2020-02 YANA MANGASAROVA
Mangasarova Yana (National Medical Research Center of Hematology)
Search for the markers of microsatellite instability that are diagnostically significant in aggressive lymphomas
822 000 rubles
Patients with primary mediastinal lymphoma are mostly young women (the median age is 30 years). Standard treatment regimens are not always effective, and in case of a relapse (recurrence of the disease), the choice of therapy is determined only by the clinical course of the disease, and not by the molecular genetic characteristics of the tumor. Currently, there are no molecular markers that determine the clinical course of the disease at the time of diagnosis, as well as no predictors of response to therapy with immune checkpoint inhibitors.
Microsatellite instability (MSI) is a marker of deficiency in the DNA mismatch repair system (MMR), and for a number of solid tumors, MSI is a direct indication for the choice of immune checkpoint inhibitors for patient treatment. Traditionally, a set of five markers of mononucleotide microsatellite repeats BAT-25, BAT-26, NR-21, NR-24 and NR-27 is used to detect MSI in solid tumors.
However, our experience of detecting microsatellite instability in aggressive lymphomas suggests that these markers may be uninformative in these tumors. MSI in these microsatellite loci is detected extremely rarely, up to 5% of all cases, and in half of them the new allele is also present in the control material, possibly characterizing not the tumor, but the patient’s genetic profile. Our pilot studies have shown that 50% of all patients with aggressive lymphomas have another variant of microsatellite instability – a change in the length of EMAST (Elevated Microsatellite Alteration at Selected Tetranucleotide repeats) tetranucleotide microsatellites. Analysis of microsatellite instability by tetranucleotide microsatellites in combination with the assessment of the expression of target antigens PD-L1, CTLA4, HLA-DR will give us the criteria for selecting patients for immunochemotherapy with the inclusion of immune checkpoint inhibitors in the treatment regime.
Based on a combination of molecular genetic and immunohistochemical criteria for patients with a relapsed disease, optimal therapy with immune checkpoint inhibitors will be proposed. The implementation of this project may further contribute to a significant improvement in treatment outcomes for patients at the onset of the disease, and in accordance with the data obtained, the first steps will be taken towards personalized treatment of patients with primary mediastinal lymphoma.