Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis
Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis
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DOI：
10.1182/blood.2020006157
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发表时间：
2021-01-14
期刊：
影响因子：
20.3
通讯作者：
Hoermann, Gregor
中科院分区：
文献类型：
--
作者：
Greiner, Georg;Sprinzl, Bettina;Hoermann, Gregor
肥大细胞增多症是一种以KIT D816V突变的克隆性肥大细胞在不同器官中扩张和严重甚至危及生命的过敏反应为特征的血液系统肿瘤。近年来，遗传性α-类胰蛋白酶血症(H-αT)被认为是一种常见的遗传性状，其编码基因TPSAB1的拷贝数增加，并与基础血清类胰蛋白酶水平升高和肥大细胞激活的风险相关。我们研究的目的是阐明肥大细胞增多症患者HαT的临床相关性。用数字聚合酶链式反应对180例肥大细胞增多症患者、180例性别匹配的对照组、720例其他髓系肿瘤患者和61例独立验证队列的肥大细胞增多症患者的TPSAB1种系拷贝数变异进行了评估。在17.2%的肥大细胞增多症患者和4.4%的对照人群中，发现编码TPSAB1拷贝数增加的Alpha-Tryptase与HαT相容(P<；.001)。与肥大细胞负荷无关，有HαT的患者的类胰蛋白酶水平高于无HαT的患者(HαT+的中位数为49.6 ng/mLvs HαT-病例的中位数为34.5 ng/mL，P=0.004)。有HαT的肥大细胞增多症患者的膜翅目毒液过敏反应和严重的心血管介质相关症状/过敏反应比无HαT的肥大细胞增多症患者更常见。肥大细胞增多症中HαT的高患病率提示编码TPSAB1拷贝数增加的种系α-类胰蛋白酶在疾病演变中可能起致病作用。综上所述，我们的数据表明，HαT是肥大细胞增多症中一种新的强大的生物标志物，有助于确定单个患者发生严重过敏反应的风险。
Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary alpha-tryptasemia (H alpha T) has been described as a common genetic trait with increased copy numbers of the alpha-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of H alpha T in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. alpha-Tryptase encoding TPSAB1 copy number gains, compatible with H alpha T, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with H alpha T exhibited higher tryptase levels than patients without H alpha T (median tryptase in H alpha T+, cases: 49.6 ng/mL vs H alpha T- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with H alpha T than in those without H alpha T. Results were confirmed in an independent validation cohort. The high prevalence of H alpha T in mastocytosis hints at a potential pathogenic role of germline alpha-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that H alpha T is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient's risk of developing severe anaphylaxis.