Hoermann Gregor, Orfao Alberto, Lyons Jonathan J, Chantran Yannick, Broesby-Olsen Sigurd, Sabato Vito, Arock Michel
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria; MLL Munich Leukemia Laboratory, Munich, Germany.
Servicio Central de Citometria, Centro de Investigacion del Cancer (CIC; CSIC/USAL), CIBERONC and Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain; Department of Medicine, University of Salamanca, Salamanca, Spain.
J Allergy Clin Immunol Pract. 2025 Aug 20. doi: 10.1016/j.jaip.2025.07.055.
Mastocytosis represents a group of rare clonal disorders characterized by accumulation of neoplastic mast cells (MC). Disease presentations range from indolent to highly aggressive forms. The discovery of somatic mutations in KIT, particularly KIT p.D816V, has revolutionized diagnosis, classification, and management of mastocytosis. KIT p.D816V, found in >85% of systemic mastocytosis (SM) cases, drives disease progression through constitutive activation of the KIT receptor. Highly sensitive techniques, such as allele-specific oligonucleotide quantitative PCR (ASO-qPCR), digital PCR (dPCR) and Flow-Super Rolling Circle Amplification (Flow-SuperRCA) have enhanced detection of KIT p.D816V, while next-generation sequencing (NGS) has allowed detection of other mutations, improving not only diagnostics and prognostication, but also monitoring of KIT p.D816V-targeted therapies. Of note, higher KIT p.D816V allele burdens, together with the presence of additional mutations in genes like DNMT3A, SRSF2, ASXL1, EZH2 and/or RUNX1, termed high risk mutations (HRM), correlate with advanced SM subtypes. Hereditary alpha-tryptasemia (HαT) is a genetic condition where increased TPSAB1 gene copy encoding alpha-tryptase usually leads to elevated serum tryptase. The incidence of HαT is increased in mastocytosis and may exacerbate mediator-related symptoms, emphasizing the importance of searching for this genetic condition in mastocytosis. To conclude, despite remaining challenges in standardization, molecular investigations may now improve diagnostics, prognostication and treatment monitoring in mastocytosis.
肥大细胞增多症是一组罕见的克隆性疾病，其特征为肿瘤性肥大细胞（MC）的积聚。疾病表现从惰性到高度侵袭性形式不等。KIT体细胞突变的发现，尤其是KIT p.D816V，彻底改变了肥大细胞增多症的诊断、分类和管理。在超过85%的系统性肥大细胞增多症（SM）病例中发现的KIT p.D816V，通过KIT受体的组成性激活驱动疾病进展。高灵敏度技术，如等位基因特异性寡核苷酸定量PCR（ASO-qPCR）、数字PCR（dPCR）和流式超滚环扩增（Flow-SuperRCA），增强了对KIT p.D816V的检测，而下一代测序（NGS）则能够检测其他突变，不仅改善了诊断和预后，还能监测针对KIT p.D816V的治疗。值得注意的是，较高的KIT p.D816V等位基因负担，以及DNMT3A、SRSF2、ASXL1、EZH2和/或RUNX1等基因中存在的其他突变（称为高风险突变，HRM），与晚期SM亚型相关。遗传性α-色氨酸血症（HαT）是一种遗传疾病，其中编码α-色氨酸酶的TPSAB1基因拷贝增加通常会导致血清色氨酸酶升高。肥大细胞增多症中HαT的发病率增加，可能会加重介质相关症状，强调了在肥大细胞增多症中寻找这种遗传疾病的重要性。总之，尽管在标准化方面仍存在挑战，但分子研究现在可能会改善肥大细胞增多症的诊断、预后和治疗监测。
