Inherited and acquired genetic biomarkers in patients with Mast Cell Activation Syndromes and Mastocytosis
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, skin and gastrointestinal tract. Those mostly comprise, among other, mast cell activation syndromes (MCAS) and both cutaneous 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 smoldering SM [SSM]) to more advanced malignant forms of the disease (aggressive SM [ASM], and SM associated with another hematological neoplasm [SM-AHN]. Currently, MCAS are classified according to the ECNM/AIM international expert consensus criteria, based on the underlying pathogenic mechanisms to the clinical manifestations of the disease, into i) primary MCAS: those who carry a mutation in the KIT gene oran aberrant CD25+ MC immune profile; ii) secondary MCAS: consisting of patients with allergy/atopy but without demonstrated mast cell clonality; iii) idiopathic MCAS with an unknown trigger, and iv) mixed MCAS with features of the previous groups. Thus, assessment of the mutational status of KIT is a key diagnostic biomarker in MCAS.
The differential diagnosis between systemic mastocytosis and primary vs. non-clonal MCAS, requires the demonstration of clonal MC in bone marrow (BM) and/or other tissues, typically with a gain-of-function KIT mutation (i.e. p.D816V in > 90% of cases). Since 2014, several studies have highlighted the potential of peripheral blood (PB) studies as a less invasive approach for early detection of
clonality in the diagnostic screening of MCAS and SM, particularly among children and adults that present without skin lesions. However, current methods have important limitations in patients with very low mutated cell burden (i.e.<0.01%). Therefore, the availability of a robust ultra-sensitive method to detect this KIT mutation in PB of patients suspicious of an underlying clonal MCAS and mastocytosis has become a major unmet clinical need. In addition to KIT mutation, other biological, clinical and biochemical features, including additional mutations in genes other than KIT, are essential to identify patients at risk for progression to
more advanced forms of SM, and several prognostic scores have been developed which include such additional mutations. In parallel, a new genetic trait, hereditary alpha-tryptasemia (HaT), recently described by Lyons et al in 2016, and associated with increased serum tryptase levels, has emerged as more prevalent in patients with mast cell diseases (10-25% of cases vs 4-6% of the general population), with a potential association with the clinical manifestations of MCAS patients.
Our study aims to evaluate the genetic landscape and potential utility of genetic biomarkers for more sensitive and minimally-invasive early diagnosis of SM and MCAS in blood. In addition, we aim to assess the potential value of these genetic biomarkers in the clinical workflow for patient monitoring and disease follow-up.