High frequency of c-KIT genetic variants in exons 9, 11, 13 and 17 and PDGFRA in exon 18 in gastric GIST tumors.

Abstract

e23525 Background: Gastrointestinal stromal tumors (GIST) are rare malignant mesenchymal neoplasms of the gastrointestinal tract, the diagnosis and treatment of which is associated with the presence of mutations in the c-KIT and PDGFRA genes. Purpose of this study was molecular genetic genotyping of GIST according to clinically significant exons of the c-KIT and PDGFRA genes. Methods: The study included patients with an immunohistochemically confirmed diagnosis of GIST who underwent treatment in the RRIO, Rostov-on-Don, for the period 2018-2019 (n = 20, median age 63.5 years, men/women–10 people each, gastric tumors). DNA was isolated from FFPE tissue using the GeneJET FFPE DNA Purification Kit, USA. The presence of mutations in exons 9, 11, 13 and 17 of c-KIT and exon 18 of PDGFRA was detected by Sanger sequencing. Results: Activating mutations in exon c-KIT were detected in 10 ps, including one substitution p.V560E and 4 deletions – p.V559_E561del, p.M552_V555delMYEV, p.W557_V559 > F and p.W557_V559 > C. These mutations cause sensitivity to imatinib. Pathogenic mutations were detected in PDGFRA exon 18: an activating deletion p.I843_D846delIMHD (2 ps) and a substitution p.D842Y, which determines imatinib resistance (2 ps). Thus, 20% of GIST cases are promising for obtaining avapritinib, the first FDA approved drug in 2020 for patients with GIST with a mutation in PDGFRA exon 18. In addition, neutral genetic variants were revealed: in 17 exon c-KIT in 16 patients, benign rs1008658, in PDGFRA 18 exon – rs3830355 (3 ps) and silent mutation p.V824V (3 ps). Conclusions: Genotyping of c-KIT and PDGFRA identified 12 types of clinically significant mutations and, in 80% of cases, the carriage of benign polymorphisms and / or SNPs of unknown clinical significance. As a result, 70% of patients from the South of Russia with GIST may be sensitive to treatment with imatinib and/or avapritinib.