Analysis of genetic biomarkers in whole peripheral blood of mastocytosis and mast cell activation syndromes
Paula Navarro
Centro de Investigación del Cáncer. Universidad de Salamanca - CSIC
Mast cell diseases are a heterogeneous group of disorders characterized by the clonal expansion and/or accumulation of abnormal mast cells in various tissues, including bone marrow and skin. These comprise, among others, mast cell activation syndromes (MCAS) and systemic mastocytosis (SM). The 5 th edition of the WHO classification recognizes five subtypes of SM, ranging from indolent (bone marrow mastocytosis [BMM], indolent SM [ISM] and shouldering SM [SSM]) to more advanced forms of the disease (aggressive SM [ASM], and SM associated with another hematological neoplasm [SM-AHN. Currently, MCAS are classified according to the international expert consensus, based on the clinical manifestations and pathogenic mechanism, into i) primary MCAS: including those who share a mutational hallmark or an aberrant CD25+ MC immune profile; ii) secondary MCAS: including those patients with allergy but without demonstrated clonality; iii) a mixed group with features of the previous ones, and vi) idiopathic patients with unknown cause.
The differential diagnosis between systemic mastocytosis and primary vs. non-clonal MCAS, requires the demonstration of clonal hallmark in the bone marrow (BM) or other tissues, typically a gain-of-function KIT mutation (i.e. p.D816V in > 95% of cases). Since 2014, several studies have highlighted the potential of peripheral blood (PB) studies as a less invasive alternative for early clonality screening. However, it has shown limitations in patients with very low mutated cell burden (i.e.<0.01%). As a result, the availability of a robust ultra-sensitive method to detect this KIT mutation in MCAS and mastocytosis patients by PB samples analysis has become a diagnostic challenge. In addition to the KIT mutation, other biological, clinical and biochemical features are essential to identify patients at risk for progression to more advanced forms of SM, and several prognostic scores have been developed for patient monitoring. In addition, new genetic traits, such as hereditary alpha-tryptasemia (HaT) recently described by Lyons, et al in 2016, seem to be more prevalent in patients with mast cell diseases, with a potential association with the clinical manifestations of MCAS patients.
Our study aims to evaluate the potential utility of these biomarkers for a non- invasive early diagnosis of SM and MCAS using peripheral blood samples in the largest cohort of patients to date. In addition, we aim to assess the potential value of these analysis in the clinical workflow for patient monitoring and the follow-up of disease progression.