The utilization of plasma protein profiles has demonstrated the potential to distinguish between patients with indolent systemic mastocytosis (SM) and those with advanced SM, according to findings from an exploratory cohort study conducted in Sweden and published in the Journal of Molecular Diagnostics.
Recognizing that mastocytosis comprises a heterogeneous group of disorders, the researchers acknowledged the ongoing need to broaden the scope of the molecular components that may contribute to the pathogenesis of this disease. They theorized that the clustering of patients based on proteomic data might help to improve the diagnosis and shed some insight into the mechanisms that underlie this clinically diverse disorder.
The investigators sought to identify plasma biomarkers that are linked to certain specific subtypes of mastocytosis via utilization of proteomic analysis, along with the cellular origin of all proteins identified. Additionally, they discussed the differences in the pathophysiologic mechanisms that underlie SM and polycythemia vera (PCV). It has been noted that the myeloproliferative condition PCV can be associated with SM, with mast cell mediators appearing to contribute to the pathogenesis of PCV-linked pruritus. PCV in itself, however, is not considered to be a mast cell disorder.
Plasma samples were collected from the Uppsala Umeå Comprehensive Cancer Consortium biobank, located in Uppsala, Sweden. All of the participants were required to have undergone a bone marrow analysis. Patients were categorized as having mastocytosis that was restricted to the skin, such as cutaneous mastocytosis (CM), or as having SM. Those with SM were further divided based on the clinical aggressiveness of the disorder as having indolent SM or advanced SM.
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The protein profiles in the plasma samples were analyzed with the use of Proximity Extension Assay technology that can target 275 plasma proteins. Samples from patients with CM, indolent SM, and advanced SM, along with a reference group of individuals with PCV, were examined. Possible cellular origin was investigated with the utilization of a single-cell RNA-sequencing dataset that was generated from patients with indolent SM.
The study cohort comprised a total of 168 patients—16 with CM, 80 with indolent SM, 12 with advanced SM and 60 with PCV. According to a principal component analysis (PCA) based on the profile of 275 plasma proteins, one cluster of individuals with CM and indolent SM was detected, which was separate from those with advanced SM. In fact, the distance between the centroids of the indolent SM and the advanced SM subgroups was statistically significant and was verified in a second PCA.
The Boruta algorithm identified 29 biomarkers that were important regarding the differentiation between indolent SM and advanced SM. The majority of these biomarkers were detected in higher levels in plasma samples obtained from those with advanced SM vs indolent SM, including the top five proteins: interleukin (IL)-1RT1, lymphocyte activation gene 3 (LAG3), tumor necrosis factor (TNF)SF13B (B-cell activating factor), EGLN1, and IL-18BP.
Moreover, single-cell RNA-sequencing analysis derived from indolent SM bone marrow cells demonstrated that “the mRNA for the identified proteins was not exclusive of mast cells.”
“Distinct plasma protein profiles show potential to refine [indolent] SM and [advanced] SM diagnoses, possibly reflecting differences in pathogenic mechanisms and diverse clinical manifestations,” the authors noted. “Whether some of these markers are associated with disease severity, specific symptoms and distinct molecular mechanisms needs to be investigated in future studies.”
