A Risk Model Developed based on Homologous Recombination Deficiency Genes for Evaluating the Drug Sensitivity and Prognostic Prediction of Lung Adenocarcinoma

Aim: This study was designed to construct a risk model based on homologous recombination deficiency (HRD) to evaluate the prognosis and drug sensitivity for patients with lung adenocarcinoma (LUAD). Background: LUAD is a subtype of lung cancer with unfavorable overall survival (OS) and prognosis. HRD has been widely studied in various tumors, but its role in LUAD has not been fully understood. Objective: We aimed to construct an HRD-related risk model for predicting the prognosis and drug sensitivity of patients with LUAD. Methods: Gene expression data of the LUAD samples were collected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We extracted HRD genes from previous literature and performed univariate COX analysis to select those closely associated with LUAD prognosis. ConsensusClusterPlus was employed to stratify the samples in the TCGA-LUAD cohort into different subtypes. A RiskScore model was established applying random forest method. Furthermore, immunotherapy response and drug sensitivity were predicted using Tumor Immune Dysfunction and Exclusion (TIDE) software and pRRophytic R package, respectively. Finally, the clinical features between High- and Low- RiskScore groups were compared. Results: A total of 16 HRD genes relevant to LUAD prognosis were selected and used to classify 3 LUAD clusters (C1, C2, and C3). Specifically, C1, with a lower TIDE score displayed higher immune infiltration and immunotherapy benefit and the optimal OS, while C2 was closely correlated with tumor-relevant pathways and had the worst OS. Finally, 4 HRD genes (RAD51AP1, BRCA1, H2AFX, and FANCL) were determined to develop a RiskScore signature. It was found that a higher RiskScore was related to more advanced stages, worse OS, and tumor development pathways. Additionally, the High-RiskScore group with a higher TIDE score was sensitive to 44 traditional chemotherapy drugs. A nomogram combined with RiskScore exhibited an accurate survival prediction ability. Conclusion: The HRD-based RiskScore played a crucial role in LUAD development, showing a strong potential to serve as a prognostic indicator for LUAD. Our findings contributed to the diagnosis of LUAD and its treatment.