scholarly journals EPCO-06. MOLECULAR DETERMINANTS OF EVOLUTION AND PROGNOSIS AMONG DIFFUSE LOWER GRADE ASTROCYTOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii70-ii70
Author(s):  
Mehul Kumar ◽  
Gregory Cairncross ◽  
Michael Blough ◽  
Pinaki Bose
Keyword(s):  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
P53 Pathway ◽  
Idh Mutations ◽  
Molecular Determinants ◽  
Biological Insight ◽  
Pdgf Signaling ◽  
Cancer Genome Atlas ◽  
Genomic Reprogramming

Abstract Gliomas with wild type (WT) isocitrate dehydrogenase (IDH) are considerably more aggressive than those with mutant IDH. To identify putative drivers of the distinct progression trajectories of IDH WT and mutant disease, we analyzed transcriptomes of lower grade astrocytomas (LGAs; grade 2–3) with retention of 1p and 19q from The Cancer Genome Atlas (TCGA; n = 347). Compared to IDH mutant LGAs, we found that PDGF signaling was significantly enriched in IDH WT LGAs and that PDGFA was the top overexpressed gene in this pathway. We identified copy number gains of chromosome 7 in WT LGAs, and methylation of the PDGFA promoter in mutant LGAs, as candidate mechanisms for the differential expression of PDGFA. High PDGFA expression and low PDGFA promoter methylation were significantly associated with poor survival in all LGAs. We also found that PDGFA expression was positively associated with aneuploidy and extracellular matrix-related immunosuppressive features in WT LGAs, underscoring the role of PDGFA as a secreted mitogen. Finally, we show that the proportion of p53 pathway mutations increase significantly with grade in IDH WT gliomas. Taken together, our findings suggest that IDH WT LGAs evolve to higher grades, and ultimately to GBM, by progressive inactivation of the p53 pathway - functioning in concert with a background of increased PDGFA expression. These data emphasize the scope of genomic reprogramming that occurs in gliomas in relation to IDH mutations and further highlight the role of PDGFA in glioma formation, progression, and prognosis. Going forward, this work provides critical biological insight that may inspire new therapeutic strategies to suppress the transformation of IDH WT LGAs to higher-grade cancers.

scholarly journals Molecular Determinants of Prognosis and Evolution in Diffuse-Lower Grade Astrocytomas

2020 ◽  
Author(s):  
Mehul Kumar ◽  
J Gregory Cairncross ◽  
Michael D Blough ◽  
Pinaki Bose
Keyword(s):  
The Cancer Genome Atlas ◽  
Low Grade ◽  
Lower Grade ◽  
Mutational Status ◽  
Molecular Determinants ◽  
Pdgf Signaling ◽  
Evolutionary Trajectories ◽  
Cancer Genome Atlas ◽  
Natural Histories ◽  
Worse Prognosis

ABSTRACTLow grade astrocytomas (LGAs) are classified based on the mutational status of the isocitrate dehydrogenase (IDH) gene. While IDH wild-type (WT) LGAs evolve rapidly to glioblastoma, mutant tumors generally have a more indolent course. To identify potential drivers of the differential progression of LGAs, we analyzed transcriptomes from The Cancer Genome Atlas. Compared to mutant LGAs, platelet-derived growth factor (PDGF) signaling is enriched in WT cases, and PDGFA is the top overexpressed gene in the pathway. Putative mechanisms for differential PDGFA expression included copy number gains of chromosome 7 in WT cases and methylation of the PDGFA promoter in mutant LGAs. Additionally, we found that high PDGFA expression is associated with aneuploidy, immunosuppressive features, and worse prognosis, and that WT LGAs use multiple means to inactivate the p53 pathway to progress to GBM. Our work highlights the contribution of PDGF gene family towards the unique behaviour of LGAs.STATEMENT OF SIGNIFICANCEThis study of gene expression in LGAs suggests that differential regulation of the PDGF pathway may underlie the different natural histories of IDH WT and IDH mutant LGAs including divergent evolutionary trajectories to GBM. This insight may inspire new therapeutic strategies to suppress the transformation of LGAs to higher-grade cancers.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

scholarly journals Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

2018 ◽  
Vol 111 (7) ◽  
pp. 664-674 ◽  
Author(s):  
Rongqiang Yang ◽  
Steven W Li ◽  
Zirong Chen ◽  
Xin Zhou ◽  
Wei Ni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptome Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Growth And Survival ◽  
Cancer Genome Atlas ◽  
Lung Adenocarcinomas ◽  
Genome Atlas

Abstract Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.

scholarly journals A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

2020 ◽  
Vol 78 (1) ◽  
pp. 34-38
Author(s):  
Burcu BITERGE-SUT
Keyword(s):  
Glioblastoma Multiforme ◽  
Malignant Gliomas ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Nonsense Mutations ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

scholarly journals Comprehensive Analysis of The Significance of Hypoxia-Related Genes in Ovarian Cancer

2021 ◽  
Author(s):  
Wancheng Zhao ◽  
Lili Yin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Principal Component ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Pca Algorithm

Abstract Background: Hypoxia-related genes have been reported to play important roles in a variety of cancers. However, their roles in ovarian cancer (OC) have remained unknown. The aim of our research was to explore the significance of hypoxia-related genes in OC patients.Methods: In this study, 15 hypoxia-related genes were screened from The Cancer Genome Atlas (TCGA) database to group the ovarian cancer patients using the consensus clustering method. Principal component analysis (PCA) was performed to calculate the hypoxia score for each patient to quantify the hypoxic status. Results: The OC patients from TCGA-OV dataset were divided into two distinct hypoxia statuses (cluster.A and cluster.B) based on the expression level of the 15 hypoxia-related genes. Most hypoxia-related genes were expressed more highly in the cluster.A group than in the cluster.B group. We also found that patients in the cluster.A group exhibited higher expression of immune checkpoint-related genes, epithelial-mesenchymal transition-related genes, and immune activation-related genes, as well as elevated immune infiltrates. PCA algorithm indicated that patients in the cluster.A group had higher hypoxia scores than that in in the cluster.B group.Conclusions: In summary, our research elucidated the vital role of hypoxia-related genes in immune infiltrates of OC. Our investigation of hypoxic status may be able to improve the efficacy of immunotherapy for OC.

scholarly journals Molecular basis of distinct oestrogen responses in endometrial and breast cancer

2019 ◽  
Vol 26 (1) ◽  
pp. 31-46 ◽  
Author(s):  
Eva Baxter ◽  
Karolina Windloch ◽  
Greg Kelly ◽  
Jason S Lee ◽  
Frank Gannon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Oestrogen Receptor Alpha ◽  
Limited Success ◽  
Cancer Genome Atlas ◽  
Using Data ◽  
Oestrogen Signalling

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.

TNFα signalling predicts poor prognosis of patients with endometrial cancer

2020 ◽  
Vol 41 (8) ◽  
pp. 1065-1073
Author(s):  
Verena Wieser ◽  
Samira Abdel Azim ◽  
Susanne Sprung ◽  
Katharina Knoll ◽  
Johanna Kögl ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Clinical Outcome ◽  
The Cancer Genome Atlas ◽  
Western World ◽  
Low Grade ◽  
Necrosis Factor Alpha ◽  
Cancer Genome Atlas ◽  
Factor Alpha ◽  
The Impact

Abstract Endometrial cancer (EC) is the most common gynaecologic tumour in the Western world. Previous studies have implicated an imbalance of oestrogens and progestogens in the development of most ECs, while the role of low-grade tissue inflammation remains largely unexplored. We investigated the impact of tumour necrosis factor alpha (TNFα), a central mediator of inflammation and spermatogenesis-associated protein 2 (SPATA2), a regulator of TNF receptor signalling, on clinical outcomes in EC. We evaluated TNFA and SPATA2 transcript levels in 239 EC patients and 25 non-malignant control tissues. Findings were validated in a cohort of 332 EC patients from The Cancer Genome Atlas (TCGA). Expression of TNFA and SPATA2 was increased in EC when compared with control tissues (P &lt; 0.001). TNFA expression correlated with SPATA2 expression in non-malignant (P = 0.003, rS = 0.568) and EC tissue (P = 0.005, rS = 0.179). High TNFA and SPATA2 expression were associated with poor recurrence-free survival (RFS; P = 0.049 and P = 0.018) and disease-specific (P = 0.034 and P = 0.002) survival. Increased SPATA2 expression was also associated with decreased overall survival (OS; P = 0.013). In multivariate analysis, both TNFA and SPATA2 were predictors of clinical outcome. The impact of SPATA2 on RFS and OS could be validated in the TCGA cohort. Our study demonstrates that ECs exhibit a TNF signature which predicts clinical outcome. These findings indicate that TNF signalling modulates the course of EC, which could be therapeutically utilized in the future.

scholarly journals Krüppel-Like Factor 7 is a Marker of Aggressive Gastric Cancer and Poor Prognosis

2017 ◽  
Vol 43 (3) ◽  
pp. 1090-1099 ◽  
Author(s):  
Zhonghua Jiang ◽  
Tingting Yu ◽  
Zhining Fan ◽  
Hongmei Yang ◽  
Xin Lin
Keyword(s):  
Gastric Cancer ◽  
Disease Free Survival ◽  
Clinicopathological Characteristics ◽  
The Cancer Genome Atlas ◽  
Strong Negative Correlation ◽  
Functional Studies ◽  
Expression Of Genes ◽  
Cancer Genome Atlas

Background/Aims: Krüppel-like factor (KLF) 7 protein is a member of the KLF transcription factor family, which plays important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation and metabolism. However, the role of KLF7 in gastric cancer (GC) is unknown. The aim of this study is to explore the role of KLF7 in GC and its correlation with clinicopathological characteristics and prognosis of GC patients. Methods: We first systematically evaluated dysregulation of the KLF family in The Cancer Genome Atlas (TCGA) GC database. Then, 252 patients who underwent surgery for GC were enrolled to validate the results from the TCGA. Functional studies were also used to explore the role of KLF7 in GC. Results: In the TCGA database, we found that KLF7 was an independent predictor for survival by both univariate and multivariate analysis (P<0.05). In a validation cohort, KLF7 expression was significantly increased in GC tissues compared with adjacent normal controls (P=0.013). High KLF7 expression correlated with inferior prognostic factors, such as T stage (P=0.022), N stage (P =0.005) and lymphovascular invasion (P=0.009). Furthermore, we observed a strong negative correlation between KLF7 expression and 5-year overall survival and disease-free survival in GC patients (P<0.05). Moreover, our in vitro studies showed a notable decrease in migration in KLF7 knockdown cells. Conclusion: KLF7 has an important role in GC progression, as it inhibits GC cell migration and may serve as a prognostic marker.

scholarly journals Epigenetic Alterations in Oesophageal Cancer: Expression and Role of the Involved Enzymes

2020 ◽  
Vol 21 (10) ◽  
pp. 3522
Author(s):  
Nair Lopes ◽  
Margareta P. Correia ◽  
Rui Henrique ◽  
Carmen Jerónimo
Keyword(s):  
Oesophageal Cancer ◽  
Therapeutic Targets ◽  
Normal Mucosa ◽  
The Cancer Genome Atlas ◽  
Epigenetic Alterations ◽  
Life Threatening ◽  
Cancer Genome Atlas ◽  
In Vitro Data

Oesophageal cancer is a life-threatening disease, accounting for high mortality rates. The poor prognosis of this malignancy is mostly due to late diagnosis and lack of effective therapies for advanced disease. Epigenetic alterations may constitute novel and attractive therapeutic targets, owing to their ubiquity in cancer and their reversible nature. Herein, we offer an overview of the most important studies which compared differences in expression of enzymes that mediate epigenetic alterations between oesophageal cancer and normal mucosa, as well as in vitro data addressing the role of these genes/proteins in oesophageal cancer. Furthermore, The Cancer Genome Atlas database was interrogated for the correlation between expression of these epigenetic markers and standard clinicopathological features. We concluded that most epigenetic players studied thus far are overexpressed in tumours compared to normal tissue. Furthermore, functional assays suggest an oncogenic role for most of those enzymes, supporting their potential as therapeutic targets in oesophageal cancer.

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