Genetic studies advancing mastocytosis management
This summary delves into new genetic data that have shaped the updated mastocytosis WHO classification system, and which also shed light on the trajectory of future guidelines.1
The effect of prognostic insights on diagnostic classification
Prognostics are critical to the development of guidelines. The WHO classification of systemic mastocytosis (SM) has undergone several refinements since 2001. In previous versions, smouldering SM (SSM) and bone marrow mastocytosis (BMM) were considered subtypes of indolent SM (ISM), but recent data have led to their re-evaluation as distinct entities. Patients with ISM and BMM have a near-normal lifespan, whereas the prognosis for those with SSM is bleaker; and patients with BMM mostly lack the skin lesions seen in ISM.1,2 Future new findings on SM genetics may lead to further understanding. The latest WHO classification of SM can be viewed here.
The implication of genetics on progression and prognosis
KIT is a major cytokine receptor activated by the ligand stem cell factor (SCF) and involved in the maturation of mast cells (MCs).3 ~90% of SM cases have a somatic point mutation in their KIT oncogene, and KIT D816V is present in >80% of cases.1,3 Most mutations are activating mutations, resulting in SCF-independent development of MCs; of 54 mutations discovered to date, 59% are activating mutations.1 KIT D816V was previously a minor criterion for SM diagnosis but this was recently updated to include any KIT mutation as a diagnostic criterion.1,2
Multilineage KIT D816V mutation and an increased allele burden are known risk factors, among others, in the progression of SM.1 The latest data on analysis methods of KIT D816V and its potential prognostic value have been explored in our previous summary.4 While much remains unknown about the genetic factors influencing the evolution and presentation of SM and cutaneous mastocytosis (CM), it is notable that CM primarily affects children while SM is more common in adults. Additionally, many childhood patients experience the disappearance of skin lesions before or at puberty, regardless of age, sex, or KIT mutational status.1
In patients with SM who develop an associated haematologic neoplasm (AHN), the most common type is chronic myelomonocytic leukaemia (CMML). KIT D816V is detectable in neoplastic cells in SM-CMML, while in other SM-AHNs, KIT expression is variable in the neoplasm itself. KIT mutations may be an early driver (especially in non-advanced SM) or late driver of oncogenesis according to different studies, but whether KIT mutations can play a role in AHN classification is yet to be determined.1
Other known drivers for AHNs include JAK2 V617F for myeloproliferative syndrome and BCR::ABL1 for Philadelphia Chromosome chronic myeloid leukaemia. Other co-mutations not specific to AHNs include TET2, ASXL1 and RAS. Many of these correlate to the type and progression of AHN and could have future use in determining patient progression.1
In advanced SM, specific mutation profiles and high variant allele frequency (VAF) lead to poorer prognosis. The integration of gene panels like SRSF2, ASXL1 and RUNX1 mutations have enhanced current prognostication algorithms, particularly by combining multiple molecular parameters into a single score.1
The effect of HαT on disease evolution
There is emerging evidence that mutations in cytokines, their receptors or hereditary alpha tryptasemia (HαT) trait may be involved in the evolution of mastocytosis. Studies in familial SM and cutaneous mastocytosis (CM) have led to theories around the HαT trait creating permissive environments for further mutations such as KIT D816V to occur. HαT results in an increased gene copy number of the tryptase gene and is found in 20% of patients with SM, and more in ISM.1,5 To find out more about tryptase, please click here. Hypotheses suggest increased amounts of tryptase could lead to bone marrow MC proliferation or affect downstream signalling and additional tissue remodelling by acting as a mitogen for fibroblasts. This could allow for the clonal expansion of KIT D816V positive cells. Currently the link between HαT trait leading to an increased risk of KIT D816V positive disease remains elusive.1
The implication of new data on anaphylaxis risk
HαT carriers with concomitant SM and an IgE-dependent allergy are at greater risk of severe anaphylaxis. Their diagnosis is often a combined form of SM and a mast cell activation syndrome. The presence of IgE and HαT are known to increase the risk of anaphylaxis, but emerging data suggest specific cytokines and their receptors, atopic diathesis or genetic predisposition to immune states might also be risk factors. Future research may allow patients to be further risk stratified for anaphylaxis upon diagnosis.1
Risk factors contributing to osteopathy
Osteopathy is an important co-morbidity linked with mastocytosis. The risk of osteoporosis, the most severe bone structure complication, is increased with age, physical inactivity, poor nutrition, vitamin D deficiency and long-term corticosteroid use. Notably, men with SM are as susceptible to osteoporosis as women, contrasting with the general population. Contributing factors include neoplastic mast cell-derived molecules, which promote bone loss, highlighting the complex interplay of genetic, epigenetic, and disease-related factors in SM-associated osteopathy.1
Conclusion
The emergence of new data has improved and refined the WHO classification and prognostication tools in SM. However, more research and consensus are needed in other areas of SM genetics to enable a better understanding of pathogenesis and improve treatment recommendations. Effective management of SM patients relies on a multidisciplinary approach, involving specialists from various fields, enabling personalised patient care and improved patient outcomes.1
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