Frequency of homologous recombination-related (HRR) genes mutations in gastric cancer.

Abstract

4031 Background: Homologous recombination deficiency (HRD) might contribute to predict response of immunotherapy and Chemotherapy response and PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. We aimed to analyze the mutational pattern of HRR genes and the relationship between HRR-related genes and clinical outcomes in gastric cancer. Methods: We prospectively sequenced 386 Chinese patients with gastric cancer using next-generation sequencing techniques with 808 cancer-related genes. 440 patients with WES data from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. Correlations between HRR genes and clinical outcomes were identified via bioinformatic analysis using TCGA datasets. Results: In the Chinese cohort, 10.4% (40/386) patients exhibited genomic alterations in HRR genes. The frequently mutated genes were BRCA2 (2.3%), ATM (1.8%), CDK12 (1.8%), BRCA1 (1.0%), CHEK2(1.0%), PALB2(0.8%), BARD1 (0.5%), RAD51B (0.5%), and RAD54L (0.3%). 8.3% patients had at least one somatic HRR genes mutation. Pathogenic germline variants were identified in 2.1% (8/386) patients. No participants carried both germline and somatic HRR gene mutations. In TCGA cohort, 19.1% (841/440) patients had at least one somatic mutation in an HRR gene. The frequently mutated genes were BRCA2 (6.4%), ATM (6.4%), CDK12 (3.2%), BRCA1 (3.2%), BARD1 (2.3%), PALB2 (2.3%), HEK2 (1.6%), CHEK1 (1.4%), BROP1 (1.1%), RAD54L (1.1%), FANCL (0.9%), RAD51D (0.9%), RAD51C (0.7%), PPP2R2A (0.5%), and RAD51B (0.5%). Chinese cohort had lower frequently somatic mutation of HRR genes compared to that in TCGA cohort (8.3% vs 19.1%, p < 0.001). Interestingly, in the TCGA cohort, patients with HRR-mut had significantly elevated tumor mutational burden, microsatellite instability status and enhanced immune activity than patients with HRR-wt. In the MSK-IMPACT cohort comprising 49 patients treated with ICIs, patients with HRR-mut had significantly better overall survival compared to those in patients with HRR-wt (p = 0.027). Conclusions: Our data suggest that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments, such as immunotherapeutic combine PARP inhibitor (PARPi) therapy. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in GC is necessary.