III. Medizinische Klinik, Hämatologie und Onkologie, Universitätsmedizin Mannheim, Mannheim, Germany;
Blood. 2013 Oct 3;122(14):2460-6. doi: 10.1182/blood-2013-04-496448. Epub 2013 Aug 19.
To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ≥3 mutations, and 11/27 patients (41%) exhibited ≥5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.
为了探究导致系统性肥大细胞增多症（SM）临床表现异质性和多种治疗效果不佳的机制，我们分析了 39 例 KIT D816V 突变的惰性 SM（n = 10）、冒烟型 SM（n = 2）、伴有克隆性血液非肥大细胞谱系疾病的 SM（SM-AHNMD，n = 5）、侵袭性 SM（n = 15）或肥大细胞白血病（n = 7）患者的额外分子异常，这些患者中有的伴有（n = 18）或不伴有（n = 4）AHNMD。我们应用下一代测序技术检测 ASXL1、CBL、IDH1/2、JAK2、KRAS、MLL-PTD、NPM1、NRAS、TP53、SRSF2、SF3B1、SETBP1、U2AF1 的突变热点区域，并分析了 EZH2、ETV6、RUNX1 和 TET2 的完整编码区。我们在 27 例晚期 SM（SM-AHNMD，5/5；侵袭性 SM/肥大细胞白血病，19/22）患者中发现了 24 例（89%）的额外分子异常，而在 12 例惰性 SM/冒烟型 SM 患者中，仅有 3 例（25%）各携带一个额外突变（U2AF1、SETBP1、CBL）（P <.001）。受影响最频繁的基因是 TET2、SRSF2、ASXL1、CBL 和 RUNX1。在晚期 SM 中，27 例患者中有 21 例（78%）携带≥3 个突变，11 例（41%）患者携带≥5 个突变。与仅携带 KIT D816V 的患者相比，携带额外异常的患者总生存期明显更短（P =.019）。我们得出结论，SM 的生物学和预后与疾病演变过程中获得的突变基因模式有关。
