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Integrative Analysis of Biomarkers Through Machine Learning Identifies Stemness Features in Colorectal Cancer.

ABSTRACT: Background: Cancer stem cells (CSCs), which are characterized by self-renewal and plasticity, are highly correlated with tumor metastasis and drug resistance. To fully understand the role of CSCs in colorectal cancer (CRC), we evaluated the stemness traits and prognostic value of stemness-related genes in CRC. Methods: In this study, the data from 616 CRC patients from The Cancer Genome Atlas (TCGA) were assessed and subtyped based on the mRNA expression-based stemness index (mRNAsi). The correlations of cancer stemness with the immune microenvironment, tumor mutational burden (TMB), and N6-methyladenosine (m6A) RNA methylation regulators were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify the crucial stemness-related genes and modules. Furthermore, a prognostic expression signature was constructed using the Lasso-penalized Cox regression analysis. The signature was validated via multiplex immunofluorescence staining of tissue samples in an independent cohort of 48 CRC patients. Results: This study suggests that high-mRNAsi scores are associated with poor overall survival in stage IV CRC patients. Moreover, the levels of TMB and m6A RNA methylation regulators were positively correlated with mRNAsi scores, and low-mRNAsi scores were characterized by increased immune activity in CRC. The analysis identified 34 key genes as candidate prognosis biomarkers. Finally, a three-gene prognostic signature (PARPBP, KNSTRN, and KIF2C) was explored together with specific clinical features to construct a nomogram, which was successfully validated in an external cohort. Conclusion: There is a unique correlation between CSCs and the prognosis of CRC patients, and the novel biomarkers related to cell stemness could accurately predict the clinical outcomes of these patients.

SUBMITTER: Wei R

PROVIDER: S-EPMC8456021 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tumor progression includes the obtainment of progenitor and stem cell-like features and the gradual loss of a differentiated phenotype. Stemness was defined as the potential for differentiation and self-renewal from the cell of origin. Previous studies have confirmed the effective application of stemness in a number of malignancies. However, the mechanisms underlying the growth and maintenance of multiple myeloma (MM) stem cells remain unclear. We calculated the stemness index for samples of MM by utilizing a novel one-class logistic regression (OCLR) machine learning algorithm and found that mRNA expression-based stemness index (mRNAsi) was an independent prognostic factor of MM. Based on the same cutoff value, mRNAsi could stratify MM patients into low and high groups with different outcomes. We identified 127 stemness-related signatures using weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Functional annotation and pathway enrichment analysis indicated that these genes were mainly involved in the cell cycle, cell differentiation, and DNA replication and repair. Using the molecular complex detection (MCODE) algorithm, we identified 34 pivotal signatures. Meanwhile, we conducted unsupervised clustering and classified the MM cohorts into three MM stemness (MMS) clusters with distinct prognoses. Samples in MMS-cluster3 possessed the highest stemness fractions and the worst prognosis. Additionally, we applied the ESTIMATE algorithm to infer differential immune infiltration among the three MMS clusters. The immune core and stromal score were significantly lower in MMS-cluster3 than in the other clusters, supporting the negative relation between stemness and anticancer immunity. Finally, we proposed a prognostic nomogram that allows for individualized assessment of the 3- and 5-year overall survival (OS) probabilities among patients with MM. Our study comprehensively assessed the MM stemness index based on large cohorts and built a 34-gene based classifier for predicting prognosis and potential strategies for stemness treatment.

Project description:Most human cancers develop from stem and progenitor cell populations through the sequential accumulation of various genetic and epigenetic alterations. Cancer stem cells have been identified from medulloblastoma (MB), but a comprehensive understanding of MB stemness, including the interactions between the tumor immune microenvironment and MB stemness, is lacking. Here, we employed a trained stemness index model based on an existent one-class logistic regression (OCLR) machine-learning method to score MB samples; we then obtained two stemness indices, a gene expression-based stemness index (mRNAsi) and a DNA methylation-based stemness index (mDNAsi), to perform an integrated analysis of MB stemness in a cohort of primary cancer samples (n = 763). We observed an inverse trend between mRNAsi and mDNAsi for MB subgroup and metastatic status. By applying the univariable Cox regression analysis, we found that mRNAsi significantly correlated with overall survival (OS) for all MB patients, whereas mDNAsi had no significant association with OS for all MB patients. In addition, by combining the Lasso-penalized Cox regression machine-learning approach with univariate and multivariate Cox regression analyses, we identified a stemness-related gene expression signature that accurately predicted survival in patients with Sonic hedgehog (SHH) MB. Furthermore, positive correlations between mRNAsi and prognostic copy number aberrations in SHH MB, including MYCN amplifications and GLI2 amplifications, were detected. Analyses of the immune microenvironment revealed unanticipated correlations of MB stemness with infiltrating immune cells. Lastly, using the Connectivity Map, we identified potential drugs targeting the MB stemness signature. Our findings based on stemness indices might advance the development of objective diagnostic tools for quantitating MB stemness and lead to novel biomarkers that predict the survival of patients with MB or the efficacy of strategies targeting MB stem cells.

Project description:PurposeOsteoarthritis (OA) stands as the most prevalent joint disorder. Mitochondrial dysfunction has been linked to the pathogenesis of OA. The main goal of this study is to uncover the pivotal role of mitochondria in the mechanisms driving OA development.Materials and methodsWe acquired seven bulk RNA-seq datasets from the Gene Expression Omnibus (GEO) database and examined the expression levels of differentially expressed genes related to mitochondria in OA. We utilized single-sample gene set enrichment analysis (ssGSEA), gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA) analyses to explore the functional mechanisms associated with these genes. Seven machine learning algorithms were utilized to identify hub mitochondria-related genes and develop a predictive model. Further analyses included pathway enrichment, immune infiltration, gene-disease relationships, and mRNA-miRNA network construction based on these hub mitochondria-related genes. genome-wide association studies (GWAS) analysis was performed using the Gene Atlas database. GSEA, gene set variation analysis (GSVA), protein pathway analysis, and WGCNA were employed to investigate relevant pathways in subtypes. The Harmonizome database was employed to analyze the expression of hub mitochondria-related genes across various human tissues. Single-cell data analysis was conducted to examine patterns of gene expression distribution and pseudo-temporal changes. Additionally, The real-time polymerase chain reaction (RT-PCR) was used to validate the expression of these hub mitochondria-related genes.ResultsIn OA, the mitochondria-related pathway was significantly activated. Nine hub mitochondria-related genes (SIRT4, DNAJC15, NFS1, FKBP8, SLC25A37, CARS2, MTHFD2, ETFDH, and PDK4) were identified. They constructed predictive models with good ability to predict OA. These genes are primarily associated with macrophages. Unsupervised consensus clustering identified two mitochondria-associated isoforms that are primarily associated with metabolism. Single-cell analysis showed that they were all expressed in single cells and varied with cell differentiation. RT-PCR showed that they were all significantly expressed in OA.ConclusionSIRT4, DNAJC15, NFS1, FKBP8, SLC25A37, CARS2, MTHFD2, ETFDH, and PDK4 are potential mitochondrial target genes for studying OA. The classification of mitochondria-associated isoforms could help to personalize treatment for OA patients.

Project description:Identification and localization of ischemic stroke (IS) lesions is routinely performed to confirm diagnosis, assess stroke severity, predict disability and plan rehabilitation strategies using magnetic resonance imaging (MRI). In basic research, stroke lesion segmentation is necessary to study complex peri-infarction tissue changes. Moreover, final stroke volume is a critical outcome evaluated in clinical and preclinical experiments to determine therapy or intervention success. Manual segmentations are performed but they require a specialized skill set, are prone to inter-observer variation, are not entirely objective and are often not supported by histology. The task is even more challenging when dealing with large multi-center datasets, multiple experimenters or large animal cohorts. On the other hand, current automatized segmentation approaches often lack histological validation, are not entirely user independent, are often based on single parameters, or in the case of complex machine learning methods, require vast training datasets and are prone to a lack of model interpretation. Methods: We induced IS using the middle cerebral artery occlusion model on two rat cohorts. We acquired apparent diffusion coefficient (ADC) and T2-weighted (T2W) images at 24 h and 1-week after IS induction. Subsets of the animals at 24 h and 1-week post IS were evaluated using histology and immunohistochemistry. Using a Gaussian mixture model, we segmented voxel-wise interactions between ADC and T2W parameters at 24 h using one of the rat cohorts. We then used these segmentation results to train a random forest classifier, which we applied to the second rat cohort. The algorithms' stroke segmentations were compared to manual stroke delineations, T2W and ADC thresholding methods and the final stroke segmentation at 1-week. Volume correlations to histology were also performed for every segmentation method. Metrics of success were calculated with respect to the final stroke volume. Finally, the trained random forest classifier was tested on a human dataset with a similar temporal stroke on-set. Manual segmentations, ADC and T2W thresholds were again used to evaluate and perform comparisons with the proposed algorithms' output. Results: In preclinical rat data our framework significantly outperformed commonly applied automatized thresholding approaches and segmented stroke regions similarly to manual delineation. The framework predicted the localization of final stroke regions in 1-week post-stroke MRI with a median Dice similarity coefficient of 0.86, Matthew's correlation coefficient of 0.80 and false positive rate of 0.04. The predicted stroke volumes also strongly correlated with final histological stroke regions (Pearson correlation = 0.88, P < 0.0001). Lastly, the stroke region characteristics identified by our framework in rats also identified stroke lesions in human brains, largely outperforming thresholding approaches in stroke volume prediction (P<0.01). Conclusion: Our findings reveal that the segmentation produced by our proposed framework using 24 h MRI rat data strongly correlated with the final stroke volume, denoting a predictive effect. In addition, we show for the first time that the stroke imaging features can be directly translated between species, allowing identification of acute stroke in humans using the model trained on animal data. This discovery reduces the gap between the clinical and preclinical fields, unveiling a novel approach to directly co-analyze clinical and preclinical data. Such methods can provide further biological insights into human stroke and highlight the differences between species in order to help improve the experimental setups and animal models of the disease.

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Integrative Analysis of Biomarkers Through Machine Learning Identifies Stemness Features in Colorectal Cancer.

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