Genetic features of indolent and advanced forms of systemic mastocytosis

Background. Mastocytosis is a group of diseases characterized by tumor proliferation of mast cells and their accumulation in organs and tissues, including skin, hematopoietic organs (bone marrow, spleen, lymph nodes), and the gastrointestinal tract, which is clinically manifested by symptoms of mast cell activation and organ infiltration in the form of hepatosplenomegaly, portal hypertension, ascites, and cytopenia. Of the greatest scientific and clinical interest is systemic mastocytosis (SM), where indolent (indolent SM, smoldering SM, SM with isolated bone marrow involvement) and advanced forms (aggressive SM, SM with associated hematological neoplasm and mast cell leukemia) are distinguished. The SM clinical course is extremely heterogeneous and diverse. Patients differ significantly from each other both in clinical manifestations and in the aggressiveness of the disease. Currently, there are no clear pathogenetic explanations for such a variety of clinical manifestations. More than 80 % of SM patients have the KITD816V mutation, and more than 50 other mutations in the KIT gene have been described. Additional mutations not associated with the KIT gene are being identified, which likely determine the SM clinical diversity. One of the directions that may help to understand the SM heterogeneity is an extended study of SM genetic characteristics using next-generation sequencing (NGS).

Aim. To study the genetic features and differences between indolent and advanced SM forms.

Materials and methods. The data of 27 SM patients (11 (41 %) men and 16 (59 %) women), observed at the Moscow City Hematology Center of the Botkin’s Hospital, were analyzed. The patients were divided into 2 groups: group 1 – patients with advanced SM variants, group 2 – patients with indolent SM variants. NGS was performed in all patients using the Illumina Myeloid Panel, which includes 40 genes.

Results. As a result of the NGS study of 27 patients, mutations of unfavorable clinical significance were found in 18 genes: CBL, CALR, JAK2, MPL, ASXL1, EZH2, NF1, SETBP1, DNMT3A, SF3B1, SRSF2, ABL1, RUNX, SH2B3, STAG2, TET2, KIT, PHF6. The frequency of additional mutations (non-driver) in the total group was as follows: TET2 – 37 %, SRSF2 – 22 %, DNMT3A/STAG2 – 19 % each, CBL – 11 %, SF3B1/NF1/PHF6 – 7 % each, ASXL1/EZH2/RUNX/SH2B3/ABL1 – 3.5 % each. In group 1 additional mutations of unfavorable clinical significance were detected in 13 (93 %) of 14 patients. In group 2 additional mutations of unfavorable clinical significance were detected in only 3 (23 %) of 13 patients. No additional mutations of adverse clinical significance were found in any of patients with indolent SM variants.

Conclusion. The results of this study suggest that additional mutations of unfavorable clinical significance determine a more aggressive SM course. In patients with SM, NGS helps in diagnosis and prognosis of the disease course.

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