Establishment and validation of a prognostic signature for lung adenocarcinoma based on metabolism-related genes.

BACKGROUND: Given that dysregulated metabolism has been recently identified as a hallmark of cancer biology, this study aims to establish and validate a prognostic signature of lung adenocarcinoma (LUAD) based on metabolism-related genes (MRGs). METHODS: The gene sequencing data of LUAD samples with clinical information and the metabolism-related gene set were obtained from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB), respectively. The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate cox regression analysis was performed to identify MRGs that related to overall survival (OS). A prognostic signature was developed by multivariate Cox regression analysis. Furthermore, the signature was validated in the GSE31210 dataset. In addition, a nomogram that combined the prognostic signature was created for predicting the 1-, 3- and 5-year OS of LUAD. The accuracy of the nomogram prediction was evaluated using a calibration plot. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in LUAD. RESULTS: A total of 116 differentially expressed MRGs were detected in the TCGA dataset. We found that 12 MRGs were most significantly associated with OS by using the univariate regression analysis in LUAD. Then, multivariate Cox regression analyses were applied to construct the prognostic signature, which consisted of six MRGs-aldolase A (ALDOA), catalase (CAT), ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), lactate dehydrogenase A (LDHA), and thymidylate synthetase (TYMS). The prognostic value of this signature was further successfully validated in the GSE31210 dataset. Furthermore, the calibration curve of the prognostic nomogram demonstrated good agreement between the predicted and observed survival rates for each of OS. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. The high-risk group patients have higher levels of immune checkpoint molecules and are therefore more sensitive to immunotherapy. Finally, we confirmed six MRGs protein and mRNA expression in six lung cancer cell lines and firstly found that ENTPD2 might played an important role on LUAD cells colon formation and migration. CONCLUSIONS: We established a prognostic signature based on MRGs for LUAD and validated the performance of the model, which may provide a promising tool for the diagnosis, individualized immuno-/chemotherapeutic strategies and prognosis in patients with LUAD.

A novel prognostic signature of metastasis-associated genes and personalized therapeutic strategy for lung adenocarcinoma patients.

Lung adenocarcinoma (LUAD) is a highly invasive and metastatic malignant tumor with high morbidity and mortality. This study aimed to construct a prognostic signature for LUAD patients based on metastasis-associated genes (MAGs). RNA expression profiles were downloaded from the Cancer Genome Atlas (TCGA) database. RRA method was applied to identify differentially expressed MAGs. A total of 192 significantly robust MAGs were determined among seven GEO datasets. MAGs were initially selected through the Lasso Cox regression analysis and 6 MAGs were included to construct a prognostic signature model. Transcriptome profile, patient prognosis, correlation between the risk score and clinicopathological features, immune cell infiltration characteristics, immunotherapy sensitivity and chemotherapy sensitivity differed between low- and high-risk groups after grouping according to median risk score. The reliability and applicability of the signature were further validated in the GSE31210, GSE50081 and GSE68465 cohort. CMap predicted 62 small molecule drugs on the base of the prognostic MAGs. Targeted drug staurosporine had hydrogen bonding with Gln-172 of SLC2A1, which is one of MAGs. Staurosporine could inhibit cell migration in A549 and H1299. We further verified mRNA and protein expression of 6 MAGs in A549 and H1299. The signature can serve as a promising prognostic tool and may provide a novel personalized therapeutic strategy for LUAD patients.

Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma.

BACKGROUND: Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients. RESULTS: Five epigenetic-related genes (ERGs) (ARRB1, PARP1, PKM, TFDP1, and YWHAZ) were identified as prognostic hub genes and used to establish a prognostic signature. According our risk score system, LUAD patients were stratified into high and low risk groups, and patients in the high risk group had a worse prognosis. ROC analysis indicated that the signature was precise in predicting the prognosis. A new nomogram was constructed based on the five hub genes, which can predict the OS of every LUAD patients. The calibration curves showed that the nomogram had better accuracy in prediction. Finally, candidate drugs that aimed at hub ERGs were identified, which included 47 compounds. CONCLUSIONS: Our epigenetic-related signature nomogram can effectively and reliably predict OS of LUAD patients, also we provide precise targeted chemotherapeutic drugs. METHODS: The genomic data and clinical data of LUAD cohort were downloaded from the TCGA database and ERGs were obtained from the EpiFactors database. GSE31210 and GSE50081 microarray datasets were included as independent external datasets. Univariate Cox, LASSO regression, and multivariate Cox analyses were applied to construct the epigenetic-related signature.

A Novel Metabolism-Related Signature as a Candidate Prognostic Biomarker for Hepatocellular Carcinoma.

PURPOSE: Given that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes (MRGs) for the diagnosis and treatment of hepatocellular carcinoma (HCC). METHODS: In total, 2752 metabolism-related gene sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). One hundred and seventy-eight the differentially expressed MRGs were identified from the ICGC cohort and TCGA cohort. Then, univariate Cox regression analysis was performed to identify these genes that were related to overall survival (OS). A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses in the ICGC dataset. The Broad Institute's Connectivity Map (CMap) was used in predicting which compounds on the basis of the prognostic MRGs. Furthermore, the signature was validated in the TCGA dataset. Finally, the expression levels of hub genes were validated in HCC cell lines by Western blotting (WB) and quantitative real-time PCR (qRT-PCR). RESULTS: We found that 17 MRGs were most significantly associated with OS in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this particular signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes. Candidate drugs that aimed at hub ERGs were identified. Finally, hub genes were chosen for validation and the protein, mRNA expression of FLVCR1, SLC5A11, and RRM2 were significantly increased in human HCC cell lines compared to normal human hepatic cell lines, which were in agreement with the results of differential expression analysis. CONCLUSION: Our data provided evidence that the metabolism-related signature could serve as a reliable prognostic and predictive tool for OS in patients with HCC.