scholarly journals Using Transcriptional Signatures to Find Cancer Drivers with LURE

2019 ◽  
Author(s):  
David Haan ◽  
Ruikang Tao ◽  
Verena Friedl ◽  
Ioannis Nikolaos Anastopoulos ◽  
Christopher K Wong ◽  
...  
Keyword(s):  
Gene Expression Signature ◽  
Telomere Maintenance ◽  
Tumor Type ◽  
Learning Framework ◽  
Rtk Signaling ◽  
Multidimensional Datasets ◽  
Cancer Drivers ◽  
Tcga Dataset ◽  
Genome Projects ◽  
Prior Relationship

Cancer genome projects have produced multidimensional datasets on thousands of samples. Yet, depending on the tumor type, 5-50% of samples have no known driving event. We introduce a semi-supervised method called Learning UnRealized Events (LURE) that uses a progressive label learning framework and minimum spanning analysis to predict cancer drivers based on their altered samples sharing a gene expression signature with the samples of a known event. We demonstrate the utility of the method on the TCGA dataset for which it produced a high-confidence result relating 53 new to 18 known mutation events including alterations in the same gene, family, and pathway. We give examples of predicted drivers involved in TP53, telomere maintenance, and MAPK/RTK signaling pathways. LURE identifies connections between genes with no known prior relationship, some of which may offer clues for targeting specific forms of cancer. Code and Supplemental Material are available on the LURE website https://sysbiowiki.soe.ucsc.edu/lure.

scholarly journals The prognostic value of long noncoding RNA SNHG16 on clinical outcomes in human cancers: a systematic review and meta-analysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chenghao Zhang ◽  
Xiaolei Ren ◽  
Jieyu He ◽  
Wanchun Wang ◽  
Chao Tu ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Prognostic Value ◽  
Meta Analysis ◽  
Clinicopathological Features ◽  
Survival Outcomes ◽  
Tumor Type ◽  
Free Survival ◽  
Expression Levels ◽  
Human Cancers ◽  
Tcga Dataset

Abstract Background Cancer has been a worldwide health problem with a high risk of morbidity and mortality, however ideal biomarkers for effective screening and diagnosis of cancer patients are still lacking. Small nucleolar RNA host gene 16 (SNHG16) is newly identified lncRNA with abnormal expression in several human malignancies. However, its prognostic value remains controversial. This meta-analysis aimed to synthesize available data to clarify the association between SNHG16 expression levels and clinical prognosis value in multiple cancers. Methods Extensive literature retrieval was conducted to identify eligible studies, and data regarding SNHG16 expression levels on survival outcomes and clinicopathological features were extracted and pooled for calculation of the hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Forest plots were applied to show the association between SNHG16 expression and survival prognosis. Additionally, The Cancer Genome Atlas (TCGA) dataset was screened and extracted for validation of the results in this meta-analysis. Results A total of eight studies comprising 568 patients were included in the final meta-analysis according to the inclusion and exclusion criteria. In the pooled analysis, high SNHG16 expression significantly predicted worse overall survival (OS) in various cancers (HR = 1.87, 95% CI 1.54–2.26, P < 0.001), and recurrence-free survival (RFS) in bladder cancer (HR = 1.68, 95% CI 1.01–2.79, P = 0.045). Meanwhile, stratified analyses revealed that the survival analysis method, tumor type, sample size, and cut-off value did not alter the predictive value of SNHG16 for OS in cancer patients. In addition, compared to the low SNHG16 expression group, patients with high SNHG16 expression were more prone to worse clinicopathological features, such as larger tumor size, advanced clinical stage, lymph node metastasis (LNM) and distant metastasis (DM). Exploration of TCGA dataset further validated that the upregulated SNHG16 expression predicted unfavorable OS and disease-free survival (DFS) in cancer patients. Conclusions The present study implicated that aberrant expression of lncRNA SNHG16 was strongly associated with clinical survival outcomes in various cancers, and therefore might serve as a promising biomarker for predicting prognosis of human cancers.

scholarly journals OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii19-iii20
Author(s):  
C Birzu ◽  
A Hillairet ◽  
M Giry ◽  
N Grandin ◽  
P Verrelle ◽  
...  
Keyword(s):  
Telomere Length ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
P Value ◽  
Who Grade ◽  
Small Subgroup ◽  
Adjusted Score ◽  
Diffuse Gliomas ◽  
Tcga Dataset

Abstract BACKGROUND The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas. MATERIAL AND METHODS We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort. RESULTS RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C>T or T>C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset. CONCLUSION We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.

scholarly journals 90-gene signature assay for tissue origin diagnosis of brain metastases

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Yulong Zheng ◽  
Yongfeng Ding ◽  
Qifeng Wang ◽  
Yifeng Sun ◽  
Xiaodong Teng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Brain Metastases ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Similarity Score ◽  
Primary Site ◽  
Tumor Type ◽  
Metastatic Brain Tumors ◽  
Expression Signature

Abstract Background Brain metastases (BM) are the most common intracranial tumors. 2–14% of BM patients present with unknown primary site despite intensive evaluations. This study aims to evaluate the performance of a 90-gene expression signature in determining the primary sites for BM samples. Methods The sequence-based gene expression profiles of 708 primary brain tumors (PBT) collected from The Cancer Genome Atlas (TCGA) database were analyzed by the 90-gene expression signature, with a similarity score for each of 21 common tumor types. We then used Optimal Binning algorithm to generate a threshold for separating PBT from BM. Eighteen PBT samples were analyzed to substantiate the reliability of the threshold. In addition, the performance of the 90-gene expression signature for molecular classification of metastatic brain tumors was validated in a cohort of 48 BM samples with the known origin. For each BM sample, the tumor type with the highest similarity score was considered tissue of origin. When a sample was diagnosed as PBT, but the similarity score below the threshold, the second prediction was considered as the primary site. Results A threshold of the similarity score, 70, was identified to discriminate PBT from BM (PBT: > 70, BM: ≤ 70) with an accuracy of 99% (703/708, 95% CI 98–100%). The 90-gene expression signature was further validated with 18 PBT and 44 BM samples. The results of 18 PBT samples matched reference diagnosis with a concordance rate of 100%, and all similarity scores were above the threshold. Of 44 BM samples, the 90-gene expression signature accurately predicted primary sites in 89% (39/44, 95% CI 75–96%) of the cases. Conclusions Our findings demonstrated the potential that the 90-gene expression signature could serve as a powerful tool for accurately identifying the primary sites of metastatic brain tumors.

scholarly journals Upregulated expression of LncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 is correlated with unfavorable clinical outcomes in cancers

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chenghao Zhang ◽  
Xiaolei Ren ◽  
Zhongyue Liu ◽  
Chao Tu
Keyword(s):  
Antisense Rna ◽  
Disease Free Survival ◽  
Cancer Prognosis ◽  
Survival Outcomes ◽  
Tumor Type ◽  
Clinicopathologic Characteristics ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
And Gender ◽  
Tcga Dataset ◽  
Stratified Analysis

Abstract Background The nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) is a long non-coding RNA aberrantly expressed in human malignancies. We aimed to analyze available data to evaluate the correlation between NNT-AS1 expression and cancer prognosis. Methods Literature retrieval was performed by systematic searching related databases from inception to April 2, 2020. Studies regarding correlation between NNT-AS1 expression, survival outcomes and clinical characteristics of cancer patients were collected and pooled to calculate the the hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs). Results Ten studies comprising 699 patients were included, all of which were conducted in China according to literature selection criteria. Overexpression of NNT-AS1 had a significant association with unfavorable overall survival (OS) (HR = 2.08, 95% CI: 1.84–2.36, P < 0.001). Stratified analysis showed that tumor type, sample size, follow-up months, and survival analysis approach did not change the predictive value of NNT-AS1 on OS. Furthermore, elevated NNT-AS1 level had significant association with distant metastasis (DM) (OR = 2.45, 95% CI: 1.39–4.30), lymph node metastasis (LNM) (OR = 3.92, 95% CI: 1.35–11.41), TNM stage (OR = 4.25, 95% CI: 1.71–10.56), and vascular invasion (OR = 3.98, 95% CI: 2.06–7.71), but was not associated with age and gender. The TCGA dataset further consistently showed that the NNT-AS1 expression was associated with poor OS and disease-free survival. Conclusions High expression of NNT-AS1 is associated with unfavorable survival outcomes and poor clinicopathologic characteristics. However, large-cohort data and geographical studies are still needed to further validate the prognostic value of NNT-AS1 in cancers.

scholarly journals Comparative Gene Expression Analysis in WM164 Melanoma Cells Revealed That β-β-Dimethylacrylshikonin Leads to ROS Generation, Loss of Mitochondrial Membrane Potential, and Autophagy Induction

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2823 ◽  
Author(s):  
Nadine Kretschmer ◽  
Alexander Deutsch ◽  
Christin Durchschein ◽  
Beate Rinner ◽  
Alexander Stallinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Membrane Potential ◽  
Skin Cancer ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Gene Expression Signature ◽  
Melanoma Cells ◽  
Ros Generation ◽  
Tumor Type ◽  
Ic50 Values

Skin cancer is currently diagnosed as one in every three cancers. Melanoma, the most aggressive form of skin cancer, is responsible for 79% of skin cancer deaths and the incidence is rising faster than in any other solid tumor type. Previously, we have demonstrated that dimethylacrylshikonin (DMAS), isolated from the roots of Onosma paniculata (Boraginaceae), exhibited the lowest IC50 values against different tumor types out of several isolated shikonin derivatives. DMAS was especially cytotoxic towards melanoma cells and led to apoptosis and cell cycle arrest. In this study, we performed a comprehensive gene expression study to investigate the mechanism of action in more detail. Gene expression signature was compared to vehicle-treated WM164 control cells after 24 h of DMAS treatment; where 1192 distinct mRNAs could be identified as expressed in all replicates and 89 were at least 2-fold differentially expressed. DMAS favored catabolic processes and led in particular to p62 increase which is involved in cell growth, survival, and autophagy. More in-depth experiments revealed that DMAS led to autophagy, ROS generation, and loss of mitochondrial membrane potential in different melanoma cells. It has been reported that the induction of an autophagic cell death represents a highly effective approach in melanoma therapy.

scholarly journals Upregulated Expression of LncRNA Nicotinamide Nucleotide Transhydrogenase Antisense RNA 1 is Correlated with Unfavorable Clinical Outcomes in Cancers

2020 ◽  
Author(s):  
Chenghao Zhang ◽  
Xiaolei Ren ◽  
Zhongyue Liu ◽  
Chao Tu
Keyword(s):  
Antisense Rna ◽  
Disease Free Survival ◽  
Cancer Prognosis ◽  
Survival Outcomes ◽  
Tumor Type ◽  
Clinicopathologic Characteristics ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
And Gender ◽  
Tcga Dataset ◽  
Stratified Analysis

Abstract Background: The nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) is a long non-coding RNA aberrantly expressed in human malignancies. We aimed to analyze available data to evaluate the correlation between NNT-AS1 expression and cancer prognosis. Methods: Literature retrieval was performed by systematic searching related databases from inception to April 2, 2020. Studies regarding correlation between NNT-AS1 expression, survival outcomes and clinical characteristics of cancer patients were collected and pooled to calculate the the hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: Ten studies comprising 699 patients were included, all of which were conducted in China according to literature selection criteria. Overexpression of NNT-AS1 had a significant association with unfavorable overall survival (OS) (HR=2.08, 95% CI: 1.84-2.36, P<0.001). Stratified analysis showed that tumor type, sample size, follow-up months, and survival analysis approach did not change the predictive value of NNT-AS1 on OS. Furthermore, elevated NNT-AS1 level had significant association with distant metastasis (DM) (OR=2.45, 95% CI: 1.39-4.30), lymph node metastasis (LNM) (OR=3.92, 95% CI: 1.35-11.41), TNM stage (OR=4.25, 95% CI: 1.71-10.56), and vascular invasion (OR=3.98, 95% CI: 2.06-7.71), but was not associated with age and gender. The TCGA dataset further consistently showed that the NNT-AS1 expression was associated with poor OS and disease-free survival. Conclusions: High expression of NNT-AS1 is associated with unfavorable survival outcomes and poor clinicopathologic characteristics. However, large-cohort data and geographical studies are still needed to further validate the prognostic value of NNT-AS1 in cancers.

scholarly journals Upregulated Expression of LncRNA Nicotinamide Nucleotide Transhydrogenase Antisense RNA 1 is Correlated with Unfavorable Clinical Outcomes in Cancers

2020 ◽  
Author(s):  
Chenghao Zhang ◽  
Xiaolei Ren ◽  
Zhongyue Liu ◽  
Chao Tu
Keyword(s):  
Antisense Rna ◽  
Disease Free Survival ◽  
Cancer Prognosis ◽  
Tumor Type ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
Hazard Ratios ◽  
Non Coding Rna ◽  
And Gender ◽  
Tcga Dataset ◽  
Stratified Analysis

Abstract Background: The nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1) is a long non-coding RNA aberrantly expressed in human malignancies. We aimed to analyze available data to evaluate the correlation between NNT-AS1 expression and cancer prognosis.Methods: Literature retrieval was performed by systematic searching related databases from inception to April 2, 2020. Studies regarding correlation between NNT-AS1 expression, survival outcomes and clinical characteristics of cancer patients were collected and pooled to calculate the the hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs).Results: Ten studies comprising 690 patients were included. Overexpression of NNT-AS1 had a significant association with unfavorable overall survival (OS) (HR=2.08, 95% CI: 1.84-2.36, P<0.001). Stratified analysis showed that tumor type, sample size, follow-up months, and survival analysis approach did not change the predictive value of NNT-AS1 on OS. Furthermore, elevated NNT-AS1 level had significant association with distant metastasis (DM) (OR=2.45, 95% CI: 1.39-4.30), lymph node metastasis (LNM) (OR=3.92, 95% CI: 1.35-11.41), TNM stage (OR=4.25, 95% CI: 1.71-10.56), and vascular invasion (OR=3.98, 95% CI: 2.06-7.71), but was not associated with age and gender. The TCGA dataset showed the NNT-AS1 expression was strongly associated with poor OS, but not disease-free survival.Conclusions: high expression of NNT-AS1 could predict unfavorable survival and clinicopathologic outcomes, indicating NNT-AS1 may serve as a novel biomarker for prognosis and therapeutic target for patients.

scholarly journals Validating a gene expression signature proposed to differentiate liposarcomas that use different telomere maintenance mechanisms

Oncogene ◽  
2011 ◽  
Vol 31 (2) ◽  
pp. 265-266
Author(s):  
K R Doyle ◽  
M A Mitchell ◽  
C L Roberts ◽  
S James ◽  
J E Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Telomere Maintenance ◽  
Expression Signature

scholarly journals Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

2019 ◽  
Author(s):  
Riyue Bao ◽  
Jason J. Luke
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Hedgehog Signaling ◽  
Human Cancer ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Type I ◽  
Tumor Type ◽  
Cancer Types

AbstractThe T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational profile may also dictate response with some oncogenes (i.e. WNT/β-catenin) known to mediate immuno-suppression. Building on these observations we performed a multi-omic analysis of human cancer correlating the T cell-inflamed gene expression signature with the somatic mutanome and transcriptome for different immune phenotypes, by tumor type and across cancers. Strong correlations were noted between mutations in oncogenes and non-T cell-inflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c and genes with unknown functions. Conversely, we observe many genes associating with the T cell-inflamed phenotype including VHL and PBRM1, among others. Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion broadly active across cancer types including HIF1A and MYC. Novel examples from specific tumors include sonic hedgehog signaling in ovarian cancer or hormone signaling and novel transcription factors across multiple tumors. Using network analysis, somatic and transcriptomic events were integrated, demonstrating that most non-T cell-inflamed tumors are influenced by multiple pathways. Validating these analyses, we observe significant inverse relationships between protein levels and the T cell-inflamed gene signature with examples including NRF2 in lung, ERBB2 in urothelial and choriogonadotropin in cervical cancer. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms. These results nominate molecular targets and drugs potentially available for immediate translation into clinical trials for patients with cancer.

scholarly journals Prognostic and clinical significance of long non-coding RNA SNHG12 expression in various cancers

2020 ◽  
Author(s):  
Chenghao Zhang ◽  
Chao Tu ◽  
Xiaolei Ren ◽  
Wenchao Zhang ◽  
Lile He ◽  
...  
Keyword(s):  
Overall Survival ◽  
Meta Analysis ◽  
Clinical Stage ◽  
The Cancer Genome Atlas ◽  
Clinicopathological Parameters ◽  
Tumor Type ◽  
Advanced Clinical Stage ◽  
Non Coding Rna ◽  
Tcga Dataset ◽  
Stratified Analysis

Abstract Background: Recently, dysregulation of lncRNA SNHG12 has been determined in kinds of cancers. However, definite prognostic value of SNHG12 remains unclear. We conducted this meta-analysis to evaluate the association between SNHG12 expression levels and caner prognosis.Methods: A literature retrieval was conducted by searching kinds of databases. The meta-analysis of prognostic and clinicopathological parameters was performed by using Revman 5.2 and Stata 12.0 software. Besides, The Cancer Genome Atlas dataset was analyzed to validate the results in our meta-analysis via using Gene Expression Profiling Interactive Analysis.Results: High SNHG12 expression significantly predicted worse overall survival (HR=1.97, 95%CI 1.56-2.48, P<0.01) and recurrence-free survival (HR=1.71, 95%CI 1.05-2.78, P<0.01). Tumor type, sample size, survival analysis method, and cut-off value did not alter SNHG12 prognosis value according to stratified analysis results. Additionally, patients with elevated SNHG12 expression were more prone to unfavorable clinicopathological outcomes, including larger tumor size, lymph node metastasis, distant metastasis, advanced clinical stage. Online cross-validation in TCGA dataset further proved that cancer patients with upregulated SNHG12 expression had worse overall survival and disease-free survival.Conclusion: Elevated SNHG12 expression was associated with poor survival and unfavorable clinicopathological features in various cancers, and therefore might be a potential prognostic biomarker in human cancers.

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