A new review published in the Journal of Allergy and Clinical Immunology in Practice highlights how genetic research, particularly on mutations in the KIT gene, are transforming diagnosis, prognosis and treatment strategies for systemic mastocytosis (SM).
Most patients with SM have the indolent subtype and carry a mutation called KIT p.D816V, which leads to unchecked mast cell growth. But researchers are increasingly uncovering additional mutations and how they influence the disease.
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Mutations in genes such as SRSF2, ASXL1 and RUNX1 (the so-called S/A/R panel) are associated with worse outcomes and are common in advanced SM. Cytogenetic abnormalities, such as missing chromosomes, also signal higher risk.
The researchers say all of these discoveries have meant molecular testing is playing an increasingly important role in SM risk assessment.
Highly sensitive blood-based tests, such as allele-specific polymerase chain reaction (PCR) and digital PCR, can detect KIT mutations at very low levels, reducing the need for invasive bone marrow biopsies. Tracking the proportion of mutated cells over time not only confirms diagnosis but also helps monitor disease progression and treatment response.
Treatment therapies are also increasingly being matched to genetics. Midostaurin and avapritinib, for example, target KIT p.D816V, while imatinib may benefit patients with alternative mutations.
Additionally, the study authors point out that a hereditary condition called alpha-tryptasemia, caused by extra copies of the TPSAB1 gene, is found in a significant number of mastocytosis patients. It raises baseline tryptase levels and worsens symptoms such as anaphylaxis, making genetic screening important not only for somatic mutations but also inherited traits.
The authors noted that while molecular testing has revolutionized the management of SM, more research is needed to advance care for people with the disease.
“Collaborative, multi-institutional studies will be essential for standardizing diagnostic techniques and validating prognostic markers,” they wrote. “Future directions in mastocytosis research may include the integration of emerging technologies, such as single-cell sequencing, to explore clonal evolution and uncover novel therapeutic targets aiming at improving outcomes and quality of life for mastocytosis patients.”
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