scholarly journals Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs

2020 ◽  
Author(s):  
Jong Hyuk Kim ◽  
Kate Megquier ◽  
Rachael Thomas ◽  
Aaron L. Sarver ◽  
Jung Min Song ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Genetic Alterations ◽  
Biological Behavior ◽  
Fusion Genes ◽  
Sequencing Data ◽  
Protein Coding ◽  
Genomic Complexity ◽  
Morphological Organization ◽  
Recurrent Mutations ◽  
Novel Protein

AbstractSporadic angiosarcomas (ASs) are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic ASs. In this study, we leveraged RNA sequencing data from thirteen human ASs and 76 spontaneous canine hemangiosarcomas (HSAs) to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the thirteen human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in ASs without fusions or TP53 mutations. We found fifteen novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in eleven of the 76 canine HSAs; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 co-occurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human ASs and canine HSAs identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data suggest that genomic instability induced by TP53 mutations might create a predisposition for fusion events that may contribute to tumor progression by promoting selection and/or enhancing fitness through activation of convergent angiogenic pathways in this vascular malignancy.One Sentence SummaryThis study shows that, while drive events of malignant vasoformative tumors of humans and dogs include diverse mutations and stochastic rearrangements that create novel fusion genes, convergent transcriptional programs govern the highly conserved morphological organization and biological behavior of these tumors in both species.

scholarly journals Classifying gastric cancer using FLORA reveals clinically relevant molecular subtypes and highlights LINC01614 as a biomarker for patient prognosis

Oncogene ◽  
2021 ◽  
Author(s):  
Yiyun Chen ◽  
Wing Yin Cheng ◽  
Hongyu Shi ◽  
Shengshuo Huang ◽  
Huarong Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Noncoding Rna ◽  
Molecular Subtype ◽  
Sequencing Data ◽  
Cell Growth And Migration ◽  
Protein Coding ◽  
Over Expression ◽  
And Migration ◽  
Patient Prognosis ◽  
Subtype 3

AbstractMolecular-based classifications of gastric cancer (GC) were recently proposed, but few of them robustly predict clinical outcomes. While mutation and expression signature of protein-coding genes were used in previous molecular subtyping methods, the noncoding genome in GC remains largely unexplored. Here, we developed the fast long-noncoding RNA analysis (FLORA) method to study RNA sequencing data of GC cases, and prioritized tumor-specific long-noncoding RNAs (lncRNAs) by integrating clinical and multi-omic data. We uncovered 1235 tumor-specific lncRNAs, based on which three subtypes were identified. The lncRNA-based subtype 3 (L3) represented a subgroup of intestinal GC with worse survival, characterized by prevalent TP53 mutations, chromatin instability, hypomethylation, and over-expression of oncogenic lncRNAs. In contrast, the lncRNA-based subtype 1 (L1) has the best survival outcome, while LINC01614 expression further segregated a subgroup of L1 cases with worse survival and increased chance of developing distal metastasis. We demonstrated that LINC01614 over-expression is an independent prognostic factor in L1 and network-based functional prediction implicated its relevance to cell migration. Over-expression and CRISPR-Cas9-guided knockout experiments further validated the functions of LINC01614 in promoting GC cell growth and migration. Altogether, we proposed a lncRNA-based molecular subtype of GC that robustly predicts patient survival and validated LINC01614 as an oncogenic lncRNA that promotes GC proliferation and migration.

scholarly journals Pan-cancer analysis of non-coding recurrent mutations and their possible involvement in cancer pathogenesis

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chie Kikutake ◽  
Minako Yoshihara ◽  
Mikita Suyama
Keyword(s):  
The Cancer Genome Atlas ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Huge Number ◽  
Protein Coding ◽  
Coding Regions ◽  
Cancer Pathogenesis ◽  
Recurrent Mutations ◽  
Cancer Genome Atlas ◽  
Pan Cancer

Abstract Cancer-related mutations have been mainly identified in protein-coding regions. Recent studies have demonstrated that mutations in non-coding regions of the genome could also be a risk factor for cancer. However, the non-coding regions comprise 98% of the total length of the human genome and contain a huge number of mutations, making it difficult to interpret their impacts on pathogenesis of cancer. To comprehensively identify cancer-related non-coding mutations, we focused on recurrent mutations in non-coding regions using somatic mutation data from COSMIC and whole-genome sequencing data from The Cancer Genome Atlas (TCGA). We identified 21 574 recurrent mutations in non-coding regions that were shared by at least two different samples from both COSMIC and TCGA databases. Among them, 580 candidate cancer-related non-coding recurrent mutations were identified based on epigenomic and chromatin structure datasets. One of such mutation was located in RREB1 binding site that is thought to interact with TEAD1 promoter. Our results suggest that mutations may disrupt the binding of RREB1 to the candidate enhancer region and increase TEAD1 expression levels. Our findings demonstrate that non-coding recurrent mutations and coding mutations may contribute to the pathogenesis of cancer.

Novel transgenic knockout model of basal-squamous bladder cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 459-459
Author(s):  
Vasty Osei Amponsa ◽  
Zongyu Zheng ◽  
Vonn Walter ◽  
Joshua Warrick ◽  
Cathy Mendelsohn ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Molecular Subtype ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Bladder Tissue ◽  
In Vivo Models ◽  
Knock Out ◽  
Genetic Ablation

459 Background: The recent description of the highly aggressive Basal-Squamous molecular subtype of bladder cancer (BLCa) requires the development of new in vivo models for the study of this clinical entity. Although loss of the transcription factor Forkhead box A1 ( FOXA1) is significantly associated with the Basal-Squamous subtype, cooperating genetic alterations are unknown. Herein, we identify genetic alterations that potentially cooperate with FOXA1 loss to drive tumorigenesis and/or the Basal-Squamous phenotype and develop a novel transgenic model for the study of Basal-Squamous BLCa. Methods: We interrogated The Cancer Genome Atlas (TCGA) BLCa study to identify common genetic alterations associated with FOXA1 copy number (CN) loss. Based on our results, we utilized a bladder-specific Cre-LoxP ( Uroplakin II-Cre) to constitutively knock-out (KO) Foxa1 and/or Pten in mouse urothelium. Two cohorts of mice were aged for 6 and 12 months, and a third cohort was exposed to the bladder-specific carcinogen N-butyl-(4-hydroxybutyl)-nitrosamine (BBN; 0.05%) for 12 weeks. Following all experiments, the bladder tissue was isolated and characterized. Results: The TCGA data revealed that combined CN loss of both FOXA1 and PTEN occurs in 17% of MI BLCa patients. At 6 months of age, our mice developed urothelial hyperplasia, whereas at 12 months of age, double KO ( Foxa1-/-/Pten-/-) mice developed carcinoma in situ (CIS) with SqD, enriched for basal (Krt5/6 and 14) and reduced in luminal (Gata3 and Pparγ) markers. Increased tumor stage was significantly associated with combined KO of at least one allele of Foxa1 and Pten following BBN exposure. Moreover, upregulation of apoptosis related genes was observed by RNA-sequencing data. Conclusions: In advanced BLCa, CN loss of FOXA1 and PTEN is common. Genetic ablation of Foxa1 and Pten results in CIS with SqD and a pathologic profile consistent with the Basal-Squamous subtype and accelerated tumor onset following carcinogen exposure. Therefore, we describe the development of a novel model for the study of Basal-Squamous BLCa potentially useful for preclinical studies.

scholarly journals Stability of SARS-CoV-2 phylogenies

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009175
Author(s):  
Yatish Turakhia ◽  
Nicola De Maio ◽  
Bryan Thornlow ◽  
Landen Gozashti ◽  
Robert Lanfear ◽  
...  
Keyword(s):  
Binding Sites ◽  
Recurrent Mutation ◽  
Lineage Tracing ◽  
Sequencing Data ◽  
Genome Sequences ◽  
Protein Coding ◽  
Sequencing Errors ◽  
Link Type ◽  
Scientific Inference ◽  
Recurrent Mutations

The SARS-CoV-2 pandemic has led to unprecedented, nearly real-time genetic tracing due to the rapid community sequencing response. Researchers immediately leveraged these data to infer the evolutionary relationships among viral samples and to study key biological questions, including whether host viral genome editing and recombination are features of SARS-CoV-2 evolution. This global sequencing effort is inherently decentralized and must rely on data collected by many labs using a wide variety of molecular and bioinformatic techniques. There is thus a strong possibility that systematic errors associated with lab—or protocol—specific practices affect some sequences in the repositories. We find that some recurrent mutations in reported SARS-CoV-2 genome sequences have been observed predominantly or exclusively by single labs, co-localize with commonly used primer binding sites and are more likely to affect the protein-coding sequences than other similarly recurrent mutations. We show that their inclusion can affect phylogenetic inference on scales relevant to local lineage tracing, and make it appear as though there has been an excess of recurrent mutation or recombination among viral lineages. We suggest how samples can be screened and problematic variants removed, and we plan to regularly inform the scientific community with our updated results as more SARS-CoV-2 genome sequences are shared (https://virological.org/t/issues-with-sars-cov-2-sequencing-data/473 and https://virological.org/t/masking-strategies-for-sars-cov-2-alignments/480). We also develop tools for comparing and visualizing differences among very large phylogenies and we show that consistent clade- and tree-based comparisons can be made between phylogenies produced by different groups. These will facilitate evolutionary inferences and comparisons among phylogenies produced for a wide array of purposes. Building on the SARS-CoV-2 Genome Browser at UCSC, we present a toolkit to compare, analyze and combine SARS-CoV-2 phylogenies, find and remove potential sequencing errors and establish a widely shared, stable clade structure for a more accurate scientific inference and discourse.

scholarly journals Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhongbo Chen ◽  
◽  
David Zhang ◽  
Regina H. Reynolds ◽  
Emil K. Gustavsson ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Purifying Selection ◽  
Whole Genome Sequencing Data ◽  
Human Lineage ◽  
Sequencing Data ◽  
Protein Coding ◽  
Potential Association ◽  
High Depth ◽  
Specific Sequences ◽  
Human Specific

AbstractKnowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.

scholarly journals Characterization of the nuclear and cytosolic transcriptomes in human brain tissue reveals new insights into the subcellular distribution of RNA transcripts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ammar Zaghlool ◽  
Adnan Niazi ◽  
Åsa K. Björklund ◽  
Jakub Orzechowski Westholm ◽  
Adam Ameur ◽  
...  
Keyword(s):  
Human Brain ◽  
Expression Analysis ◽  
Differential Expression Analysis ◽  
Adult Brain ◽  
Sequencing Data ◽  
Human Brain Tissue ◽  
Protein Coding ◽  
Rna Transcripts ◽  
Nuclear Rna ◽  
The Impact

AbstractTranscriptome analysis has mainly relied on analyzing RNA sequencing data from whole cells, overlooking the impact of subcellular RNA localization and its influence on our understanding of gene function, and interpretation of gene expression signatures in cells. Here, we separated cytosolic and nuclear RNA from human fetal and adult brain samples and performed a comprehensive analysis of cytosolic and nuclear transcriptomes. There are significant differences in RNA expression for protein-coding and lncRNA genes between cytosol and nucleus. We show that transcripts encoding the nuclear-encoded mitochondrial proteins are significantly enriched in the cytosol compared to the rest of protein-coding genes. Differential expression analysis between fetal and adult frontal cortex show that results obtained from the cytosolic RNA differ from results using nuclear RNA both at the level of transcript types and the number of differentially expressed genes. Our data provide a resource for the subcellular localization of thousands of RNA transcripts in the human brain and highlight differences in using the cytosolic or the nuclear transcriptomes for expression analysis.

Genetic Alterations at 13q14 May Correlate with Differences in the Biological Behavior of Prostate Cancer between Japanese and Caucasian Men

2010 ◽  
Vol 84 (4) ◽  
pp. 461-466 ◽  
Author(s):  
Taku Misumi ◽  
Yoshiaki Yamamoto ◽  
Tomoyuki Murakami ◽  
Yoshihisa Kawai ◽  
Hideaki Ito ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Alterations ◽  
Biological Behavior ◽  
Caucasian Men

Screening and survival analysis of melanoma immunodrug response-related genes and the function of magnetic nanoparticles in gene extraction

2021 ◽  
Vol 11 (8) ◽  
pp. 1306-1312
Author(s):  
Li Song ◽  
Ningchao Du ◽  
Haitao Luo ◽  
Furong Li
Keyword(s):  
Survival Analysis ◽  
Magnetic Nanoparticles ◽  
Drug Response ◽  
High Throughput Sequencing ◽  
Cox Proportional Hazards ◽  
Sequencing Data ◽  
Protein Coding ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
Rna Genes

This study aimed to identify the association of protein coding and long non coding RNA genes with immunotherapy response in melanoma. Based on RNA sequencing data of melanoma specimens, the expression levels of protein coding and long non coding RNA genes were calculated using the Kallisto RNA-seq quantification method, and differently expressed genes were detected using the DESeq2 method. Cox proportional hazards regression was used to evaluate the effects of gene expression on survival. According to the clinical data of 14 patients with drug response and 11 patients without drug response, 18 protein coding genes and 14 long non coding RNAs showed differential expressions (multiple of difference > 2 and P < 0.01 after correction), among which the coding genes of differential expression were significantly enriched through the process of cell adhesion (P < 0.01). The results of survival analysis showed that 18 coding genes and 14 long non coding RNA genes had significant effects on patient survival (P < 0.01). In this study, magnetic nanoparticles can be used to extract genomic DNA and total RNA due to their paramagnetism and biocompatibility, then transcriptome high-throughput sequencing was performed. The method has the advantages of removing dangerous reagents such as phenol and chloroform, replacing inorganic coating such as silica with organic oil, and shortening reaction time. Protein coding and long non coding RNA genes as well as magnetic nanoparticles may serve as potential cancer immune biomarker targets for developing future oncological treatments.

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