A Comprehensive Analysis of the Effects of Key Mitophagy Genes on the Progression and Prognosis of Lung Adenocarcinoma

SIMPLE SUMMARY: Dysfunction and dysregulation of mitochondrial dynamics are implicated in tumorigenesis. To avoid mitochondrial dysfunction, a quality control mechanism called mitophagy is developed in cells. A series of mitophagy-related genes were identified to be associated with lung cancer. However, there was no comprehensive genetic and transcriptional analysis of all key mitophagy genes in lung adenocarcinoma (LUAD) progression, prognosis and therapeutics. Here, we performed a comprehensive analysis of the gene expression, copy number variation and mutation of key mitophagy genes in the tumor progression of LUAD. The clustering analysis identified two groups of LUAD with a significantly different prognosis. Further analyses of gene mutation, genome profile, immune cell infiltration and drug sensitivity were performed between these two groups. We also constructed a mitophagy related signature that could predict the prognosis of LUAD, which was validated in external database. This study was valuable for LUAD prognostic prediction and treatment decision. ABSTRACT: The aim of our study was to perform a comprehensive analysis of the gene expression, copy number variation (CNV) and mutation of key mitophagy genes in the progression and prognosis of lung adenocarcinoma (LUAD). We obtained the data from The Cancer Genome Atlas (TCGA). Clustering analysis was performed to stratify the mitophagy related groups. The least absolute shrinkage and selection operator (LASSO) based cox model was used to select hub survival genes. An independent validation cohort was retrieved from Gene Expression Omnibus database. We found 24 out of 27 mitophagy genes were aberrantly expressed between tumor and normal samples. CNV gains were associated with higher expression of mitophagy genes in 23 of 27 mitophagy genes. The clustering analysis identified high and low risk mitophagy groups with distinct survival differences. The high risk mitophagy groups had higher tumor mutation burden, stemness phenotype, total CNVs and lower CD4+ T cells infiltration. Drugs targeted to high risk mitophagy groups were identified including the PI3K/AKT/mTOR inhibitor, HDAC inhibitor and chemotherapy agents such as cisplatin and gemcitabine. In addition, the differentially expressed genes (DEGs) were identified between mitophagy groups. Further univariate Cox analysis of each DEG and subsequent LASSO-based Cox model revealed a mitophagy-related prognostic signature. The risk score model of this signature showed a strong ability to predict the overall survival of LUAD patients in training and validation datasets. In conclusion, the mitophagy genes played an important role in the progression and prognosis of LUAD, which might provide useful information for the treatment of LUAD.