A significant genetic association has been observed between the KIT M541L variant and mastocytosis—systemic mastocytosis (SM) and cutaneous mastocytosis (CM), in particular—according to findings from a case-control study recently published in Oncotarget.
In patients with mastocytosis, clonal proliferation, along with the presence of mast cells (MCs) in both cutaneous and noncutaneous organs/body systems, is reported. The disorder has been investigated primarily among individuals of European ancestry.
Most of the patients diagnosed with mastocytosis experience MC-mediator symptoms, but signs and symptoms of the disease do vary, based on the extent of tissue involvement and the MC burden. Generally, children experience transient CM, whereas adults typically experience chronic SM, accompanied by typical cutaneous disease manifestations.
“KIT is a tyrosine receptor expressed on the surface of MCs, melanocytes, germ cells, hematopoietic stem cells[,] and gastrointestinal stromal cells,” the study authors wrote.
Among individuals with SM, KIT D816V is the most commonly reported somatic variant, whereas KIT M541L is mainly a germline variant. In fact, in vivo findings have suggested that “there may be an effect on proliferation and survival of MCs expressing KIT M541L.”
Read more about SM prognosis
It is well recognized that expression of heterozygous KIT M541L has been reported predominantly among those with pediatric mastocytosis. In the current study, the researchers sought to evaluate the prevalence of the KIT M541L variant in 100 pediatric and adult patients with mastocytosis (54 males and 46 females), compared with 500 ancestry-matched controls without mastocytosis (from the 1000 Genomes Project database) and 23 individuals with idiopathic anaphylaxis. They also compared the clinical symptoms and laboratory data from those with SM and CM, as well as the bone marrow histopathology, between patients who were heterozygous or homozygous for KIT M541L.
All of the study participants had been enrolled in the National Institutes of Health Institutional Review Board–approved protocol (ClinicalTrials.gov Identifier: NCT00044122) following approved informed consent from parents and assent for children older than six years of age. Among the 100 patients with mastocytosis, 81 were case controls, and 19 exhibited the KIT M541L variant.
Overall, 89.4% of the patients with the KIT M541L variant were diagnosed with indolent SM (ISM) and had a coexisting KIT D816V mutation. Of note, one of the patients who had ISM and a homozygous KIT M541L variant reported no additional KIT mutations. Further, no significant differences in peripheral blood parameters were reported between the groups.
Patients with mastocytosis who carried the KIT M541L variant did not exhibit any significant differences in symptoms compared with a matched reference cohort of individuals without the KIT M541L variant. There were no significant associations observed among patients with idiopathic anaphylaxis.
“To our knowledge, this is the first case[-]control study to show a significant genetic association with mastocytosis at the KIT M541L locus,” the authors stated.
