Association between homologous recombination deficiency and tumor mutational burden in lung cancer.

Abstract

e21043 Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age < 45:5.4%, 45-65:59.6%, > 65:34.9%) compared to 60 in the rest of the patients (age < 45:11.3%, 45-65:61.3%, > 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p < 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p < 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p < 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.