scholarly journals Identification of a methylomics-associated nomogram for predicting overall survival of stage I–II lung adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Heng Wang ◽  
Chuangye Wei ◽  
Peng Pan ◽  
Fengfeng Yuan ◽  
Jiancheng Cheng

AbstractThe aim of this paper was to identify DNA methylation based biomarkers for predicting overall survival (OS) of stage I–II lung adenocarcinoma (LUAD) patients. Methylation profile data of patients with stage I–II LUAD from The Cancer Genome Atlas (TCGA) database was used to determine methylation sites-based hallmark for stage I–II LUAD patients’ OS. The patients were separated into training and validation datasets by using median risk score as cutoff. Univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses were employed to develop a DNA methylation signature for OS of patients with stage I–II LUAD. As a result, an 11-DNA methylation signature was determined to be critically associated with the OS of patients with stage I–II LUAD. Analysis of receiver operating characteristics (ROC) suggested a high prognostic effectiveness of the 11-DNA methylation signature in patients with stage I–II LUAD (AUC at 1, 3, 5 years in training set were (0.849, 0.879, 0.831, respectively), validation set (0.742, 0.807, 0.904, respectively), entire TCGA dataset (0.747, 0.818, 0.870, respectively). Kaplan–Meier survival analyses exhibited that survival was significantly longer in the low-risk cohort compared to the high-risk cohort in the training dataset (P = 7e − 07), in the validation dataset (P = 1e − 08), and in the all-cohort dataset (P = 6e − 14). In addition, a nomogram was developed based on molecular factor (methylation risk score) as well as clinical factors (age and cancer status) (AUC at 1, 3, 5 years entire TCGA dataset were 0.770, 0.849, 0.979, respectively). The result verified that our methylomics-associated nomogram had a strong robustness for predicting stage I–II LUAD patients’ OS. Furthermore, the nomogram combined clinical and molecular factors to determine an individualized probability of recurrence for patients with stage I–II LUAD, which stood for a major advance in the field of personalized medicine for pulmonary oncology. Collectively, we successfully identified a DNA methylation biomarker and a DNA methylation-based nomogram to predict the OS of patients with stage I–II LUAD.

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Wu ◽  
Yuqing Lou ◽  
Yi-Min Ma ◽  
Jun Xu ◽  
Tieliu Shi

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer with heterogeneous outcomes and diverse therapeutic responses. To classify patients into different groups and facilitate the suitable therapeutic strategy, we first selected eight microRNA (miRNA) signatures in The Cancer Genome Atlas (TCGA)-LUAD cohort based on multi-strategy combination, including differential expression analysis, regulatory relationship, univariate survival analysis, importance clustering, and multivariate combinations analysis. Using the eight miRNA signatures, we further built novel risk scores based on the predefined cutoff and beta coefficients and divided the patients into high-risk and low-risk groups with significantly different overall survival time (p-value < 2 e−16). The risk-score model was confirmed with an independent dataset (p-value = 4.71 e−4). We also observed that the risk scores of early-stage patients were significantly lower than those of late-stage patients. Moreover, our model can also provide new insights into the current clinical staging system and can be regarded as an alternative system for patient stratification. This model unified the variable value as the beta coefficient facilitating the integration of biomarkers obtained from different omics data.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuelong Wang ◽  
Bin Zhou ◽  
Yuxin Xia ◽  
Jianxin Zuo ◽  
Yanchao Liu ◽  
...  

Abstract Background DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. Method The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. Result We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47–3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19–3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. Conclusions The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.


2020 ◽  
Author(s):  
Xuelong Wang ◽  
Bin Zhou ◽  
Yuxin Xia ◽  
Jianxin Zuo ◽  
Yanchao Liu ◽  
...  

Abstract Background DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. Method: The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated expression correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. Result We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47–3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19–3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. Conclusions The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.


2021 ◽  
Vol 18 (6) ◽  
pp. 7837-7860
Author(s):  
Linbo Zhang ◽  
◽  
Mei Xin ◽  
Peng Wang

<abstract> <p>Since multiple studies have reported that small nucleolar RNAs (snoRNAs) can be serve as prognostic biomarkers for cancers, however, the prognostic values of snoRNAs in lung adenocarcinoma (LUAD) remain unclear. Therefore, the main work of this study is to identify the prognostic snoRNAs of LUAD and conduct a comprehensive analysis. The Cancer Genome Atlas LUAD cohort whole-genome RNA-sequencing dataset is included in this study, prognostic analysis and multiple bioinformatics approaches are used for comprehensive analysis and identification of prognostic snoRNAs. There were seven LUAD prognostic snoRNAs were screened in current study. We also constructed a novel expression signature containing five LUAD prognostic snoRNAs (snoU109, SNORA5A, SNORA70, SNORD104 and U3). Survival analysis of this expression signature reveals that LUAD patients with high risk score was significantly related to an unfavourable overall survival (adjusted P = 0.01, adjusted hazard ratio = 1.476, 95% confidence interval = 1.096-1.987). Functional analysis indicated that LUAD patients with different risk score phenotypes had significant differences in cell cycle, apoptosis, integrin, transforming growth factor beta, ErbB, nuclear factor kappa B, mitogen-activated protein kinase, phosphatidylinositol-3-kinase and toll like receptor signaling pathway. Immune microenvironment analysis also indicated that there were significant differences in immune microenvironment scores among LUAD patients with different risk score. In conclusion, this study identified an novel expression signature containing five LUAD prognostic snoRNAs, which may be serve as an independent prognostic indicator for LUAD patients.</p> </abstract>


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaodong Yang ◽  
Yuexin Zheng ◽  
Zhihai Han ◽  
Xiliang Zhang

Abstract Background As a marker of differentiation, Killer cell lectin like receptor G1 (KLRG1) plays an inhibitory role in human NK cells and T cells. However, its clinical role remains inexplicit. This work intended to investigate the predictive ability of KLRG1 on the efficacy of immune-checkpoint inhibitor in the treatment of lung adenocarcinoma (LUAD), as well as contribute to the possible molecular mechanisms of KLRG1 on LUAD development. Methods Using data from the Gene Expression Omnibus, the Cancer Genome Atlas and the Genotype-Tissue Expression, we compared the expression of KLRG1 and its related genes Bruton tyrosine kinase (BTK), C-C motif chemokine receptor 2 (CCR2), Scm polycomb group protein like 4 (SCML4) in LUAD and normal lung tissues. We also established stable LUAD cell lines with KLRG1 gene knockdown and investigated the effect of KLRG1 knockdown on tumor cell proliferation. We further studied the prognostic value of the four factors in terms of overall survival (OS) in LUAD. Using data from the Gene Expression Omnibus, we further investigated the expression of KLRG1 in the patients with different responses after immunotherapy. Results The expression of KLRG1, BTK, CCR2 and SCML4 was significantly downregulated in LUAD tissues compared to normal controls. Knockdown of KLRG1 promoted the proliferation of A549 and H1299 tumor cells. And low expression of these four factors was associated with unfavorable overall survival in patients with LUAD. Furthermore, low expression of KLRG1 also correlated with poor responses to immunotherapy in LUAD patients. Conclusion Based on these findings, we inferred that KLRG1 had significant correlation with immunotherapy response. Meanwhile, KLRG1, BTK, CCR2 and SCML4 might serve as valuable prognostic biomarkers in LUAD.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunlei Wu ◽  
Quanteng Hu ◽  
Dehua Ma

AbstractLung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. We downloaded the gene expression profile and immune-related gene set from the TCGA and ImmPort database, respectively, to establish immune-related gene pairs (IRGPs). Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis, and multivariable Cox regression analysis to screen and develop an IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from the GEO set was used to validate this signature. The relationship of 22 tumor-infiltrating immune cells (TIICs) to the immune risk score was also investigated. An IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in the TCGA set was 0.867 and 0.870, respectively. Similar results were observed in the AUCs of GEO set 1, 2 and 3 (GEO set 1 [1-year: 0.819; 3-year: 0.803]; GEO set 2 [1-year: 0.834; 3-year: 0.870]; GEO set 3 [1-year: 0.955; 3-year: 0.827]). Survival analysis demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that the risk score was an independent prognostic factor. The immune risk score was highly associated with several TIICs (Plasma cells, memory B cells, resting memory CD4 T cells, and activated NK cells). We developed a novel IRGPs signature for predicting 1- and 3- year overall survival in LUAD, which would be helpful for prognosis assessment of LUAD.


2021 ◽  
Vol 12 ◽  
Author(s):  
Min Zhou ◽  
Shasha Hong ◽  
Bingshu Li ◽  
Cheng Liu ◽  
Ming Hu ◽  
...  

Background: DNA methylation affects the development, progression, and prognosis of various cancers. This study aimed to identify DNA methylated-differentially expressed genes (DEGs) and develop a methylation-driven gene model to evaluate the prognosis of ovarian cancer (OC).Methods: DNA methylation and mRNA expression profiles of OC patients were downloaded from The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases. We used the R package MethylMix to identify DNA methylation-regulated DEGs and built a prognostic signature using LASSO Cox regression. A quantitative nomogram was then drawn based on the risk score and clinicopathological features.Results: We identified 56 methylation-related DEGs and constructed a prognostic risk signature with four genes according to the LASSO Cox regression algorithm. A higher risk score not only predicted poor prognosis, but also was an independent poor prognostic indicator, which was validated by receiver operating characteristic (ROC) curves and the validation cohort. A nomogram consisting of the risk score, age, FIGO stage, and tumor status was generated to predict 3- and 5-year overall survival (OS) in the training cohort. The joint survival analysis of DNA methylation and mRNA expression demonstrated that the two genes may serve as independent prognostic biomarkers for OS in OC.Conclusion: The established qualitative risk score model was found to be robust for evaluating individualized prognosis of OC and in guiding therapy.


2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Xiaofei Wang ◽  
Jie Qiao ◽  
Rongqi Wang

Abstract The present study aimed to construct a novel signature for indicating the prognostic outcomes of hepatocellular carcinoma (HCC). Gene expression profiles were downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. The prognosis-related genes with differential expression were identified with weighted gene co-expression network analysis (WGCNA), univariate analysis, the least absolute shrinkage and selection operator (LASSO). With the stepwise regression analysis, a risk score was constructed based on the expression levels of five genes: Risk score = (−0.7736* CCNB2) + (1.0083* DYNC1LI1) + (−0.6755* KIF11) + (0.9588* SPC25) + (1.5237* KIF18A), which can be applied as a signature for predicting the prognosis of HCC patients. The prediction capacity of the risk score for overall survival was validated with both TCGA and ICGC cohorts. The 1-, 3- and 5-year ROC curves were plotted, in which the AUC was 0.842, 0.726 and 0.699 in TCGA cohort and 0.734, 0.691 and 0.700 in ICGC cohort, respectively. Moreover, the expression levels of the five genes were determined in clinical tumor and normal specimens with immunohistochemistry. The novel signature has exhibited good prediction efficacy for the overall survival of HCC patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaobin Zhang ◽  
Yi He ◽  
Haiyong Gu ◽  
Zhichao Liu ◽  
Bin Li ◽  
...  

BackgroundEsophageal cancer (EC) is a common malignant tumor. MicroRNAs (miRNAs) play a key role in the occurrence and metastasis and are closely related to the prognosis of EC. Therefore, it will provide a powerful tool to predict the overall survival (OS) of EC patients based on miRNAs expression in EC tissues and blood samples.MethodsFive independent databases, TCGA, GSE106817, GSE113486, GSE122497, and GSE112264, were used to construct nine-miRna signature and nomograms for prognosis. The bioinformatics analysis was used to predict the enrichment pathways of targets.ResultsA total of 132 overexpressed miRNAs and 23 suppressed miRNAs showed significant differential expression in both EC serum and tissue samples compared with normal samples. We also showed that nine miRNAs were related to the prognosis of EC. Higher levels of miR-15a-5p, miR-92a-3p, miR-92a-1-5p, miR-590-5p, miR-324-5p, miR-25-3p, miR-181b-5p, miR-421, and miR-93-5p were correlated to the shorter survival time in patients with EC. In addition, we constructed a risk prediction model based on the levels of nine differentially expressed miRNAs (DEMs) and found that the OS time of EC patients with high-risk score was shorter than that of EC patients with low-risk score. Furthermore, our results showed that the risk prediction scores of EC samples were higher than those of normal samples. Finally, the area under the curve (AUC) was used to analyze the risk characteristics of EC and normal controls. By calculating the AUC and the calibration curve, the RNA signature showed a good performance. Bioinformatics analysis showed that nine DEMs were associated with several crucial signaling, including p53, FoxO, PI3K-Akt, HIF-1, and TORC1 signaling. Finally, 14 messenger RNAs (mRNAs) were identified as hub targets of nine miRNAs, including BTRC, SIAH1, RNF138, CDC27, NEDD4L, MKRN1, RLIM, FBXO11, RNF34, MYLIP, FBXW7, RNF4, UBE3C, and RNF111. TCGA dataset validation showed that these hub targets were significantly differently expressed in EC tissues compared with normal samples.ConclusionWe have constructed maps and nomograms of nine-miRna risk signals associated with EC prognosis. Bioinformatics analysis revealed that nine DEMs were associated with several crucial signaling, including p53, FoxO, PI3K-Akt, HIF-1, and TORC1 signaling, in EC. We think that this study will provide clinicians with an effective decision-making tool.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Cheng ◽  
Kezuo Hou ◽  
Yizhe Wang ◽  
Yang Chen ◽  
Xueying Zheng ◽  
...  

BackgroundLung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, with high incidence and mortality. To improve the curative effect and prolong the survival of patients, it is necessary to find new biomarkers to accurately predict the prognosis of patients and explore new strategy to treat high-risk LUAD.MethodsA comprehensive genome-wide profiling analysis was conducted using a retrospective pool of LUAD patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE18842, GSE19188, GSE40791 and GSE50081 and The Cancer Genome Atlas (TCGA). Differential gene analysis and Cox proportional hazard model were used to identify differentially expressed genes with survival significance as candidate prognostic genes. The Kaplan–Meier with log-rank test was used to assess survival difference. A risk score model was developed and validated using TCGA-LUAD and GSE50081. Additionally, The Connectivity Map (CMAP) was used to predict drugs for the treatment of LUAD. The anti-cancer effect and mechanism of its candidate drugs were studied in LUAD cell lines.ResultsWe identified a 5-gene signature (KIF20A, KLF4, KRT6A, LIFR and RGS13). Risk Score (RS) based on 5-gene signature was significantly associated with overall survival (OS). Nomogram combining RS with clinical pathology parameters could potently predict the prognosis of patients with LUAD. Moreover, gliclazide was identified as a candidate drug for the treatment of high-RS LUAD. Finally, gliclazide was shown to induce cell cycle arrest and apoptosis in LUAD cells possibly by targeting CCNB1, CCNB2, CDK1 and AURKA.ConclusionThis study identified a 5-gene signature that can predict the prognosis of patients with LUAD, and Gliclazide as a potential therapeutic drug for LUAD. It provides a new direction for the prognosis and treatment of patients with LUAD.


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