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Background: Gastric cancer is one of the most prevalent gastrointestinal cancers. Mortality is high, and improved treatments are needed. A better understanding of the pathophysiology of the disease and discovery of biomarkers for targeted therapies are paramount for therapeutic progress. CDX2, a transcription factor of hindgut specification, is induced in several gastric cancers, especially with intestinal differentiation, and could be helpful for defining sub-types with particular characteristics. Methods: Gastric cancers with induced CDX2 mRNA expression were identified from the gastric cohort of The Cancer Genome Atlas (TCGA) and were compared with cancers that had no CDX2 mRNA induction. Induced CDX2 mRNA expression was defined as mRNA expression z-score relative to all samples above 0, and non-induced CDX2 mRNA expression was defined as mRNA expression z-score relative to all samples below −1. Results: Patients with gastric cancers with CDX2 mRNA induction were older, had less frequently diffuse histology, and more often had mutations in TP53 and KMT2B and amplifications in MYC. CDX2 induction was correlated with HNF4α induction and was reversely correlated with SOX2. Gastric cancers with CDX2 mRNA induction showed lower PD-L1 expression than cancers with lower CDX2 expression but did not differ in CLDN18 mRNA expression. Progression-free and overall survival of the two groups was also not significantly different. Conclusion: Gastric cancers with CDX2 mRNA induction displayed specific characteristics that differentiate them from cancers with no CDX2 induction and could be of interest for optimizing current and future therapies. [ABSTRACT FROM AUTHOR]

Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma (GBM), which is the most malignant form of glioma. The implications and underlying mechanisms of protein glycosylation in GSC phenotypes and GBM malignancy are not fully understood. The implication of protein glycosylation and the corresponding candidate genes on the stem cell properties of GSCs and poor clinical outcomes in GBM were investigated, using datasets from the Gene Expression Omnibus, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas, accompanied by biological validation in vitro. N-linked glycosylation was significantly associated with GSC properties and the prognosis of GBM in the integrated bioinformatics analyses of clinical specimens. N-linked glycosylation was associated with the glioma grade, molecular biomarkers, and molecular subtypes. The expression levels of the asparagine-linked glycosylation (ALG) enzyme family, which is essential for the early steps in the biosynthesis of N-glycans, were prominently associated with GSC properties and poor survival in patients with GBM with high stem-cell properties. Finally, the oxidative phosphorylation pathway was primarily enriched in GSCs with a high expression of the ALG enzyme family. These findings suggest the role of N-linked glycosylation in the regulation of GSC phenotypes and GBM malignancy. [ABSTRACT FROM AUTHOR]

Background: The aberrant expression of serpin family E member 1 (SERPINE1) is associated with carcinogenesis. This study assessed the alteration of SERPINE1 expression for an association with gastric adenocarcinoma prognosis. Methods: The Cancer Genome Atlas (TCGA) dataset was applied to investigate the impact of SERPINE1 expression on the survival of patients afflicted with gastric cancer. Subsequently, 136 samples from the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University were subjected to qRT-PCR and Western blot to validate the expression level of SERPINE1 between tumor and adjacent normal tissues. The correlation between the expression of SERPINE1 with the clinicopathological features in TCGA patients was analyzed using Wilcoxon signed-rank and logistic regression tests. The potential molecular mechanism associated with SERPINE1 expression in gastric cancer were confirmed using gene set enrichment analysis (GSEA). Results: The TCGA data showed that SERPINE1 was overexpressed in tumor tissues compared to normal mucosae and associated with the tumor T stage and pathological grade. SERPINE1 overexpression was associated with the poor overall survival (OS) of patients. The findings were confirmed with 136 patients, that is, SERPINE1 expression was associated with poor OS (hazard ratio (HR): 1.82; 95% confidence interval (CI): 0.84–1.83; p = 0.012)) as an independent predictor (HR: 2.11, 95% CI: 0.81–2.34; p = 0.009). The resulting data were further processed by GSEA showed that SERPINE1 overexpression was associated with the activation of EPITHELIAL_MESENCHYMAL_TRANSITION, TNFA_SIGNALING_VIA_NFKB, INFLAMMATORY_RESPONSE, ANGIOGENESIS, and HYPOXIA. Conclusions: SERPINE1 overexpression is associated with a poor gastric cancer prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The discovery of prognostic biomarkers constitutes an important issue because it allows the tailoring of therapeutic treatments, thus avoiding over-treatment and side effects. In this context, reliable prognostic biomarkers advance the field of precision oncology. Such biomarkers are usually discovered in the tumor tissue, which is not an easy task given the inaccessibility of malignant tissue in many types of cancer. In this work, we could identify a prognostic signature consisting of eight genes for prostate cancer patients. This biosignature was identified in peripheral blood samples, which are easy to access and, importantly, have a significant prognostic value for various types of cancer. Prostate cancer (PCa) is one of the most common male cancers worldwide and one of the deadliest if unsuccessfully treated. Τhe need for reliable, easily accessible immune-related molecular biomarkers that could be combined with clinically defined criteria, including PSA and Gleason score, to accurately predict PCa patients' clinical outcomes is emerging. Herein, we describe for the first time a blood-identified immune-related gene signature comprising eight upregulated multi-functional genes associated with poor prognosis. Next-generation sequencing (NGS) analysis of PCa patients' peripheral blood samples revealed a more than three-fold upregulation of each of the eight genes as compared to samples originating from healthy donors. The construction of gene and protein interaction networks revealed different extents of the functional implications of these genes in the regulation of cell proliferation and immune responses. Analysis of the available data from The Cancer Genome Atlas (TCGA) regarding gene expression and survival of prostate adenocarcinoma (PRAD) and pan-cancer (PANCAN) patients revealed that intra-tumoral upregulation of this eight-gene signature (8-GS) was associated with poor 5-year progression-free intervals in PCa patients, even in those with high Gleason scores, and also with an unfavorable prognosis for cancer patients irrespective of the cancer type and even in the early stages. These observations suggest that further investigation of the 8-GS prospectively in randomized clinical trials, in which clinical benefit in terms of evaluating time to disease progression can be assessed, is warranted. [ABSTRACT FROM AUTHOR]

(1) Background: Oxidative stress is crucial in carcinogenesis and the response of tumors to treatment. Antioxidant genes are important determinants of resistance to chemotherapy and radiotherapy. We hypothesized that genes involved in the oxidative stress response may be valuable as prognostic biomarkers for the survival of cancer patients and as druggable targets. (2) Methods: We mined the KM Plotter and TCGA Timer2.0 Cistrome databases and investigated 205 antioxidant genes in 21 different tumor types within the context of this investigation. (3) Results: Of 4347 calculations with Kaplan–Meier statistics, 84 revealed statistically significant correlations between high gene expression and worse overall survival (p < 0.05; false discovery rate ≤ 5%). The tumor types for which antioxidant gene expression was most frequently correlated with worse overall survival were renal clear cell carcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma. Seventeen genes were clearly overexpressed in tumors compared to their corresponding normal tissues (p < 0.001), possibly qualifying them as druggable targets (i.e., ALOX5, ALOX5AP, EPHX4, G6PD, GLRX3, GSS, PDIA4, PDIA6, PRDX1, SELENOH, SELENON, STIP1, TXNDC9, TXNDC12, TXNL1, TXNL4A, and TXNRD1). (4) Conclusions: We concluded that a sub-set of antioxidant genes might serve as prognostic biomarkers for overall survival and as druggable targets. Renal and liver tumors may be the most suitable entities for this approach. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson's correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely CCNB1, CCNB2, CDK2, CDK4, CHECK1, E2F1, FANCD2, and PRKDC) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Basal cell carcinoma is the most common human cancer. Most BCCs are low-risk and are easily treated; however, 1–2% are aggressive and highly destructive to the surrounding skin, called advanced BCC. It was discovered that this subtype has a different immune profile than routine BCC, and they contain a special type of stem cell population that helps them grow and spread. There is currently no reliable laboratory model for advanced BCC, making it hard to further study it and find new treatments. For these reasons, this project was conducted using genomic data from 11,000 tumours coming from 33 non-BCC cancer types. Using computational biology, we have compared the immune cell makeup of the tumour microenvironments to determine the top three most similar cancers, which we will call BCC "relatives". We will examine how these "relatives" develop and grow, as well as current existing treatments and their response to such treatments. Basal cell carcinoma (BCC) is the most common form of skin cancer, contributing to nearly a third of new cancer cases in Western countries. Most BCCs are considered low risk "routine" lesions that can either be excised through surgery or treated with chemotherapeutic agents. However, around 1–2% of BCC cases are locally aggressive, present a high risk of metastasis, and often develop chemoresistance, termed advanced BCC. There currently exists no animal model or cell line that can recapitulate advanced BCC, let alone intermediate-risk and high-risk early BCC. We previously found that aggressive BCC tumours presented a Th2 cytokine inflammation profile, mesenchymal stem cell properties, and macrophage-induced tumoral inflammation. In this study, we aimed to identify potential BCC "relatives" among solid-organ malignancies who present similar immune cell proportions in their microenvironment compositions. Using immune cell type deconvolution by CIBERSORTx, and cell type enrichment by xCell, we determined three cancers with the most similar tumour microenvironments as compared to BCC. Specifically, chromophobe renal cell carcinoma, sarcoma, and skin cutaneous melanoma presented significance in multiple cell types, namely in CD4+ T lymphocytes, gammadelta T lymphocytes, and NK cell populations. Consequently, further literature analysis was conducted to understand similarities between BCC and its "relatives", as well as investigating novel treatment targets. By identifying cancers most like BCC, we hope to propose prospective druggable pathways, as well as to gain insight on developing a reliable animal or cell line model to represent advanced BCC. [ABSTRACT FROM AUTHOR]

In 2021, the fifth edition of the WHO classification of tumors of the central nervous system (WHO CNS5) was published. Molecular features of tumors were directly incorporated into the diagnostic decision tree, thus affecting both the typing and staging of the tumor. It has changed the traditional approach, based solely on histopathological classification. The Cancer Genome Atlas project (TCGA) is one of the main sources of molecular information about gliomas, including clinically annotated transcriptomic and genomic profiles. Although TCGA itself has played a pivotal role in developing the WHO CNS5 classification, its proprietary databases still retain outdated diagnoses which frequently appear incorrect and misleading according to the WHO CNS5 standards. We aimed to define the up-to-date annotations for gliomas from TCGA's database that other scientists can use in their research. Based on WHO CNS5 guidelines, we developed an algorithm for the reclassification of TCGA glioma samples by molecular features. We updated tumor type and diagnosis for 828 out of a total of 1122 TCGA glioma cases, after which available transcriptomic and methylation data showed clustering features more consistent with the updated grouping. We also observed better stratification by overall survival for the updated diagnoses, yet WHO grade 3 IDH-mutant oligodendrogliomas and astrocytomas are still indistinguishable. We also detected altered performance in the previous diagnostic transcriptomic molecular biomarkers (expression of SPRY1, CRNDE and FREM2 genes and FREM2 molecular pathway) and prognostic gene signature (FN1, ITGA5, OSMR, and NGFR) after reclassification. Thus, we conclude that further efforts are needed to reconsider glioma molecular biomarkers. [ABSTRACT FROM AUTHOR]

Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78], of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package "tmesig" was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the "stats" package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted. [ABSTRACT FROM AUTHOR]

In the last years, the TCGA-based molecular classifier have been progressively integrated in the management of endometrial carcinoma. While molecular assays are increasingly available across pathology laboratories, the additional costs will expectedly be compensated by a reduction in overtreatments and a prevention of recurrences. The additional time might be shortened by assessing molecular markers on biopsy specimens. Retrospective data suggest that the molecular classifier will have a major impact of on the risk stratification, with many patients having their risk class down- or upstaged based on POLE mutations or p53 abnormalities, respectively. However, there are still several issues to be resolved, such as the prognostic value of the TCGA classifier in each FIGO stage, or the type of adjuvant treatment most suitable for each molecular group. Other issues regard the prognostic stratification of the mismatch repair-deficient and "no specific molecular profile" groups, which currently follows the same criteria; however, the former seems to be prognostically consistent regardless of FIGO grade and histotype, whereas the latter appears highly heterogeneous. Numerous clinical, histological, immunohistochemical and molecular markers have been proposed to refine the TCGA classification, but their prognostic value is still undefined. Hopefully, prospective data collected in the next years will help resolving these issues. [ABSTRACT FROM AUTHOR]

Simple Summary: Kidney cancer diagnoses make up over 2% of newly identified cancers each year. SoLute Carrier 22 (SLC22) genes are expressed in normal functioning kidneys and are responsible for transport of myriad metabolites, xenobiotics, antioxidants and other small molecules, but their role in kidney cancer is not well understood. We assessed the relationship between the expression of SLC22 genes and survival in patients with kidney cancer and found expression patterns of multiple SLC22 genes to be associated with overall survival as well as with disease progression. We sought to interpret this data in the context of physiological information from previous studies by us and others. Furthermore, network analysis indicated the importance of SLC22 genes and identified additional genes that might be therapeutic targets. (1) Background: Many transporters of the SLC22 family (e.g., OAT1, OAT3, OCT2, URAT1, and OCTN2) are highly expressed in the kidney. They transport drugs, metabolites, signaling molecules, antioxidants, nutrients, and gut microbiome products. According to the Remote Sensing and Signaling Theory, SLC22 transporters play a critical role in small molecule communication between organelles, cells and organs as well as between the body and the gut microbiome. This raises the question about the potential role of SLC22 transporters in cancer biology and treatment. (2) Results: In two renal cell carcinoma RNA-seq datasets found in TCGA, KIRC and KIRP, there were multiple differentially expressed (DE) SLC22 transporter genes compared to normal kidney. These included SLC22A6, SLC22A7, SLC22A8, SLC22A12, and SLC22A13. The patients with disease had an association between overall survival and expression for most of these DE genes. In KIRC, the stratification of patient data by pathological tumor characteristics revealed the importance of SLC22A2, SLC22A6, and SLC22A12 in disease progression. Interaction networks combining the SLC22 with ADME genes supported the centrality of SLC22 transporters and other transporters (ABCG2, SLC47A1) in disease progression. (3) Implications: The fact that many of these genes are uric acid transporters is interesting because altered uric acid levels have been associated with kidney cancer. Moreover, these genes play key roles in processing metabolites and chemotherapeutic compounds, thus making them potential therapeutic targets. Finally, our analyses raise the possibility that current approaches may undertreat certain kidney cancer patients with low SLC22 expression and only localized disease while possibly overtreating more advanced disease in patients with higher SLC22 expression. Clinical studies are needed to investigate these possibilities. [ABSTRACT FROM AUTHOR]

Background: Research on the discovery of tumor biomarkers based on big data analysis is actively being conducted. This study aimed to secure foundational data for identifying new biomarkers of breast cancer via breast cancer datasets in The Cancer Genome Atlas (TCGA). Methods: The mRNA profiles of 526 breast cancer and 60 adjacent non-cancerous breast tissues collected from TCGA datasets were analyzed via MultiExperiment Viewer and GraphPad Prism. Diagnostic performance was analyzed by identifying the pathological grades of the selected differentially expressed (DE) mRNAs and the expression patterns of molecular subtypes. Results: Via DE mRNA profile analysis, we selected 14 mRNAs with downregulated expression (HADH, CPN2, ADAM33, TDRD10, SNF1LK2, HBA2, KCNIP2, EPB42, PYGM, CEP68, ING3, EMCN, SYF2, and DTWD1) and six mRNAs with upregulated expression (ZNF8, TOMM40, EVPL, EPN3, AP1M2, and SPINT2) in breast cancer tissues compared to that in non-cancerous tissues (p < 0.001). Conclusions: In total, 20 DE mRNAs had an area under cover of 0.9 or higher, demonstrating excellent diagnostic performance in breast cancer. Therefore, the results of this study will provide foundational data for planning preliminary studies to identify new tumor biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinical and molecular advances have improved knowledge and treatment prospects for cancer, yet hepatocellular carcinoma (HCC), the most common form of liver cancer, still ranks significantly higher in terms of the global cancer burden. Herein, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancers with a particular focus on HCC. Hepatocellular carcinoma (HCC) is at the forefront of the global cancer burden, and biomarkers for HCC are constantly being sought. Interestingly, RGS (Regulators of G protein signaling) proteins, which negatively regulate GPCR signaling, have been associated with various cancers, with some members of the RGS family being associated with liver cancer as well. Considering this, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancer types with special emphasis on HCC. By using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, our analysis revealed that (a) RGS20 was strongly upregulated in tumor tissue compared with adjacent normal tissue of HCC patients; (b) RGS20 was strongly associated with some important clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p < 0.001), RGS20 was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p < 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways and long intergenic non-coding RNAs (lincRNAs: LINC00511, PVT1, MIR4435-2HG, BCYRN1, and MAPKAPK5-AS1) that exhibit oncogenic potential. Taken together, we showed that RGS20 correlates with a few HCC-associated lincRNAs harboring oncogenic potential and is markedly upregulated in HCC patients. Our analysis further supports the putative function of RGS proteins, particularly RGS20, in cancer. [ABSTRACT FROM AUTHOR]

Tumor mutation burdens (TMBs) act as an indicator of immunotherapeutic responsiveness in various tumors. However, the relationship between TMBs and immune cell infiltrates in hepatocellular carcinoma (HCC) is still obscure. The present study aimed to explore the potential diagnostic markers of TMBs for HCC and analyze the role of immune cell infiltration in this pathology. We used OA datasets from The Cancer Genome Atlas database. First, the "maftools" package was used to screen the highest mutation frequency in all samples. R software was used to identify differentially expressed genes (DEGs) according to mutation frequency and perform functional correlation analysis. Then, the gene ontology (GO) enrichment analysis was performed with "clusterProfiler", "enrichplot", and "ggplot2" packages. Finally, the correlations between diagnostic markers and infiltrating immune cells were analyzed, and CIBERSORT was used to evaluate the infiltration of immune cells in HCC tissues. As a result, we identified a total of 359 DEGs in this study. These DEGs may affect HCC prognosis by regulating fatty acid metabolism, hypoxia, and the P53 pathway. The top 15 genes were selected as the hub genes through PPI network analysis. SRSF1, SNRPA1, and SRSF3 showed strong similarities in biological effects, NCBP2 was demonstrated as a diagnostic marker of HCC, and high NCBP2 expression was significantly correlated with poor over survival (OS) in HCC. In addition, NCBP2 expression was correlated with the infiltration of B cells (r = 0.364, p = 3.30 × 10−12), CD8+ T cells (r = 0.295, p = 2.71 × 10−8), CD4+ T cells, (r = 0.484, p = 1.37 × 10−21), macrophages (r = 0.551, p = 1.97 × 10−28), neutrophils (r = 0.457, p = 3.26 × 10−19), and dendritic cells (r = 0.453, p = 1.97 × 10−18). Immune cell infiltration analysis revealed that the degree of central memory T-cell (Tcm) infiltration may be correlated with the HCC process. In conclusion, NCBP2 can be used as diagnostic markers of HCC, and immune cell infiltration plays an important role in the occurrence and progression of HCC. [ABSTRACT FROM AUTHOR]

Since the current melanoma clinicopathological staging system remains restricted to predicting survival outcomes, establishing precise prognostic targets is needed. Here, we used gene expression signature (GES) classification and Cox regression analyses to biologically characterize melanoma cells at the single-cell level and construct a prognosis-related gene signature for melanoma. By analyzing publicly available scRNA-seq data, we identified six distinct GESs (named: "Anti-apoptosis", "Immune cell interactions", "Melanogenesis", "Ribosomal biogenesis", "Extracellular structure organization", and "Epithelial-Mesenchymal Transition (EMT)"). We verified these GESs in the bulk RNA-seq data of patients with skin cutaneous melanoma (SKCM) from The Cancer Genome Atlas (TCGA). Four GESs ("Immune cell interactions", "Melanogenesis", "Ribosomal biogenesis", and "Extracellular structure organization") were significantly correlated with prognosis (p = 1.08 × 10−5, p = 0.042, p = 0.001, and p = 0.031, respectively). We identified a prognostic signature of melanoma composed of 45 genes (MPS_45). MPS_45 was validated in TCGA-SKCM (HR = 1.82, p = 9.08 × 10−6) and three other melanoma datasets (GSE65904: HR = 1.73, p = 0.006; GSE19234: HR = 3.83, p = 0.002; and GSE53118: HR = 1.85, p = 0.037). MPS_45 was independently associated with survival (p = 0.002) and was proved to have a high potential for predicting prognosis in melanoma patients. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) represents the most malignant glioma among astrocytomas and is a lethal form of brain cancer. Many RAB genes are involved in different cancers but RAB42 (Ras-associated binding 42) is seldom studied in GBM. Our study aimed to explore the role of RAB42 expression in the development and prognosis of GBM. Methods: All GBM patient data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The relevance of RAB42 expression to the clinicopathologic characteristics of GBM patients was analyzed. The overall survival (OS) significance was determined using log-rank. Significantly enriched KEGG pathways were screened using gene set enrichment analysis (GSEA). Results: High expression of RAB42 was observed in GBM specimens compared with normal samples, which was also verified in cell lines and tissue samples. Elevated RAB42 expression was correlated with higher GBM histological grade. The prognosis of GBM patients with high RAB42 expression was worse than those with lower RAB42. A total of 35 pathways, such as the P53 pathway, were significantly activated in highly RAB42-expressed GBM samples. Conclusions: High RAB42 expression is related to the development of GBM, and RAB42 is a probable prognostic marker for GBM. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic cancer, in part due to resistance to platinum-based chemotherapy reported among 20% of patients. This study aims to generate novel hypotheses of the biological mechanisms underlying chemotherapy resistance, which remain poorly understood. Differential expression analyses of mRNA- and microRNA-sequencing data from HGSOC patients of The Cancer Genome Atlas identified 21 microRNAs associated with angiogenesis and 196 mRNAs enriched for adaptive immunity and translation. Coexpression network analysis identified three microRNA networks associated with chemotherapy response enriched for lipoprotein transport and oncogenic pathways, as well as two mRNA networks enriched for ubiquitination and lipid metabolism. These network modules were replicated in two independent ovarian cancer cohorts. Moreover, integrative analyses of the mRNA/microRNA sequencing and single-nucleotide polymorphisms (SNPs) revealed potential regulation of significant mRNA transcripts by microRNAs and SNPs (expression quantitative trait loci). Thus, we report novel transcriptional networks and biological pathways associated with resistance to platinum-based chemotherapy in HGSOC patients. These results expand our understanding of the effector networks and regulators of chemotherapy response, which will help to improve the management of ovarian cancer. [ABSTRACT FROM AUTHOR]

Introduction: PTEN gene mutations are frequently found in the genetic landscape of high-grade gliomas since they influence cell proliferation, proangiogenetic pathways, and antitumoral immune response. The present bioinformatics analysis explores the PTEN gene expression profile in HGGs as a prognostic factor for survival, especially focusing on the related immune microenvironment. The effects of PTEN mutation on the susceptibility to conventional chemotherapy were also investigated. Methods: Clinical and genetic data of GBMs and normal tissue samples were acquired from The Cancer Genome Atlas (TCGA)-GBM and Genotype-Tissue Expression (GTEx) online databases, respectively. The genetic differential expressions were analyzed in both groups via the one-way ANOVA test. Kaplan–Meier survival curves were applied to estimate the overall survival (OS) and disease-free survival (DFS). The Genomics of Drug Sensitivity in Cancer platform was chosen to assess the response of PTEN-mutated GBMs to temozolomide (TMZ). p < 0.05 was fixed as statistically significant. On Tumor Immune Estimation Resource and Gene Expression Profiling Interactive Analysis databases, the linkage between immune cell recruitment and PTEN status was assessed through Spearman's correlation analysis. Results: PTEN was found mutated in 22.2% of the 617 TCGA-GBMs patients, with a higher log2-transcriptome per million reads compared to the GTEx group (255 samples). Survival curves revealed a worse OS and DFS, albeit not significant, for the high-PTEN profile GBMs. Spearman's analysis of immune cells demonstrated a strong positive correlation between the PTEN status and infiltration of Treg (ρ = 0.179) and M2 macrophages (ρ = 0.303). The half-maximal inhibitor concentration of TMZ was proven to be lower for PTEN-mutated GBMs compared with PTEN wild-types. Conclusions: PTEN gene mutations prevail in GBMs and are strongly related to poor prognosis and least survival. The infiltrating immune lymphocytes Treg and M2 macrophages populate the glioma microenvironment and control the mechanisms of tumor progression, immune escape, and sensitivity to standard chemotherapy. Broader studies are required to confirm these findings and turn them into new therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPV) are detected in 70-80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where the viral genome remains episomal, one where the viral genome integrates into the host genome and a third where there is a mixture of both integrated and episomal HPV genomes. Our recent work suggests that this third category has been mischaracterized as having integrated HPV genomes; evidence indicates that this category consists of virus-human hybrid episomes. Most of these hybrid episomes are consistent with being maintained by replication from HPV origin. We discuss our evidence to support this new paradigm, how such genomes can arise, and more importantly the implications for the clinical management of HPV positive head and neck cancers following accurate determination of the viral genome status. [ABSTRACT FROM AUTHOR]

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues. [ABSTRACT FROM AUTHOR]

This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses ( p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0-41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2-10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively ( p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma.

Simple Summary: We studied mismatch repair (MMR) deficiency as a predictive and prognostic biomarker in endometrial carcinoma. MMR deficiency was associated with poor outcome only when p53 aberrant and polymerase-ϵ mutant tumors were excluded from the MMR proficient subgroup, in accordance with molecular classification based on The Cancer Genome Atlas. MMR deficiency was associated with an increased risk of death in the absence of various clinicopathologic risk factors, but the outcome was not worsened when such risk factors were present. The proportion of pelvic relapses and lymphatic dissemination, defined as primary lymph node involvement or relapses in regional lymph nodes, were higher in the MMR deficient subgroup. In conclusion, the effect of MMR deficiency on the outcome of endometrial carcinoma depends on how MMR proficiency is defined. MMR deficiency is associated with an increased risk of death in the absence of established risk factors and a unique pattern of disease spread. The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as "no specific molecular profile" (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas. [ABSTRACT FROM AUTHOR]

Accurate nuclear segmentation in histopathology images plays a key role in digital pathology. It is considered a prerequisite for the determination of cell phenotype, nuclear morphometrics, cell classification, and the grading and prognosis of cancer. However, it is a very challenging task because of the different types of nuclei, large intraclass variations, and diverse cell morphologies. Consequently, the manual inspection of such images under high-resolution microscopes is tedious and time-consuming. Alternatively, artificial intelligence (AI)-based automated techniques, which are fast and robust, and require less human effort, can be used. Recently, several AI-based nuclear segmentation techniques have been proposed. They have shown a significant performance improvement for this task, but there is room for further improvement. Thus, we propose an AI-based nuclear segmentation technique in which we adopt a new nuclear segmentation network empowered by residual skip connections to address this issue. Experiments were performed on two publicly available datasets: (1) The Cancer Genome Atlas (TCGA), and (2) Triple-Negative Breast Cancer (TNBC). The results show that our proposed technique achieves an aggregated Jaccard index (AJI) of 0.6794, Dice coefficient of 0.8084, and F1-measure of 0.8547 on TCGA dataset, and an AJI of 0.7332, Dice coefficient of 0.8441, precision of 0.8352, recall of 0.8306, and F1-measure of 0.8329 on the TNBC dataset. These values are higher than those of the state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Simple Summary: Prognostic markers are used to predict the aggressiveness of a cancer and to help decide the best treatment for individual patients. Despite intense research, reliable prognostic markers for oral cancer are still few. The aim of the present study was to validate selected prognostic markers for head and neck cancer identified by unbiased approaches in oral tongue cancer, a specific subsite of head and neck cancer. From a list of 790 markers, we selected three based on reported prognostic value as well as expression pattern and availability of validated antibodies. These were analyzed on transcriptional and protein level in a cohort of 121 oral tongue cancers. Only one of the markers showed significant prognostic value when controlling for established prognostic parameters. Our study highlights the need to evaluate prognostic markers in homogeneous groups of cancers and to control for established prognostic parameters. The Pathology Atlas is an open-access database that reports the prognostic value of protein-coding transcripts in 17 cancers, including head and neck cancer. However, cancers of the various head and neck anatomical sites are specific biological entities. Thus, the aim of the present study was to validate promising prognostic markers for head and neck cancer reported in the Pathology Atlas in oral tongue squamous cell carcinoma (OTSCC). We selected three promising markers from the Pathology Atlas (CALML5, CD59, LIMA1), and analyzed their prognostic value in a Norwegian OTSCC cohort comprising 121 patients. We correlated target protein and mRNA expression in formalin-fixed, paraffin-embedded cancer tissue to five-year disease-specific survival (DSS) in univariate and multivariate analyses. Protein expression of CALML5 and LIMA1 were significantly associated with five-year DSS in the OTSCC cohort in univariate analyses (p = 0.016 and p = 0.043, respectively). In multivariate analyses, lymph node metastases, tumor differentiation, and CALML5 were independent prognosticators. The prognostic role of the other selected markers for head and neck cancer patients identified through unbiased approaches could not be validated in our OTSCC cohort. This underlines the need for subsite-specific analyses for head and neck cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapies have shown great promise in cancer treatment. However, the intra-heterogeneity is a major barrier to reasonably classifying the potential benefited patients. Comprehensive heterogeneity analysis is needed to solve these clinical issues. In this study, the samples from pan-cancer and independent breast cancer datasets were divided into four tumor immune microenvironment (TIME) subtypes based on tumor programmed death ligand 1 (PD-L1) expression level and tumor-infiltrating lymphocyte (TIL) state. As the combination of the TIL Z score and PD-L1 expression showed superior prediction of response to ICI in multiple data sets compared to other methods, we used the TIL Z score and PD-L1 to classify samples. Therefore, samples were divided by combined TIL Z score and PD-L1 to identify four TIME subtypes, including type I (3.24%), type II (43.24%), type III (6.76%), and type IV (46.76%). Type I was associated with favorable prognosis with more T and DC cells, while type III had the poorest condition and composed a higher level of activated mast cells. Furthermore, TIME subtypes exhibited a distinct genetic and transcriptional feature: type III was observed to have the highest mutation rate (77.92%), while co-mutations patterns were characteristic in type I, and the PD-L1 positive subgroup showed higher carbohydrates, lipids, and xenobiotics metabolism compared to others. Overall, we developed a robust method to classify TIME and analyze the divergence of prognosis, immune cell composition, genomics, and transcriptomics patterns among TIME subtypes, which potentially provides insight for classification of TIME and a referrable theoretical basis for the screening benefited groups in the ICI immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Human bladder cancer, one of the most common cancers worldwide, is a molecularly heterogenous and complex disease. Identifying novel prognostic biomarkers and establishing new predictive signatures are important for personalized medicine and effective treatment of bladder cancer patients. Autophagy, a cell self-maintenance process that removes damaged organelles and misfolded proteins, displays both tumor promotion and suppression activities. The aim of our study is to investigate the function of autophagy-related genes in bladder cancer with the main focus on their contribution to prognostic outcome. By analyzing data obtained from The Cancer Genome Atlas (TCGA), we identified 32 autophagy-related genes that were highly associated with overall survival of bladder cancer patients. Further statistical assessment established an 11-autophagy-related-gene signature as an effective prognostic biomarker to predict the survival outcomes of bladder cancer patients. Background: Survival rates for highly invasive bladder cancer (BC) patients have been very low, with a 5-year survival rate of 6%. Accurate prediction of tumor progression and survival is important for diagnosis and therapeutic decisions for BC patients. Our study aims to develop an autophagy-related-gene (ARG) signature that helps to predict the survival of BC patients. Methods: RNA-seq data of 403 BC patients were retrieved from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) database. Univariate Cox regression analysis was performed to identify overall survival (OS)-related ARGs. The Lasso Cox regression model was applied to establish an ARG signature in the TCGA training cohort (N = 203). The performance of the 11-gene ARG signature was further evaluated in a training cohort and an independent validation cohort (N = 200) using Kaplan-Meier OS curve analysis, receiver operating characteristic (ROC) analysis, as well as univariate and multivariate Cox regression analysis. Results: Our study identified an 11-gene ARG signature that is significantly associated with OS, including APOL1, ATG4B, BAG1, CASP3, DRAM1, ITGA3, KLHL24, P4HB, PRKCD, ULK2, and WDR45. The ARGs-derived high-risk bladder cancer patients exhibited significantly poor OS in both training and validation cohorts. The prognostic model showed good predictive efficacy, with the area under the ROC curve (AUCs) for 1-year, 3-year, and 5-year overall survival of 0.702 (0.695), 0.744 (0.640), and 0.794 (0.658) in the training and validation cohorts, respectively. A prognostic nomogram, which included the ARGs-derived risk factor, age and stage for eventual clinical translation, was established. Conclusion: We identified a novel ARG signature for risk-stratification and robust prediction of overall survival for BC patients. [ABSTRACT FROM AUTHOR]

The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention. [ABSTRACT FROM AUTHOR]

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC. [ABSTRACT FROM AUTHOR]

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-β pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine. [ABSTRACT FROM AUTHOR]

Existing methods often fail to recognize the conversions for the biological roles of the pairs of genes and microRNAs (miRNAs) between the tumor and normal samples. We have developed a novel cluster scoring method to identify messenger RNA (mRNA) and miRNA interaction pairs and clusters while considering tumor and normal samples jointly. Our method has identified 54 significant clusters for 15 cancer types selected from The Cancer Genome Atlas project. We also determined the shared clusters across tumor types and/or subtypes. In addition, we compared gene and miRNA overlap between lists identified in our liver hepatocellular carcinoma (LIHC) study and regulatory relationships reported from human and rat nonalcoholic fatty liver disease studies (NAFLD). Finally, we analyzed biological functions for the single significant cluster in LIHC and uncovered a significantly enriched pathway (phospholipase D signaling pathway) with six genes represented in the cluster, symbols: DGKQ, LPAR2, PDGFRB, PIK3R3, PTGFR and RAPGEF3. [ABSTRACT FROM AUTHOR]

NGFI-A binding protein 2 (NAB2) represses the transcriptional activation of early growth response protein-1 (EGR1), a tumor-suppressor. However, Epidermal Growth Factor (EGF) promotes tumor progression even with significant EGR1 upregulation. The molecular mechanism through which NAB2 is involved in cancer is largely unknown. Therefore, we evaluated how the NAB2-mediated suppression of EGR1 facilitates head and neck squamous cell carcinoma (HNSCC) cancer progression, in association with Sp1, which competes with EGR1 as a transcriptional regulator. The effect of NAB2 on EGR1/SP1 binding to the consensus promoter sequences of MMP2 and MMP9 was evaluated by chromatin immunoprecipitation (ChIP) and promoter luciferase assay. The correlation between EGR1-NAB2 expression and metastatic status was investigated using The Cancer Genome Atlas (TCGA) for HNSCC patients. Our data showed that NAB2 knockdown in FaDu and YD-10B HNSCC cells alleviated EGF-dependent increase of Matrigel invasion. In addition, NAB2 upregulation in EGF-treated FaDu cell diminishes EGR1 transcriptional activity, resulting in the upregulation of Sp1-dependent tumor-promoting genes. TCGA data analysis of 483 HNSCC tumors showed that higher levels of both EGR1 and NAB2 mRNA were significantly associated with metastasis, corresponding to in vitro results. Our data suggest that NAB2 upregulation facilitates EGF-mediated cancer cell invasion through the transactivation of Sp1-dependent tumor-promoting genes. These results provide insight into the paradoxical roles of EGF-EGR1 in cancer progression. [ABSTRACT FROM AUTHOR]

To drive high-quality omics translational research using The Cancer Genome Atlas (TCGA) data, a TCGA Pan-Cancer Clinical Data Resource was proposed. However, there is an out-of-step issue between clinical outcomes and the omics data of TCGA for skin cutaneous melanoma (SKCM), due to the majority of metastatic samples. In clinical cases, the survival time started from the initial SKCM diagnosis, while the omics data were characterized at TCGA sampling. This study aimed to address this issue by proposing an observed survival interval (OBS), which was defined as the time interval from TCGA sampling to patient death or last follow-up. We compared the OBS with the usual recommended overall survival (OS) by associating them with both clinical data and microRNA sequencing data of TCGA-SKCM. We found that the OS of primary SKCM was significantly shorter than that of metastatic SKCM, while the opposite happened if OBS was compared. OS was associated with the pathological stage of both primary and metastatic SKCM, while OBS was associated with the pathological stage of primary SKCM but not that of metastatic SKCM. Five previously cross-validated survival-associated microRNAs were found to be associated with the OBS rather than OS in metastatic SKCM. Thus, the OBS was more appropriate for associating microRNA-omics data of TCGA-SKCM than OS, and it is a timely supplement to TCGA Pan-Cancer Clinical Data Resource. [ABSTRACT FROM AUTHOR]

In the era of large genetic and genomic datasets, it has become crucially important to validate results of individual studies using data from publicly available sources, such as The Cancer Genome Atlas (TCGA). However, how generalizable are results from either an independent or a large public dataset to the remainder of the population? The study presented here aims to answer that question. Utilizing next generation sequencing data from endometrial and ovarian cancer patients from both the University of Iowa and TCGA, genomic admixture of each population was analyzed using STRUCTURE and ADMIXTURE software. In our independent data set, one subpopulation was identified, whereas in TCGA 4–6 subpopulations were identified. Data presented here demonstrate how different the genetic substructures of the TCGA and University of Iowa populations are. Validation of genomic studies between two different population samples must be aware of, account for and be corrected for background genetic substructure. [ABSTRACT FROM AUTHOR]

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1wt than in IDH1mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1mut and IDH1wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders. [ABSTRACT FROM AUTHOR]