Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with esophageal and gastric cancer.

Abstract

e16000 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 1237 Chinese patients with esophageal and gastric cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 623 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 25.1% (62/247) esophageal cancer (EC) patients and 20.71% (205/990) gastric cancer (GC) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were CHEK2 (7%) in EC and ATM (8%) in GC. The germline HRR (gHRR) gene mutations were identified in 48.16% (118/245) EC patients and 50.66% (498/983) GC patients. BRCA2 was the most common mutant gene (22% in EC and 9% in GC). 4.84% EC patients and 4.14% GC patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 8.09 vs 4.41, p < 0.001; GC, 8.09 vs 4.26, p < 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (EC, 5.67 vs 5.67, p = 0.903; GC, 4.96 vs 4.41, p = 0.356). In the TCGA cohort, 15.68% (29/185) EC patients and 23.97% (105/438) GC patients exhibited sHRR gene mutations. The most common mutant gene was ATM (5% in EC and 10% in GC). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 4.78 vs 2.75, p < 0.001; GC, 21.23 vs 2.65, p < 0.001). For the TCGA gastric cancer cohort, the patients with sHRR-Mut had a significantly better median overall survival compared to the ones with sHRR-WT (46.9 months vs 26.5 months, p = 0.043). Conclusions: Our data reported the genetic landscape of HRR genes in Chinese esophageal and gastric cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. In gastric cancer, patients carried somatic HRR gene mutations had a significantly prolonged OS.