Homologous Recombination-Related (HRR) Gene Mutations in Patients with Glioma and Their Relevance to Genomic Characteristics, Tumor Mutation Burden (TMB), and Prognosis.

e14023 Background: Homologous Recombination Repair (HRR) is one of the core repair methods for DNA double strand damage and the mutations of HRR pathway gene may be the main cause of many cancers. However, there is little research on the potential correlation between the molecular characteristics of HRR pathway genes and glioma. Our study explored HRR gene mutations in glioma patients and its relevance to genomic characteristics, tumor mutation burden (TMB) and prognosis. Methods: Samples from 367 glioma patients with a median age of 46 were detected by 551-gene panel or whole-exome sequencing (WES), and the WES data of 894 glioma patients were extracted from TCGA database ( http://cancergenome.nih.gov ). Among 367 glioma patients, 151 patients occurred HRR somatic mutations. Among them, 47.68% (72/151) patients carried HRR related pathogenic mutation (P/LP), and 52.32% (79/151) patients carried HRR benign/likely benign/variant of uncertain significance mutations (B/LB/VUS). The patients were divided into two groups according to whether patients carried HRR related pathogenic mutation, HRR P/LP group (72) and Non-HRR P/LP group (295). The differences of genomic characteristics, TMB and prognosis between HRR P/LP group and Non-HRR P/LP group were analyzed. Results: In 151 glioma patients harboring HRR somatic mutations, PTEN had the highest mutation frequency (49%; 74/151), followed by CHEK2, DNMT3A, BRCA2 and ATM, with mutation frequency of 11% (17/151), 10% (15/151), 9% (14/151）and 9% (14/151). Patients of HRR P/LP group and HRR B/LB/UVS group showed a significant difference at HRR pathway genes, including PTEN, RAD50, MSH6 and RAD21. In addition, differences of non-HRR pathway genes in HRR P/LP group and Non-HRR P/LP group were found. The mutation frequency of these differential genes was generally high in HRR P/LP group. However, compared to Non-HRR P/LP group, the mutation frequency of IDH1 in HRR P/LP group was significantly higher (Non-HRR P/LP 32% VS HRR P/LP 10%; P＜0.0001). The TMB value in Non-HRR P/LP group was significantly higher than that in HRR P/LP group (P＜0.0001), and the same trend of TMB in two groups was discovered in TCGA cohort (P＜0.0001). Importantly, a significant difference of overall survival (OS) in TCGA database was found between HRR P/LP group and Non-HRR P/LP group (P＜0.0001, HR =2.17, 95%CI: 1.54-3.06), and the median OS were 17.6 and 34.9 months, respectively. Conclusions: This study showed HRR pathway genes status was significantly related to the genomic characteristics, TMB and prognosis of glioma patients. Compared to patients in HRR P/LP group, patients in Non-HRR P/LP group had higher mutation frequency of IDH1, lower TMB value and better prognosis. The relationship between HRR pathway genes and glioma needs to be further explored.