Abstract 6556: A gene signature of DNA damage response pathway is predictive of patient clinical outcomes and is associated with tumor immune microenvironment of lung adenocarcinoma
Authors: Zhang Xiaoli , Zhang Junran 
Published: April 2023

DNA damage response (DDR) is crucial to prevent the accumulation of DNA lesions that can lead to genomic instability and promote tumorigenesis. Dysregulation of DDR pathways also provides therapeutic opportunities for new cancer therapy. Given that lung cancer displays a high level of genetic mutation and genomic instability, a comprehensive understanding of the dysregulation of DDR genes in lung cancer, especially non-small cell lung cancer (NSCLC) which accounts for 85% of all lung cancer cases, will be critical for identifying new genes contributing to tumorigenesis and novel targets for lung cancer therapy.

The goal of this study is to identify novel targets for lung cancer treatment through a comprehensive analysis of DDR genes and its association with patient survival, genomic mutation/instability, tumor immune microenvironment (TIME), and tumor proliferation ability. To this end, we have comprehensively characterized the expression of 276 DDR genes using the Cancer Genome Atlas (TCGA) and other publicly available data of lung adenocarcinoma (LUAD), the most common NSCLC. We found that 36 out of 276 DDR genes are dysregulated with majority being upregulated in tumors and are associated with patient overall survival (OS) and progression free survival (PFS) based on the TCGA LUAD cohort. A gene expression signature, i.e., DDR gene expression dysregulation score (DDRDS), was constructed based on the geometric mean of the differentially expressed genes that were also associated with patient OS. Patients with a higher DDRDS showed significantly worse OS and PFS, more advanced tumor stage, a higher tumor mutational burden (TMB), neoantigen load, and homologous recombination deficiency (HRD) score. In addition, tumors with higher DDRDS displayed an increase in CD4+ activated memory T-cells, CD8+ T- cells, M0 and M1 macrophage, and NK cells, but a decrease in B cells, CD4+ resting memory T-cells, monocytes, and dendritic cells in TIME. Further, these tumors also showed a higher expression of immune check point molecules PD1 and PD-L1. Lastly, gene set enrichment analysis demonstrated that these tumors had significantly increased nuclear division, DNA replication, chromosome segregation, and cell cycles, reflecting the aggressiveness of the disease. Hence, despite the previous studies demonstrating that mutation and deletion defects in DDR genes are frequent in tumors, we found that the dysregulated DDR genes are mainly upregulated, and DDRDS based on the dysregulated expression of DDR genes is associated with the alteration in TMB/HRD/TIME, tumor aggressiveness, and ultimately patient outcomes. These results suggested that patients with a higher tumor DDRDS are associated with poor prognosis but might benefit from immune checkpoint blockade-associated immunotherapy.

Citation Format: Xiaoli Zhang, Junran Zhang. A gene signature of DNA damage response pathway is predictive of patient clinical outcomes and is associated with tumor immune microenvironment of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6556.