Prognostic and immune implications of a novel ferroptosis-related ten-gene signature in lung adenocarcinoma.

Lung cancer has been the focus of attention for many researchers in recent years due to its leading contribution to cancer-related death worldwide, with lung adenocarcinoma (LUAD) being the most common histological type. Ferroptosis, a novel iron-dependent form of regulated cell death, can be induced by sorafenib. Emerging evidence shows that triggering ferroptosis has potential as a cancer therapy. This work aimed to build a ferroptosis-related gene signature for predicting the outcome of LUAD. The TCGA-LUAD dataset was set as the training cohort, and the GSE72094 and GSE68465 datasets were set as the validation cohorts. Sixty-two ferroptosis-related genes were retrieved from the literature. A univariate Cox regression model was constructed for the training cohort to preliminarily screen for potential prognostic ferroptosis-related genes. A gene signature was generated from a LASSO Cox regression model and assessed with the training and validation cohorts through Kaplan-Meier, Cox, and ROC analyses. In addition, the correlation between the risk score and autophagy-related genes was determined by the Pearson test. Finally, GSEA and immune infiltrating analyses were performed to better study the functional annotation of the signature and the role of each kind of immune cell. A ten-gene signature was constructed from the training cohort and validated in three cohorts by Kaplan-Meier and Cox regression analyses, revealing its independent prognostic value in LUAD. Moreover, a ROC analysis conducted with all cohort data confirmed the predictive ability of the ten-gene signature for LUAD prognosis. A total of 62.85% (308/490) of autophagy-related genes were found to be significantly correlated with risk scores. GSEA detailed the exact pathways related to the gene signature, and immune-infiltrating analyses identified crucial roles for resting mast cells and resting dendritic cells in the prognosis of LUAD. We identified a novel ferroptosis-related ten-gene signature (PHKG2, PGD, PEBP1, NCOA4, GLS2, CISD1, ATP5G3, ALOX15, ALOX12B, and ACSL3) that can accurately predict LUAD prognosis and is closely linked to resting mast cells and resting dendritic cells.

Ma C ，Li F ，Luo H 《-》

Development and Validation of a Robust Ferroptosis-Related Prognostic Signature in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Ferroptosis is a newly recognized process of cell death, which is different from other forms of cell death in morphology, biochemistry, and genetics, and has played a vital role in cancer biology. This study aimed to identify a ferroptosis-related gene signature associated with LUAD prognosis. Dataset TCGA-LUAD which came from the TCGA portal was taken as the training cohort. GSE72094 and GSE68465 from the GEO database were treated as validation cohorts. Two hundred fifty-nine ferroptosis-related genes were retrieved from the FerrDb database. In the training cohort, Kaplan-Meier and univariate Cox analyses were conducted for preliminary screening of ferroptosis-related genes with potential prognostic capacity. These genes then entered into the LASSO Cox regression model, constructing a gene signature. The latter was then evaluated in the training and validation cohorts via Kaplan-Meier, Cox, and ROC analyses. In addition, the correlations between risk score and autophagy were examined by Pearson correlation coefficient. The analyses of GSEA and immune infiltrating were performed for better studying the function annotation of the gene signature and the character of each kind of immune cells played in the tumor microenvironment. A 15-gene signature was found from the training cohort and validated by Kaplan-Meier and Cox regression analyses, revealing its independent prognosis value in LUAD. Moreover, the ROC analysis was conducted, confirming a strong predictive ability that this signature owned for LUAD prognosis. One hundred fifty-one of 222 (68.01%) autophagy-related genes were discovered significantly correlated with risk scores. Analyses of GSEA and immune infiltration exhibited in detail the specific pathways that associate with the 15-gene signature and identified the crucial roles of resting mast cells and resting dendritic cells owned in the prognosis of the 15-gene signature. In this present study, a novel ferroptosis-related 15-gene signature (RELA, ACSL3, YWHAE, EIF2S1, CISD1, DDIT4, RRM2, PANX1, TLR4, ARNTL, LPIN1, HERPUD1, NCOA4, PEBP1, and GLS2) was built. It could accurately predict the prognosis of LUAD and was related to resting mast cells and resting dendritic cells, which provide potential for the personalized outcome prediction and the development of new therapies in LUAD population.

Zhang A ，Yang J ，Ma C ，Li F ，Luo H ... -  《Frontiers in Cell and Developmental Biology》

Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis.

It is reported that ferroptosis has close relation with tumorigenesis and drug resistance. However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes VDAC2, GLS2, FLT3, TLR4, PHKG2, phosphogluconate dehydrogenase (PGD), PANX1, KRAS, PEBP1, ALOX15, and ALOX12B, and suppressor genes ACSL3, CISD1, FANCD2, and SLC3A2) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature's predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (TLR4, PHKG2, PEBP1, GLS2, FLT3, ALOX15, ACSL3, CISD1, FANCD2, and SLC3A2) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of KRAS, PGD, and ALOX15 were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of KRAS and PGD was positively related to tumor mutation burden, indicating that KRAS and PGD could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened KRAS and PGD as potential novel immunotherapy biomarkers.

Ren Z ，Hu M ，Wang Z ，Ge J ，Zhou X ，Zhang G ，Zheng H ... -  《-》

Identification of a Novel Tumor Microenvironment-Associated Eight-Gene Signature for Prognosis Prediction in Lung Adenocarcinoma.

Lung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major types of lung cancer. Accumulating evidence suggests the tumor microenvironment is correlated with the tumor progress and the patient's outcome. This study aimed to establish a gene signature based on tumor microenvironment that can predict patients' outcomes for LUAD. Dataset TCGA-LUAD, downloaded from the TCGA portal, were taken as training cohort, and dataset GSE72094, obtained from the GEO database, was set as validation cohort. In the training cohort, ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to preliminarily screen prognostic genes. Besides, the LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. In addition, the correlation between tumor mutational burden (TMB) and risk score was evaluated by Spearman test. GSEA and immune infiltrating analyses were conducted for understanding function annotation and the role of the signature in the tumor microenvironment. An eight-gene signature was built, and it was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen. The eight-gene signature was further proven to be independent of other clinico-pathologic parameters via the Cox regression analyses. Moreover, the ROC analysis demonstrated that this signature owned a better predictive power of LUAD prognosis. The eight-gene signature was correlated with TMB. Furthermore, GSEA and immune infiltrating analyses showed that the exact pathways related to the characteristics of eight-genes signature, and identified the vital roles of Mast cells resting and B cells naive in the prognosis of the eight-gene signature. Identifying the eight-gene signature (INSL4, SCN7A, STAP1, P2RX1, IKZF3, MS4A1, KLRB1, and ACSM5) could accurately identify patients' prognosis and had close interactions with Mast cells resting and B cells naive, which may provide insight into personalized prognosis prediction and new therapies for LUAD patients.

Ma C ，Luo H ，Cao J ，Zheng X ，Zhang J ，Zhang Y ，Fu Z ... -  《Frontiers in Molecular Biosciences》

A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma.

Luo H ，Ma C 《Diagnostics》