Dataset Information

PLEK2 Gene Upregulation Might Independently Predict Shorter Progression-Free Survival in Lung Adenocarcinoma.

ABSTRACT: OBJECTIVE:This study aimed to explore PLEK2 expression profile, its prognostic value, and the potential genomic alterations associated with its dysregulation in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). MATERIALS AND METHODS:Data from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Kaplan-Meier plotter were used in combination for bioinformatic analysis. RESULTS:PLEK2 mRNA was significantly upregulated in both LUAD and LUSC compared with their respective normal controls. PLEK2 upregulation showed independent prognostic value in progression-free survival (PFS) (HR: 1.169, 95%CI: 1.033 -1.322, p = 0.014). PLEK2 mRNA expression was positively correlated with invasion, cell cycle, DNA damage, and DNA repair of LUAD cells at the single-cell level. Genomic analysis showed that gene-level amplification might not directly lead to increased PLEK2 expression. Methylation profile analysis found 4 CpG sites (cg12199376, cg14437634, cg17641252, and cg06724236) had at least a weakly negative correlation with PLEK2 expression, among which cg12199376, cg14437634 and cg17641252 locate around the first exon of the gene. CONCLUSIONS:Increased PLEK2 expression might be a specific prognostic biomarker of poor PFS in LUAD patients. Its expression had significant positive correlations with invasion, cell cycle, DNA damage, and DNA repair of LUAD cells at the single-cell level. Promoter hypomethylation might be a potential mechanism leading to its upregulation.

SUBMITTER: Zhang W

PROVIDER: S-EPMC7588770 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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<i>PLEK2</i> Gene Upregulation Might Independently Predict Shorter Progression-Free Survival in Lung Adenocarcinoma.

Zhang Wenqian W Li Tong T Hu Bin B Li Hui H

Technology in cancer research & treatment 20200101

<h4>Objective</h4>This study aimed to explore <i>PLEK2</i> expression profile, its prognostic value, and the potential genomic alterations associated with its dysregulation in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).<h4>Materials and methods</h4>Data from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Kaplan-Meier plotter were used in combination for bioinformatic analysis.<h4>Results</h4><i>PLEK2</i> mRNA was significantly upregulated in bo ...[more]

PMID: 33084541

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Project description:Complement factor B (CFB) serves a pivotal role in the alternative signaling pathway of the complement system and exerts a key role in the labelling of target particles, resulting from effective clearance of the target. The present study aimed to investigate the association between low expression levels of CFB and the clinical features and survival status of patients with lung adenocarcinoma (LUAD). Patient data were based on RNA-sequencing and clinical data from The Cancer Genome Atlas database. All patients were divided into two groups based on the median expression of CFB. Kaplan-Meier curve and univariate Cox regression analyses were used to investigate the association between CFB and survival status. Gene set enrichment analysis was used to examine the effects of CFB expression on signaling pathway impairment. Furthermore, reverse transcription-quantitative PCR (RT-qPCR) and western blotting were used to verify the relative expression levels of CFB in LUAD tissues. The data revealed that residual tumor classification, Karnofsky performance score and cancer stage were associated with overall survival, and that Karnofsky performance score and stage were associated with disease-free survival. The results demonstrated that high expression levels of CFB were associated with increased patient overall and disease-free survival according to both continuous and categorical models. The results of multivariate analysis identified that high expression levels of CFB were associated with increased overall and disease-free survival according to both the continuous model [hazard ratio (HR), 0.48; 95% confidence interval (95% CI), 0.25-0.93; P=0.029 for overall survival; HR, 0.29; 95% CI, 0.15-0.59; P=0.001 for disease-free survival] and the categorical model (HR, 0.46; 95% CI, 0.22-0.93; P=0.031 for overall survival; HR, 0.25; 95% CI, 0.12-0.55; P=0.001 for disease-free survival) after adjusting for corresponding covariates (residual tumour classification, Karnofsky performance score and stage). Furthermore, the results of both RT-qPCR and western blotting indicated that the relative mRNA and protein expression levels of CFB in lung tumor tissues were downregulated compared with those in adjacent non-tumor tissues. Collectively, the present results suggested that CFB expression was an independent predictor of overall and disease-free survival in patients with LUAD.

Project description:BackgroundThe role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment.MethodsHere we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups.ResultsWe revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype.ConclusionsWe discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.

Project description:BackgroundLung adenocarcinoma (LUAD) is the most common histological type of lung cancers, which is the primary cause of cancer-related mortality worldwide. Growing evidence has suggested that tumor microenvironment (TME) plays a pivotal role in tumorigenesis and progression. Hence, we investigate the correlation of TME related genes with LUAD prognosis.MethodThe information of LUAD gene expression data was obtained from The Cancer Genome Atlas (TCGA). According to their immune/stromal scores calculated by the ESTIMATE algorithm, differentially expressed genes (DEGs) were identified. Then, we performed univariate Cox regression analysis on DEGs to obtain genes that are apparently bound up with LUAD survival (SurGenes). Functional annotation and protein-protein interaction (PPI) was also conducted on SurGenes. By validating the SurGenes with data sets of lung cancer from the Gene Expression Omnibus (GEO), 106 TME related SurGenes were generated. Further, intersection analysis was executed between the 106 TME related SurGenes and hub genes from PPI network, PTPRC and CD19 were obtained. Gene Set Enrichment Analysis and CIBERSORT analysis were performed on PTPRC and CD19. Based on the TCGA LUAD dataset, we conducted factor analysis and Step-wise multivariate Cox regression analysis for 106 TME related SurGenes to construct the prognostic model for LUAD survival prediction. The LUAD dataset in GEO (GSE68465) was used as the testing dataset to confirm the prognostic model. Multivariate Cox regression analysis was used between risk score from the prognostic model and clinical parameters.ResultA total of 106 TME related genes were collected in our research totally, which were markedly correlated with the overall survival (OS) of LUAD patient. Bioinformatics analysis suggest them mainly concentrated on immune response, cell adhesion, and extracellular matrix. More importantly, among 106 TME related SurGenes, PTPRC and CD19 were highly interconnected nodes among PPI network and correlated with immune activity, exhibiting significant prognostic potential. The prognostic model was a weighted linear combination of the 106 genes, by which the low-OS LUAD samples could be separated from the high-OS samples with success. This model was also able to rebustly predict the situation of survival (training set: p-value < 0.0001, area under the curve (AUC) = 0.649; testing set: p-value = 0.0009, AUC = 0.617). By combining with clinical parameters, the prognostic model was optimized. The AUC achieved 0.716 for 3 year and 0.699 for 5 year.ConclusionA series of TME-related prognostic genes were acquired in this research, which could reflect immune disorders within TME, and PTPRC and CD19 show the potential to be an indicator for LUAD prognosis and tumor microenvironment modulation. The prognostic model constructed base on those prognostic genes presented a high predictive ability, and may have clinical implications in the overall survival prediction of LUAD.

Dataset Information

PLEK2 Gene Upregulation Might Independently Predict Shorter Progression-Free Survival in Lung Adenocarcinoma.

Publications

<i>PLEK2</i> Gene Upregulation Might Independently Predict Shorter Progression-Free Survival in Lung Adenocarcinoma.

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