Identification of Subtypes and a Prognostic Gene Signature in Colon Cancer Using Cell Differentiation Trajectories.
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ABSTRACT:
SUBMITTER: Xiang R
PROVIDER: S-EPMC8710730 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundColon cancer is a worldwide leading cause of cancer-related mortality, and the prognosis of colon cancer is still needed to be improved. This study aimed to construct a prognostic model for predicting the prognosis of colon cancer.MethodsThe gene expression profile data of colon cancer were obtained from the TCGA, GSE44861, and GSE44076 datasets. The WGCNA module genes and common differentially expressed genes (DEGs) were used to screen out the prognosis-associated DEGs, which were used to construct a prognostic model. The performance of the prognostic model was assessed and validated in the TCGA training and microarray validation sets (GSE38832 and GSE17538). At last, the model and prognosis-associated clinical factors were used for the construction of the nomogram.ResultsFive colon cancer-related WGCNA modules (including 1160 genes) and 1153 DEGs between tumor and normal tissues were identified, inclusive of 556 overlapping DEGs. Stepwise Cox regression analyses identified there were 14 prognosis-associated DEGs, of which 12 DEGs were included in the optimized prognostic gene signature. This prognostic model presented a high forecast ability for the prognosis of colon cancer both in the TCGA training dataset and the validation datasets (GSE38832 and GSE17538; AUC > 0.8). In addition, patients' age, T classification, recurrence status, and prognostic risk score were associated with the prognosis of TCGA patients with colon cancer. The nomogram was constructed using the above factors, and the predictive 3- and 5-year survival probabilities had high compliance with the actual survival proportions.ConclusionsThe 12-gene signature prognostic model had a high predictive ability for the prognosis of colon cancer.
| S-EPMC7807455 | biostudies-literature
Project description:Both tumour-infiltrating immune cells and inflammation-related genes that can mediate immune infiltration contribute to the initiation and prognosis of patients with colon cancer. In this study, we developed a method to predict the survival outcomes among colon cancer patients and direct immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and captured inflammation-related genes from the GeneCards database. The package "ConsensusClusterPlus" was used to generate molecular subtypes based on inflammation-related genes obtained by differential expression analysis and univariate Cox analysis. A prognostic signature including four genes (PLCG2, TIMP1, BDNF and IL13) was also constructed and was an independent prognostic factor. Cluster 2 and higher risk scores meant worse overall survival and higher expression of human leukocyte antigen and immune checkpoints. Immune cell infiltration calculated by the estimate, CIBERSORT, TIMER, ssGSEA algorithms, tumour immune dysfunction and exclusion (TIDE), and tumour stemness indices (TSIs) were also compared on the basis of inflammation-related molecular subtypes and the risk signature. In addition, analyses of stratification, somatic mutation, nomogram construction, chemotherapeutic response prediction and small-molecule drug prediction were performed based on the risk signature. We finally used qRT-PCR to detect the expression levels of four genes in colon cancer cell lines and obtained results consistent with the prediction. Our findings demonstrated a four-gene prognostic signature that could be useful for prognostication in colon cancer patients and designing personalized treatments, which could provide new versions of personalized management for these patients.
| S-EPMC8733947 | biostudies-literature
Project description:Previously studies have shown that apoptosis-related genes play an essential role in normal cell turnover, maintaining the immune system function, and inducing cell death. However, their prognostic roles in clear cell renal cell carcinoma (ccRCC) have not been thoroughly investigated. In the present study, apoptosis-related genes expression profiles from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database were used as training dataset and external validation dataset, respectively. According to the systematical analysis of the apoptosis-related gene expression profile, we constructed a gene signature to determine the role of apoptosis-related genes in the survival of ccRCC. We discovered that patients in the low-risk group have a better survival than high-risk group and the signature could serve as an independent prognostic factor. A nomogram, including a signature and clinical factors, were constructed to estimate the individual survival probability. The Gene set enrichment analysis (GSEA) identified some significant pathways which may contribute to understanding the underlying mechanism of ccRCC. In addition, the prognostic efficiency of the risk model was further validated in the disease free survival (DFS) and the ICGC dataset, respectively. We also identified three molecular subtypes (named C1, C2, and C3) based on apoptosis-related gene expression. We found that C1 was corresponding to a worse survival outcome and showed a high drug sensitivity of sorafenib and sunitinib. C2 and C3 were corresponding to a better survival outcome and presented a low drug sensitivity to sorafenib and sunitinib. Moreover, we found that C2 and C3 have more likelihood to be respond to immunotherapy. Together, the apoptosis-related gene signature and three molecular subtypes may promote the understanding of the underlying molecular mechanism of ccRCC, and provided reference for developing individualized treatment of the ccRCC patients.
| S-EPMC8100811 | biostudies-literature
Project description:Cancer stem cells play crucial roles in the development of colon cancer (COAD). This study tried to explore new markers for predicting the prognosis of colon cancer based on stem cell-related genes. In our study, 424 COAD samples from TCGA were divided into three subtypes based on 412 stem cell-related genes; there were significant differences in prognosis, clinical characteristics, and immune scores between these subtypes. 694 genes were screened between subgroups. Subsequently a six-gene signature (DYDC2, MS4A15, MAGEA1, WNT7A, APOD, and SERPINE1) was established. This model had strong robustness and stable predictive performance in cohorts of different platforms. Taken together, the six-gene signature constructed in this study could be used as a novel prognostic marker for COAD patients.
| S-EPMC7933554 | biostudies-literature
Project description:BackgroundNecroptosis is a novel programmed cell death pathway proposed in 2005, which is mainly activated by the tumor necrosis factor (TNF) family and mediates cellular disassembly via receptor interacting serine/threonine kinase 1 (RIPK1), receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL). We tried to analyze the relationship of necroptosis-related genes (NRGs) expression with colon adenocarcinoma (COAD) and propose potential therapeutic targets through immunological analysis.MethodsFirst, we evaluated the expression of NRGs in COAD patients and constructed a prognostic signature. The prognostic signature was validated using The Cancer Genome Atlas (TCGA)-COAD and GSE39582 datasets, respectively. And the Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and principal component analysis were used to evaluate the signature. Then we analyzed the enrichment of NRGs in the signature using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, we analyzed the immunological characteristics of the COAD patients by single sample gene set enrichment analysis (ssGSEA) and predicted the possible immune checkpoints.ResultsWe constructed a prognostic signature with 8 NRGs (RIPK3, MLKL, TRAF2, CXCL1, RBCK1, CDKN2A, JMJD7-PLA2G4B and CAMK2B). The Kaplan-Meier analysis, ROC curves, and principal component analysis demonstrated good predictivity of the signature. In addition, we constructed a nomogram with good individualized predictive ability (C-index =0.772). The immunological analysis revealed that the prognosis of COAD was associated with autoimmune function, and we proposed 10 potential therapeutic targets.ConclusionsOverall, we constructed an NRGs prognostic signature and suggested potential therapeutic targets for the COAD treatment.
| S-EPMC10583017 | biostudies-literature
Project description:Purpose HER2 gene amplification or protein overexpression (HER2+) defines a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. We aimed to investigate the heterogeneous biological appearance and clinical behavior of HER2+ tumors using molecular profiling. Materials and Methods Hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stage, histological grade and estrogen receptor (ER) status was used to construct a HER2-derived prognostic predictor that was further evaluated in several large independent breast cancer data sets. Results Unsupervised analysis identified three subtypes of HER2+ tumors with mixed stage, histological grade and ER-status. One subtype had a significantly worse clinical outcome. A prognostic predictor was created based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2+ breast cancer across multiple independent breast cancer data sets and identify a sizable HER2+ group with long disease-free survival and low mortality. Significant correlation to prognosis was also observed in basal-like, ER−, lymph node positive or high-grade tumors, irrespective of HER2-status. The predictor included genes associated to immune response, tumor invasion and metastasis. Conclusion The HER2-derived prognostic predictor provides further insight into the heterogeneous biology of HER2+ tumors and may become useful for improved selection of patients that need additional treatment with new drugs targeting the HER2 pathway. Array comparative genomic hybridization (aCGH) identified 58 breast tumors with amplification of HER2 from a larger cohort of approx 500 tumors breast. Global gene expression profiles were obtained using 70-mer oligonucleotide microarrays. Unsupervised hierarchical clustering of the 58 tumors, using Pearson correlation and complete linkage, identified three main clusters. One cluster showed significantly poorer clinical outcome. Significance of microarray (SAM) analysis was performed to identify 158 genes separating the poor outcome cluster compared to the other two clusters. Gene expression centroids, based on the 158 genes, were created for each cluster for validation in independent breast cancer data sets.
| S-ECPF-GEOD-18328 | biostudies-other
Project description:BackgroundColon cancer (CC) is a malignant tumor with a high incidence and poor prognosis. Accumulating evidence shows that the immune signature plays an important role in the tumorigenesis, progression, and prognosis of CC. Our study is aimed at establishing a novel robust immune-related gene pair signature for predicting the prognosis of CC.MethodsGene expression profiles and corresponding clinical information are obtained from two public data sets: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, GSE39582). We screened out immune-related gene pairs (IRGPs) associated with prognosis in the discovery cohort. Lasso-Cox proportional hazard regression was used to develop the best prognostic signature model. According to this, the patients in the validation cohort were divided into high immune-risk group and low immune-risk group, and the prediction ability of the signature model was verified by survival analysis and independent prognostic analysis.ResultsA total of 17 IRGPs composed of 26 IRGs were used to construct a prognostic-related risk scoring model. This model accurately predicted the prognosis of CC patients, and the patients in the high immune-risk group indicated poor prognosis in the discovery cohort and validation cohort. Besides, whether in univariate or multivariate analysis, the IRGP signature was an independent prognostic factor. T cell CD4 memory resting in the low-risk group was significantly higher than that in the high-risk group. Functional analysis showed that the biological processes of the low-risk group included "TCA cycle" and "RNA degradation," while the high-risk group was enriched in the "CAMs" and "focal adhesion" pathways.ConclusionWe have successfully established a signature model composed of 17 IRGPs, which provides a novel idea to predict the prognosis of CC patients.
| S-EPMC8166469 | biostudies-literature
Project description:BACKGROUND:The identification of high-risk colorectal cancer (CRC) patient is key to individualized treatment after surgery and reliable prognostic biomarkers are needed identifying high-risk CRC patients. METHODS:We developed a gene pair based prognostic signature that could can the prognosis risk in patients with CRC. This study retrospectively analyzed 4 public CRC datasets, and 1123 patients with CRC were divided into a training cohort (n?=?300) and 3 independent validation cohorts (n?=?507, 226, and 90 patients). RESULTS:A signature of 9 prognosis-related gene pairs (PRGPs) consisting of 17 unique genes was constructed. Then, a PRGP index (PRGPI) was constructed and divided patients into high- and low-risk groups according to the signature score. Patients in the high-risk group showed a poorer relapse-free survival than the low-risk group in both the training cohort [hazard ratio (HR) range, 4.6, 95% confidence interval (95% CI), 2.55-8.32; P?<?.0001] and meta-validation set (hazard ratio range, 4.09, 95% CI, 1.99-8.39; P?<?.0001). The PRGPI signature achieved a higher accuracy [mean concordance index (C-index): 0.6?0.74] than a commercialized molecular signature (mean C-index, 0.48?0.56) for estimation of relapse-free survival in comparable validation sets. CONCLUSION:The gene pair based prognostic signature is a promising biomarker for estimating relapse-free survival of CRC.
| S-EPMC6211904 | biostudies-literature
Project description:BackgroundImmunogenic cell death (ICD) is considered a promising type of regulated cell death and exerts effects by activating the adaptive immune response, reshaping the tumor environment (TME) and improving therapeutic efficacy. However, the potential roles and prognostic value of ICD-associated genes in gastric cancer (GC) remain unclear.MethodsThe RNA expression data and clinical information of 1090 GC patients from six cohorts were collected. Consensus clustering was used to identify three distinct molecular subtypes. Then, a robust prognostic ICD_score for predicting prognosis was built via WGCNA and LASSO Cox regression according to the TCGA cohort, and the predictive capability of the ICD_score in GC patients was validated in the other cohorts. ICD-related immune features were analyzed using a CIBERSORT method and verified by immunofluorescence.ResultsWe found that ICD-related gene variations were correlated with clinical outcomes, tumor immune microenvironment (TIME) characteristics and treatment response. We then constructed an ICD signature that classifies cases as low- and high-ICD_score groups. The high-ICD_score group indicates unfavorable OS, a more advanced TNM stage, and presents an immune-suppressed phenotype, which has more infiltrations of pro-tumor immune cells, such as macrophages, which was verified by immunofluorescence. In addition, a nomogram containing the ICD_score showed a high predictive accuracy with AUCs of 0.715, 0.731 and 0.8 on Years 1, 3, and 5.ConclusionWe performed the first and synthesis ICD analysis in GC and built a clinical application tool based on the ICD signature, which paved a new path for assessing prognosis and guiding individual treatment.
| S-EPMC10046021 | biostudies-literature
Project description:The aim of the present study was to examine the molecular factors associated with the prognosis of colon cancer. Gene expression datasets were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases to screen differentially expressed genes (DEGs) between colon cancer samples and normal samples. Survival?related genes were selected from the DEGs using the Cox regression method. A co?expression network of survival?related genes was then constructed, and functional clusters were extracted from this network. The significantly enriched functions and pathways of the genes in the network were identified. Using Bayesian discriminant analysis, a prognostic prediction system was established to distinguish the positive from negative prognostic samples. The discrimination efficacy of the system was validated in the GSE17538 dataset using Kaplan?Meier survival analysis. A total of 636 and 1,892 DEGs between the colon cancer samples and normal samples were screened from the TCGA and GSE44861 dataset, respectively. There were 155 survival?related genes selected. The co?expression network of survival?related genes included 138 genes, 534 lines (connections) and five functional clusters, including the signaling pathway, cellular response to cAMP, and immune system process functional clusters. The molecular function, cellular components and biological processes were the significantly enriched functions. The peroxisome proliferator?activated receptor signaling pathway, Wnt signaling pathway, B cell receptor signaling pathway, and cytokine?cytokine receptor interactions were the significant pathways. A prognostic prediction system based on a 65?gene signature was established using this co?expression network. Its discriminatory effect was validated in the TCGA dataset (P=3.56e?12) and the GSE17538 dataset (P=1.67e?6). The 65?gene signature included kallikrein?related peptidase 6 (KLK6), collagen type XI ?1 (COL11A1), cartilage oligomeric matrix protein, wingless?type MMTV integration site family member 2 (WNT2) and keratin 6B. In conclusion, a 65?gene signature was screened in the present study, which showed a prognostic prediction effect in colon adenocarcinoma. KLK6, COL11A1, and WNT2 may be suitable prognostic predictors for colon adenocarcinoma.
| S-EPMC5810222 | biostudies-literature