Frequency of mutations in homologous recombination genes in patients with different histological types of gastric cancer.

Abstract

e16031 Background: Gastric cancer (GC) is the leading cause of cancer-related death worldwide. Despite advances in treatment methods, poor prognosis and low 5-year survival rates persist, especially in recurrent and metastatic GC. Given this problem, there is a need to search for biomarkers to study additional treatment methods in patients with GC. The purpose of the study was to estimate the frequency of mutations in homologous recombination genes in tumor material of patients with gastric cancer. Methods: The study was conducted on a group of 48 patients with stage IB-IIIC gastric cancer, aged 40 to 83 years (median 64 years), who underwent planned treatment at the National Medical Research Centre for Oncology of the Ministry of Health of the Russian Federation in 2021-2023. According to the classification by P. Lauren, the intestinal type was verified in 24 patients, diffuse – 4, mixed – 3, and unspecified – 17. Gene mutation screening was performed using NGS on the MiSeq Dx genetic sequencer (Illumina, Inc.) using the MiSeq Reagent kit v2 300 cycles. DNA libraries were prepared using the Solo-test ABC Plus kit (Oncoatlas). Mutation analysis was performed using the “maftools” package of the R 4.5.1 computing environment. Results: Based on the results of the NGS study, 22 genetic variants were detected: 11 somatic and 11 germline mutations. The frequency of mutations in the ATM gene was 40.9%, BRCA1 – 22.7%, BRCA2 – 13.6%, CHEK2 – 9.1%, FANCL – 9.1%, RAD51C – 4.5%. The frequency of mutations in the genes of homologous recombination in patients with different histological types of gastric cancer was 35.4% (n = 17), of which 64.7% (n = 11) were patients with the intestinal type, 23.5% (n = 4) with an unspecified type, and 5.9% (n = 1) each were patients with mixed and diffuse gastric cancer. Mutations in the ATM, BRCA1 , BRCA2 , and FANCL genes were detected in patients with the intestinal type of gastric cancer (n = 16), while in patients with an unspecified type, mutations were detected in the ATM , FANCL , CHEK2 , and RAD51C genes (n = 4). In patients with the mixed type, mutations were identified only in the ATM gene (n = 1), and in patients with the diffuse type, mutations were identified in the CHEK2 gene (n = 1). Conclusions: The detected genetic variants in the ATM , BRCA1 , BRCA2 , CHEK2 , FANCL and RAD51C in various histological types of gastric cancer are of interest for further research. These results open up possibilities for the treatment of patients with gastric cancer using PARPi inhibitors, which act on the principle of synthetic lethality in combination with homologous recombination deficiency.