率 (VAF) 已被证明与骨髓纤维化 (MF) 患者的不良预后相关。然而，JAK2V617F VAF 和 HMR 突变之间的关系仍不确定。为了解决这个问题，我们使用靶向下一代测序技术分析了 124 名 MF 患者的 54 个髓系肿瘤相关基因的突变状态。对来自多个国际中心的三个队列进行了外部验证分析。在 JAK2 突变患者中，HMR 突变的存在会导致 JAK2V617F VAF 较低的患者预后不良，但 JAK2V617F VAF 较高的患者则不会。生存分析显示各验证队列的结果一致。在多变量分析中，无论年龄、MIPSS70、MIPSS70 v2 和 GIPSS 风险组如何，同时发生的 HMR 和较低的 JAK2V617F VAF 被确定为生存的独立不良预后因素。突变共现测试显示不同队列中没有共同的突变模式，排除了其他并发突变的潜在混杂效应。重要的是，HMR/JAK2V617F VAF (≤50%) 状态的整合显着增强了现有的预后模型，更高的 c 指数和时间依赖性 ROC 分析证明了这一点。进行连续随访的单细胞研究有必要破译 MF 的克隆进化及其与 JAK2V617F VAF 动力学的关系。© 2024。作者，获得 Springer Nature Limited 的独家许可。
In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.