Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why

Abstract

More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell accumulation and survival. The most frequent mutation is KIT p.D816V, but other rarer mutations can also be found. These mutations often have a very low variant allele frequency (VAF), well below the sensitivity of common next-generation sequencing (NGS) methods used in routine diagnostic panels. Highly sensitive methods are developing for detecting mutations. This review summarizes the current indications on the recommended methods and on how to manage and interpret molecular data for the diagnosis and follow-up of patients with mastocytosis.

Keywords: KIT; digital PCR; gene mutations; systemic mastocytosis.

Figure 2

Entire spectrum of KIT mutations. On the left, the protein structure is shown with its various domains. In the center, the corresponding gene structure is depicted, highlighting the different exons that encode each domain. On the right, the mutations identified in the respective exons are indicated. Variant of uncertain significance (VUS) are highlighted in blue. TMD: trans-membrane domain. JMD: juxtamembrane domain. TK1: tyrosine kinase domain 1. TK2: tyrosine kinase domain 2. ± means that the mutation is present in less than 1% of the patients, + in 1%–5% of the patients, ++ in 5%–20% of the patients, +++ >20% of all adult patients. The figure is adapted from Valent P et al. [58].

Figure 1

Illustration of KIT receptor activation by stem cell factor (SCF), triggering downstream signaling pathways: JAK/STAT, PLCγ MAPK/ERK, and PI3K/AKT, which collectively contribute to cell survival, proliferation, and migration.