Systemic Mastocytosis: Molecular Landscape and Implications for Treatment

Abstract

Over the past decade we have witnessed major advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted on the way we diagnose and manage it. Advances in molecular testing has indeed run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease. Assessing the molecular landscape in each individual SM patient is nowadays important for diagnosis, prognosis, treatment and monitoring of therapeutic efficacy. This is facilitated by the routine availability of novel technologies like digital PCR and NGS. This review aims to summarize the pathogenesis of the disease, discuss the value of molecular diagnostic testing and how it should be performed, and provide an overview of present and future therapeutic concepts based on fine molecular characterization of SM patients.

Review and Updates on Systemic Mastocytosis and Related Entities

“…The KIT D816V mutation (exon 17) is frequently detected (>90%) in adult SM. Other less common mutations at codon 816 of KIT, including D816F, D816Y, D816G, D816H, D816I, and mutations such as F522C, V560G, I817V, N819Y, L799F, D820G, N822L, N822I, InsVI815-816, E839K, S840N, and S849I, have also been reported in SM [22,52,53]. KIT mutations in the extracellular domain (e.g., deletion of codon 419 in exon 8 or p.A502_Y503dup in exon 9), TM domain (e.g., KIT p.F522C), or JM domain (e.g., KIT p.V560G) are found more frequently in indolent SM [10].…”

“…KIT mutations in the extracellular domain (e.g., deletion of codon 419 in exon 8 or p.A502_Y503dup in exon 9), TM domain (e.g., KIT p.F522C), or JM domain (e.g., KIT p.V560G) are found more frequently in indolent SM [10]. However, several non-D816V mutations have also been identified in MCL and MCS, such as F522C, V654A, p.A502_Y503dup, and V560G [53]. A high variant allele frequency (VAF) has been reported to be associated with the progression of indolent SM into advanced SM [54].…”

Systemic Mastocytosis: Multidisciplinary Approach

“…should be ruled out with PNA-mediated PCR technique on BM samples or sorted MC with a sensitivity of 0.1%. 4,19,[38][39][40] Moreover, mutations in other regions of a KIT gene may be assessed by NGS. 40 Molecular testing in PB with an ASO-qPCRbased method or ddPCR may be used as a screening method in patients with suspicion of SM.…”

“… 4 , 19 , 38 – 40 Moreover, mutations in other regions of a KIT gene may be assessed by NGS. 40 Molecular testing in PB with an ASO-qPCR-based method or ddPCR may be used as a screening method in patients with suspicion of SM. 36 , 41 However, it must be taken into account that about 30% of BMM and 10% of ISM patients result negative for the mutation assessed in PB, also with sensitive techniques.…”

“… Abbreviation: MC: mast cells, BM: bone marrow; PB: peripheral blood; SM systemic mastocytosis, ASO-qPCR: allele specific oligonucleotide quantitative polymerase chain reaction (PCR); ddPCR: digital droplet PCR; PNA: peptide nucleic acid; MPN: myeloproliferative neoplasia. * 40 …”