Identification of SLX4 as the most frequently mutated gene in homologous recombination deficiency in Asian gastric cancer.

Abstract

4570 Background: Gastric cancer is the third most common malignancy worldwide. Homologous recombination (HR) is a type of genetic recombination, and homologous recombination deficiency (HRD) is highly involved in multiple types of cancers and can predict response to anticancer therapies. However, homologous recombination deficiency is not well characterized in patients with Asian gastric cancer. Methods: 196 Asian patients with gastric cancer were analyzed in this study. A list of 102 genes related to HRD was compiled based on previous literature. Haplox 605-gene panel was used to capture the sequencing library. Mutations related to HRD were analyzed following next-generation sequencing. In addition, tumor mutational burden (TMB) was calculated by dividing the total number of mutations by the size of the coding region. The correlation analysis between HRD and TMB was also conducted. Results: In total, 43 (21.94%) of 196 Asian patients with gastric cancer harbored at least one HRD gene. The top 10 mutant HRD genes included SLX4 (3.57%), ATR (2.04%), RECQL (1.53%), NBN (1.53%), ERCC4 (1.53%), BAP1 (1.53%), ATM (1.53%), RAD54L (1.02%), BRCA1 (1.02%) and PARP1 (1.02%). In addition, the occurrence of HRD mutations was significantly correlated with a higher TMB. The median TMB of HRD group (8.28 muts/Mb) was significantly higher than that of the Non-HRD group (3.07 muts/Mb) (p < 0.01). The overall upper quantile value (4.80 muts/Mb) was used to screen patients with high TMB (TMB-H). The TMB-H in HRD group was significantly higher than the Non-HRD group (44.19% VS 17.92%, p < 0.01). Conclusions: Our study described that SLX4 was the most frequently mutated HR-related gene in Asian gastric cancer. Moreover, the positive correlation with homologous recombination deficiency (HRD) and tumor mutational burden (TMB) was observed in these patients.