Abstract
Background: Lung cancer is the leading cause of cancer-related death worldwide, of which lung adenocarcinoma (LUAD) is one of the main histological subtypes. Mitochondria are vital for maintaining the physiological function, and their dysfunction has been found to be correlated with tumorigenesis and disease progression. Although, some mitochondrial-related genes have been found to correlate with the clinical outcomes of multiple tumors solely. The integrated relationship between nuclear mitochondrial genes (NMGs) and the prognosis of LUAD remains unclear.Methods: The list of NMGs, gene expression data, and related clinical information of LUAD were downloaded from public databases. Bioinformatics methods were used and obtained 18 prognostic related NMGs to construct a risk signature.Results: There were 18 NMGs (NDUFS2, ATP8A2, SCO1, COX14, COA6, RRM2B, TFAM, DARS2, GARS, YARS2, EFG1, GFM1, MRPL3, MRPL44, ISCU, CABC1, HSPD1, and ETHE1) identified by LASSO regression analysis. The mRNA expression of these 18 genes was positively correlated with their relative linear copy number alteration (CNA). Meanwhile, the established risk signature could effectively distinguish high- and low-risk patients, and its predictive capacity was validated in three independent gene expression omnibus (GEO) cohorts. Notably, a significantly lower prevalence of actionable EGFR alterations was presented in patients with high-risk NMGs signature but accompanied with a more inflame immune tumor microenvironment. Additionally, multicomponent Cox regression analysis showed that the model was stable when risk score, tumor stage, and lymph node stage were considered, and the 1-, 3-, and 5-year AUC were 0.74, 0.75, and 0.70, respectively.Conclusion: Together, this study established a signature based on NMGs that is a prognostic biomarker for LUAD patients and has the potential to be widely applied in future clinical settings.
Highlights
Mitochondria are complex organelles of bioenergetic, biosynthetic, and signaling that are correlated to several diseases, including cardiovascular diseases, neurological disorders, and metabolism disorders (Vyas et al, 2016; Genovese et al, 2020)
One study found that the nuclear mitochondrial genes (NMGs) NDUFS1 and NDUFS8 had significant prognostic power in the patients with non-small cell lung cancer (NSCLC) by analyzed immunohistochemical staining and RNA expression data (Su et al, 2016)
Among the 26 genes, the hazard ratio (HR) of seven genes (ATP8A2, CABC1, TK2, ANT1, RRM2B, COX14, and ISCU) was less than 1, while the HR of the remaining 19 genes was more than 1, which indicated that the 7 genes were associated with a poor prognosis in lung adenocarcinoma (LUAD) patients
Summary
Mitochondria are complex organelles of bioenergetic, biosynthetic, and signaling that are correlated to several diseases, including cardiovascular diseases, neurological disorders, and metabolism disorders (Vyas et al, 2016; Genovese et al, 2020). All remaining mitochondrial functions proteins (∼1,300) are encoded in the nuclear DNA (nDNA). Following their translation, they are imported into the organelle through the import machinery instead (Anderson et al, 1981; DiMauro and Schon, 2003; Schon and Przedborski, 2011). One study found that the NMGs NDUFS1 and NDUFS8 (encoding subunits of mitochondrial complex 1) had significant prognostic power in the patients with non-small cell lung cancer (NSCLC) by analyzed immunohistochemical staining and RNA expression data (Su et al, 2016). The integrated relationship between nuclear mitochondrial genes (NMGs) and the prognosis of LUAD remains unclear
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