Identification of a Glycosyltransferase Signature for Predicting Prognosis and Immune Microenvironment in Neuroblastoma

Neuroblastoma (NB) is one of the most common solid tumors in children. Glycosyltransferases (GTs) play a crucial role in tumor development and immune escape and have been used as prognostic biomarkers in various tumors. However, the biological functions and prognostic significance of GTs in NB remain poorly understood. The expression data from Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were collected as training and testing data. Based on a progression status, differentially expressed GTs were identified. We constructed a GTscore through support vector machine, least absolute shrinkage and selection operator, and Cox regression in NB, which included four prognostic GTs and was an independent prognostic risk factor for NB. Patients in the high GTscore group had an older age, MYCN amplification, advanced International Neuroblastoma Staging System stage, and high risk. Samples with high GTscores revealed high disialoganglioside (GD2) and neuron-specific enolase expression levels. In addition, a lack of immune cell infiltration was observed in the high GTscore group. This GTscore was also associated with the expression of chemokines (CCL2, CXCL9, and CXCL10) and immune checkpoint genes (cytotoxic T-lymphocyte–associated protein 4, granzyme H, and granzyme K). A low GTscore was also linked to an enhanced response to anti–PD-1 immunotherapy in melanoma patients, and one type of tumor was also derived from neuroectodermal cells such as NB. In conclusion, the constructed GTscore revealed the relationship between GT expression and the NB outcome, GD2 phenotype, and immune infiltration and provided novel clues for the prediction of prognosis and immunotherapy response in NB.

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Transcript levels of spindle and kinetochore-associated complex 1/3 as prognostic biomarkers correlated with immune infiltrates in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-89628-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

De-Chen Yu ◽

Xiang-Yi Chen ◽

Xin Li ◽

Hai-Yu Zhou ◽

De-Quan Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Complex ◽

Immune Cell ◽

Prognostic Significance ◽

Tumor Development ◽

Disease Free Survival ◽

Tumor Grade ◽

Tumor Stage ◽

Prognostic Biomarkers ◽

High Expression

AbstractThe spindle and kinetochore-associated protein complex (Ska) is an essential component in chromosome segregation. It comprises three proteins (Ska1, Ska2, and Ska3) with theorized roles in chromosomal instability and tumor development, and its overexpression has been widely reported in a variety of tumors. However, the prognostic significance and immune infiltration of Ska proteins in hepatocellular carcinoma (HCC) are not completely understood. The bioinformatics tools Oncomine, UALCAN, gene expression profiling interactive analysis 2 (GEPIA2), cBioPortal, GeneMANIA, Metascape, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of the Ska protein complex in HCC patients. We found that the mRNA expression of the Ska complex was markedly upregulated in HCC. High expression of the Ska complex is closely correlated with tumor stage, patient race, tumor grade, and TP53 mutation status. In addition, high expression of the Ska complex was significantly correlated with poor disease-free survival, while the high expression levels of Ska1 and Ska3 were associated with shorter overall survival. The biological functions of the Ska complex in HCC primarily involve the amplification of signals from kinetochores, the mitotic spindle, and (via a MAD2 invasive signal) unattached kinetochores. Furthermore, the expression of the complex was positively correlated with tumor-infiltrating cells. These results may provide new insights into the development of immunotherapeutic targets and prognostic biomarkers for HCC.

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Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer

Cancer Control ◽

10.1177/1073274820903383 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482090338

Author(s):

Fabian Haak ◽

Isabelle Obrecht ◽

Nadia Tosti ◽

Benjamin Weixler ◽

Robert Mechera ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Cell ◽

Cox Regression ◽

Prognostic Significance ◽

Tumor Necrosis Factor Receptor ◽

Tissue Microarrays ◽

Cell Infiltration ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Kaplan Meier

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients’ survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

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Unveiling the immune infiltrate modulation in cancer and response to immunotherapy by MIXTURE—an enhanced deconvolution method

Briefings in Bioinformatics ◽

10.1093/bib/bbaa317 ◽

2020 ◽

Author(s):

Elmer A Fernández ◽

Yamil D Mahmoud ◽

Florencia Veigas ◽

Darío Rocha ◽

Matías Miranda ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Cells ◽

Immune Cell ◽

Immune Escape ◽

Intratumor Heterogeneity ◽

Support Vector ◽

Tumor Immune Escape ◽

Immune Infiltrate ◽

Tumor Biopsies

Abstract The accurate quantification of tumor-infiltrating immune cells turns crucial to uncover their role in tumor immune escape, to determine patient prognosis and to predict response to immune checkpoint blockade. Current state-of-the-art methods that quantify immune cells from tumor biopsies using gene expression data apply computational deconvolution methods that present multicollinearity and estimation errors resulting in the overestimation or underestimation of the diversity of infiltrating immune cells and their quantity. To overcome such limitations, we developed MIXTURE, a new ν-support vector regression-based noise constrained recursive feature selection algorithm based on validated immune cell molecular signatures. MIXTURE provides increased robustness to cell type identification and proportion estimation, outperforms the current methods, and is available to the wider scientific community. We applied MIXTURE to transcriptomic data from tumor biopsies and found relevant novel associations between the components of the immune infiltrate and molecular subtypes, tumor driver biomarkers, tumor mutational burden, microsatellite instability, intratumor heterogeneity, cytolytic score, programmed cell death ligand 1 expression, patients’ survival and response to anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed cell death protein 1 immunotherapy.

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Molecular Staging of Intracranial Ependymoma in Children and Adults

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.3359 ◽

2010 ◽

Vol 28 (19) ◽

pp. 3182-3190 ◽

Cited By ~ 155

Author(s):

Andrey Korshunov ◽

Hendrik Witt ◽

Thomas Hielscher ◽

Axel Benner ◽

Marc Remke ◽

...

Keyword(s):

Genetic Markers ◽

Survival Data ◽

Copy Number ◽

Cox Regression ◽

Prognostic Significance ◽

Staging System ◽

Comparative Genomic ◽

Molecular Staging ◽

Copy Number Aberrations ◽

Intracranial Ependymoma

Purpose The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria. Patients and Methods As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data. Results In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers. Conclusion Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.

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An Immune-Related Prognostic Signature for Predicting Clinical Outcomes and Immune Landscape in IDH-Mutant Lower-Grade Gliomas

Journal of Oncology ◽

10.1155/2021/3766685 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Gang Xiao ◽

Xuan Gao ◽

Lifeng Li ◽

Chao Liu ◽

Zhiyuan Liu ◽

...

Keyword(s):

High Risk ◽

Clinical Outcomes ◽

Immune Cell ◽

Cox Regression ◽

Immune Escape ◽

Gene Signature ◽

Individual Therapy ◽

Lower Grade ◽

Prognostic Signature ◽

Cox Regression Analysis

Background. IDH mutation is the most common in diffuse LGGs, correlated with a favorable prognosis. However, the IDH-mutant LGGs patients with poor prognoses need to be identified, and the potential mechanism leading to a worse outcome and treatment options needs to be investigated. Methods. A six-gene immune-related prognostic signature in IDH-mutant LGGs was constructed based on two public datasets and univariate, multivariate, and LASSO Cox regression analysis. Patients were divided into low- and high-risk groups based on the median risk score in the training and validation sets. We analyzed enriched pathways and immune cell infiltration, applying the GSEA and the immune evaluation algorithms. Results. Stratification and multivariate Cox analysis unveiled that the six-gene signature was an independent prognostic factor. The signature (0.806/0.795/0.822) showed a remarkable prognostic performance, with 1-, 3-, and 5-year time-dependent AUC, higher than for grade (0.612/0.638/0.649) and 1p19q codeletion status (0.606/0.658/0.676). High-risk patients had higher infiltrating immune cells. However, the specific immune escape was observed in the high-risk group after immune activation, owing to increasing immunosuppressive cells, inhibitory cytokines, and immune checkpoint molecules. Moreover, a novel nomogram model was developed to evaluate the survival in IDH-mutant LGGs patients. Conclusion. The six-gene signature could be a promising prognostic biomarker, which is promising to promote individual therapy and improve the clinical outcomes of IDH-mutant gliomas. The study also refined the current classification system of IDH-mutant gliomas, classifying patients into two subtypes with distinct immunophenotypes and overall survival.

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Bioinformatic analysis of the inner heterogeneity within MYCN non-amplified pediatric neuroblastoma sub-group

10.21203/rs.3.rs-48689/v1 ◽

2020 ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Clinical Outcomes ◽

Cox Regression ◽

Prognostic Significance ◽

Young Patients ◽

Bioinformatic Analysis ◽

Mycn Amplification ◽

Expression Levels ◽

Kaplan Meier

Abstract Background: Pediatric neuroblastoma is divided into MYCN amplified and MYCN non-amplified sub-groups. However, the extent of heterogeneity within MYCN amplified or non-amplified pediatric neuroblastoma is unclear.Methods: The prognostic significance of age and MYCN amplification was determined through multivariate cox regression and Kaplan-Meier survival analysis. MYCN non-amplified pediatric neuroblastoma patients were divided into different sub-consensuses using non-negative matrix factorization (NMF) based on the gene expression profiling. Genes particularly expressed in MYCN non-amplified young neuroblastoma patients were identified using Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. The prognostic effects of ALCAM, CACNA2D3, DST, EPB41L4A and KIFIB in MYCN non-amplified pediatric neuroblastoma patients were determined by Kaplan-Meier survival.Results: Age and MYCN amplification were independent prognostic factors in pediatric neuroblastoma. MYCN non-amplified pediatric neuroblastoma comprised young and old two distinct sub-groups. Compared with MYCN non-amplified old neuroblastoma patients, MYCN non-amplified young neuroblastoma patients had better clinical outcomes. MYCN non-amplified pediatric neuroblastoma was divided into three sub-consensuses through NMF assay and each sub-consensus was with significantly different clinical outcomes. However, MYCN amplified pediatric neuroblastoma was relatively homogeneous, and could not divide into sub-groups with different clinical outcomes by age or by NMF assay. ALCAM, CACNA2D3, DST, EPB41L4A and KIFIB were highly expressed in MYCN non-amplified young neuroblastoma patients. Moreover, the high expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIFIB were associated with the favorable prognosis of MYCN non-amplified neuroblastoma patients. We also found that DST was an independent prognostic factor in MYCN non-amplified neuroblastoma patients and MYCN non-amplified neuroblastoma young patients with high DST expression levels had the best clinical overall survival.Conclusions: MYCN non-amplified neuroblastoma was a heterogeneous disease and could be divided into sub-groups based on age or the expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIFIB. MYCN non-amplified neuroblastoma young patients with high DST expression levels had the best clinical overall survival.

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Comprehensive Analysis of the Prognostic Significance of Hsa-miR-100-5p and Its Related Gene Signature in Stomach Adenocarcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.736274 ◽

2021 ◽

Vol 9 ◽

Author(s):

Gaoming Wang ◽

Ludi Yang ◽

Miao Hu ◽

Renhao Hu ◽

Yongkun Wang ◽

...

Keyword(s):

High Risk ◽

Cox Regression ◽

Prognostic Significance ◽

Tumor Development ◽

Risk Groups ◽

Gene Signature ◽

Risk Scores ◽

Prognostic Signature ◽

Cox Regression Analysis ◽

Stomach Adenocarcinoma

Stomach adenocarcinoma (STAD) is one of the most common cancers in the world. However, the prognosis of STAD remains poor, and the therapeutic effect of chemotherapy and immunotherapy varies from person to person. MicroRNAs (miRNAs) play vital roles in tumor development and metastasis and can be used for cancer diagnosis and prognosis. In this study, hsa-miR-100-5p was identified as the only dysregulated miRNA in STAD samples through an analysis of three miRNA expression matrices. A weighted gene co-expression network analysis (WGCNA) was performed to select hsa-miR-100-5p-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a miR-100-5p-related prognostic signature. Kaplan–Meier analyses, nomograms, and univariate and multivariate Cox regression analyses were used to evaluate the prognostic signature, which was subsequently identified as an independent risk factor for STAD patients. We investigated the tumor immune environment between low- and high-risk groups and found that, among component types, M2 macrophages contributed the most to the difference between these groups. A drug sensitivity analysis suggested that patients with high-risk scores may be more sensitive to docetaxel and cisplatin chemotherapy and that patients in the low-risk group may be more likely to benefit from immunotherapy. Finally, external cohorts were evaluated to validate the robustness of the prognostic signature. In summary, this study may provide new ideas for developing more individualized therapeutic strategies for STAD patients.

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Transcriptional expression of ZICs as an independent indicator of survival in gliomas

10.21203/rs.3.rs-28764/v1 ◽

2020 ◽

Author(s):

Zhao cheng Han ◽

Jingnan Jia ◽

Yangting Lv ◽

Rongyanqi Wang ◽

Kegang Cao

Keyword(s):

Immune Cell ◽

Cox Regression ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Prognostic Significance ◽

Gene Mutations ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Expression Levels ◽

Ppi Networks

Abstract Background: The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Methods: Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas(HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyses were performed with Metascape. PPI networks were constructed using STRING. Result: The expression levels of ZIC1/2/4 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/2/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined with high ZIC4 expression was related to favourable OS in glioblastoma multiforme (GBM). ZIC mutations were associated with poor prognosis in LGG patients and related to favourable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving arrhythmogenic right ventricular cardiomyopathy (ARVC) and tissue morphogenesis. The PPI network revealed that some coexpressed proteins of ZICs played a role in the pathogenesis of gliomas. Conclusions: Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.

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The prognostic significance of different proportion of signet-ring cells of colorectal carcinoma

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2021.5856 ◽

2021 ◽

Author(s):

Wei Chen ◽

Huajun Cai ◽

Kui Chen ◽

Xing Liu ◽

Weizhong Jiang ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Cox Regression ◽

Prognostic Significance ◽

Staging System ◽

Signet Ring Cell ◽

Significant Difference ◽

Signet Ring ◽

Ajcc Staging System ◽

Ajcc Staging

While the prognosis of patients with partial SRCC (PSRCC) has been rarely reported, colorectal signet-ring cell carcinoma (SRCC) has been associated with poor prognosis. The aim of this study was to analyze the prognosis of patients with different SRC composition and establish a prediction model. A total of 91 patients with SRC component were included in the study. These patients were divided into two groups: SRCC group (SRC composition > 50%; n=41) and partial SRCC (PSRCC) group (SRC composition ≤ 50%; n=50). COX regression model was used to identify independent prognostic factors for overall survival (OS). A predictive nomogram was established and compared with the 7th AJCC staging system. After a median follow-up of 16 months, no significant difference in OS was observed in either group. Preoperative carcinoembryonic antigen (CEA) level, pN stage, M stage, preoperative ileus, and adjuvant chemotherapy were independent prognostic risk factors for OS (p<0.05). A nomogram for predicting the overall survival of colorectal SRCC was established with a C-index of 0.800, and it showed better performance than that of the 7th AJCC staging system (p<0.001). In summary, the ratio of SRC component was not an independent prognostic factor of the OS. Those patients with less than 50% of SRC component should be given the same clinical attention. A predictive nomogram for survival based on five independent prognostic factors was developed and showed better performance than the 7th AJCC staging system. This resulted to be helpful for individualized prognosis prediction and risk assessment.

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Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

10.21203/rs.3.rs-23681/v2 ◽

2020 ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Transcription Factor ◽

Poor Prognosis ◽

Target Genes ◽

Cox Regression ◽

Expression Profiles ◽

Prognostic Significance ◽

Gene Set Enrichment Analysis ◽

Mycn Amplification ◽

Prognostic Relevance ◽

The Poor

Abstract Background: Neuroblastoma patients with MYCN amplification are associated with poor prognosis. However, the prognostic relevance of MYCN associated genes in neuroblastoma is unclear. Methods: The expression profiles of MYCN associated genes were identified from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. Enriched transcription factors and signaling pathways were determined using gene set enrichment analysis (GSEA). Kaplan-Meier plotter was used to identify the prognostic relevance of MYCN associated genes. Multivariate cox regression and Spearman’s correlation were used to determine the correlation coefficients of MYCN associated genes.Results: In TARGET and GSE85047 datasets, neuroblastoma patients with MYCN amplification were associated with worse prognosis. Transcription factor MYC was positively associated with MYCN amplification in GSEA assay. We identified 13 MYC target genes which were increased in neuroblastoma patients with MYCN amplification in TARGET, GSE19274 and GSE85047 datasets. Moreover, six out of the 13 MYC target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL and PRMT1 were associated with adverse prognosis in TARGET and GSE85047 datasets. Transcription factor E2F1 was up-regulated by MYCN amplification and associated with the poor prognosis of neuroblastoma. Furthermore, RPS19 in ribosome signaling pathway was also associated with MYCN amplification and correlated with the poor prognosis of neuroblastoma. At last, we showed that most of MYCN target genes were correlated with each other. However, EIF4G1 was an independent prognostic marker. And the prognostic effects of the combination of MYCN amplification and EIF4G1 expression were more significant than MYCN or EIF4G1 alone.Conclusions: MYCN target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL, PRMT1, E2F1 and RPS19 had significant prognostic effects in pediatric neuroblastoma. And neuroblastoma patients without MYCN amplification and low EIF4G1 expression had best prognosis.

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