scholarly journals The landscape of coding RNA editing events in pediatric cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ji Wen ◽  
Michael Rusch ◽  
Samuel W. Brady ◽  
Ying Shao ◽  
Michael N. Edmonson ◽  
...  
Keyword(s):  
Rna Editing ◽  
Pediatric Cancer ◽  
Normal Tissue ◽  
De Novo ◽  
Tissue Expression ◽  
Genome Project ◽  
Coding Regions ◽  
Pediatric Cancers ◽  
Cancer Subtype ◽  
Coding Variants

Abstract Background RNA editing leads to post-transcriptional variation in protein sequences and has important biological implications. We sought to elucidate the landscape of RNA editing events across pediatric cancers. Methods Using RNA-Seq data mapped by a pipeline designed to minimize mapping ambiguity, we investigated RNA editing in 711 pediatric cancers from the St. Jude/Washington University Pediatric Cancer Genome Project focusing on coding variants which can potentially increase protein sequence diversity. We combined de novo detection using paired tumor DNA-RNA data with analysis of known RNA editing sites. Results We identified 722 unique RNA editing sites in coding regions across pediatric cancers, 70% of which were nonsynonymous recoding variants. Nearly all editing sites represented the canonical A-to-I (n = 706) or C-to-U sites (n = 14). RNA editing was enriched in brain tumors compared to other cancers, including editing of glutamate receptors and ion channels involved in neurotransmitter signaling. RNA editing profiles of each pediatric cancer subtype resembled those of the corresponding normal tissue profiled by the Genotype-Tissue Expression (GTEx) project. Conclusions In this first comprehensive analysis of RNA editing events in pediatric cancer, we found that the RNA editing profile of each cancer subtype is similar to its normal tissue of origin. Tumor-specific RNA editing events were not identified indicating that successful immunotherapeutic targeting of RNA-edited peptides in pediatric cancer should rely on increased antigen presentation on tumor cells compared to normal but not on tumor-specific RNA editing per se.

scholarly journals Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

2021 ◽  
Vol 7 (3) ◽  
pp. 47
Author(s):  
Marios Lange ◽  
Rodiola Begolli ◽  
Antonis Giakountis
Keyword(s):  
Disease Onset ◽  
Cancer Genome ◽  
Driver Mutations ◽  
Nucleotide Polymorphisms ◽  
Structural Variations ◽  
Coding Regions ◽  
Functional Variants ◽  
Coding Variants ◽  
Clinical Potential

The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

scholarly journals Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome

2021 ◽  
Author(s):  
Jet van der Spek ◽  
Joery den Hoed ◽  
Lot Snijders Blok ◽  
Alexander J. M. Dingemans ◽  
Dick Schijven ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Human Phenotype ◽  
Variable Expressivity ◽  
Pathogenic Variants ◽  
Reduced Penetrance ◽  
Coding Variants

Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.

scholarly journals Complete chloroplast genome of Hordeum brevisubulatum: Genome organization, synonymous codon usage, phylogenetic relationships, and comparative structure analysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261196
Author(s):  
Guangxin Cui ◽  
Chunmei Wang ◽  
Xiaoxing Wei ◽  
Hongbo Wang ◽  
Xiaoli Wang ◽  
...  
Keyword(s):  
Phylogenetic Relationships ◽  
Genome Engineering ◽  
De Novo ◽  
Synonymous Codon ◽  
Northern China ◽  
Synonymous Codon Usage ◽  
The Other ◽  
Coding Regions ◽  
Cp Genome ◽  
Hordeum Brevisubulatum

Background Hordeum brevisubulatum, known as fine perennial forage, is used for soil salinity improvement in northern China. Chloroplast (cp) genome is an ideal model for assessing its genome evolution and the phylogenetic relationships. We de novo sequenced and analyzed the cp genome of H. brevisubulatum, providing a fundamental reference for further studies in genetics and molecular breeding. Results The cp genome of H. brevisubulatum was 137,155 bp in length with a typical quadripartite structure. A total of 130 functional genes were annotated and the gene of accD was lost in the process of evolution. Among all the annotated genes, 16 different genes harbored introns and the genes of ycf3 and rps12 contained two introns. Parity rule 2 (PR2) plot analysis showed that majority of genes had a bias toward T over A in the coding strand in all five Hordeum species, and a slight G over C in the other four Hordeum species except for H. bogdanil. Additionally, 52 dispersed repeat sequences and 182 simple sequence repeats were identified. Moreover, some unique SSRs of each species could be used as molecular markers for further study. Compared to the other four Hordeum species, H. brevisubulatum was most closely related to H. bogdanii and its cp genome was relatively conserved. Moreover, inverted repeat regions (IRa and IRb) were less divergent than other parts and coding regions were relatively conserved compared to non-coding regions. Main divergence was presented at the SSC/IR border. Conclusions This research comprehensively describes the architecture of the H. brevisubulatum cp genome and improves our understanding of its cp biology and genetic diversity, which will facilitate biological discoveries and cp genome engineering.

Performance Comparison of Computational Prediction Methods for the Function and Pathogenicity of Non-coding Variants

2021 ◽  
Author(s):  
Zheng Wang ◽  
Guihu Zhao ◽  
Bin Li ◽  
Zhenghuan Fang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Computational Methods ◽  
Method Development ◽  
De Novo ◽  
Autism Spectrum ◽  
Common Variant ◽  
Tool Selection ◽  
Somatic Variant ◽  
Germline Variant ◽  
Regulatory Variant ◽  
Coding Variants

Non-coding variants in the human genome greatly influence some traits and complex diseases by their own regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in the human non-coding sequences. However, it is difficult for users with insufficient knowledge about the performances of computational methods to select appropriate computational methods from dozens of methods. In order to solve this problem, we assessed 12 performance measures of 24 methods on four independent non-coding variant benchmark datasets: (Ⅰ) rare germline variant from ClinVar, (Ⅱ) rare somatic variant from COSMIC, (Ⅲ) common regulatory variant dataset, and (Ⅳ) disease associated common variant dataset. All 24 tested methods performed differently under various conditions, indicating that these methods have varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable in the rare germline variant from ClinVar with area under curves (AUCs) of 0.4481 - 0.8033 and poor in the rare somatic variant from COSMIC (AUCs: 0.4984 - 0.7131), common regulatory variant dataset (AUCs: 0.4837 - 0.6472), and disease associated common variant dataset (AUCs: 0.4766 -0.5188). We also compared the prediction performance among 24 methods for non-coding de novo mutations in autism spectrum disorder and found that the CADD and CDTS methods showed better performance. Summarily, we assessed the performances of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and new method development in interpreting non-coding variants.

Multicenter Analysis of Genomically Targeted Single Patient Use Requests for Pediatric Neoplasms

2021 ◽  
Author(s):  
Himalee S. Sabnis ◽  
David S. Shulman ◽  
Benjamin Mizukawa ◽  
Nancy Bouvier ◽  
Ahmet Zehir ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Drug Administration ◽  
Pediatric Cancer ◽  
Drug Targets ◽  
De Novo ◽  
Food And Drug Administration ◽  
Hematologic Malignancies ◽  
New Drugs ◽  
Single Patient ◽  
Patient Use

PURPOSE The US Food and Drug Administration–expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

A porcine brain-wide RNA editing landscape

2020 ◽  
Author(s):  
Jinrong Huang ◽  
Lin Lin ◽  
Zhanying Dong ◽  
Ling Yang ◽  
Tianyu Zheng ◽  
...  
Keyword(s):  
Rna Editing ◽  
Repetitive Sequences ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Protein Coding ◽  
Porcine Brain ◽  
Coding Regions ◽  
Pig Brain ◽  
Genome Wide ◽  
A Genome

Abstract Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is an essential post-transcriptional modification. Although hundreds of thousands of RNA editing sites have been reported in mammals, brain-wide analysis of the RNA editing in the mammalian brain remains rare. Here, a genome-wide RNA editing investigation is performed in 119 samples, representing 30 anatomically defined subregions in the pig brain. We identify a total of 682,037 A-to-I RNA editing sites of which 97% are not identified before. Within the pig brain, cerebellum and olfactory bulb are regions with most edited transcripts. The editing level of sites residing in protein-coding regions are similar across brain regions, whereas region-distinct editing is observed in repetitive sequences. Highly edited conserved recoding events in pig and human brain are found in neurotransmitter receptors, demonstrating the evolutionary importance of RNA editing in neurotransmission functions. The porcine brain-wide RNA landscape provides a rich resource to better understand the evolutionally importance of post-transcriptional RNA editing.

scholarly journals Non-Coding RNA Editing in Cancer Pathogenesis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1845 ◽  
Author(s):  
Giulia Romano ◽  
Michela Saviana ◽  
Patricia Le ◽  
Howard Li ◽  
Lavender Micalo ◽  
...  
Keyword(s):  
Rna Editing ◽  
Genome Project ◽  
Rna Transcripts ◽  
Sequencing Technologies ◽  
Cancer Pathogenesis ◽  
Clinical Biomarkers ◽  
Non Coding Rna ◽  
Bioinformatic Approaches ◽  
The Subject ◽  
The Human Genome Project

In the last two decades, RNA post-transcriptional modifications, including RNA editing, have been the subject of increasing interest among the scientific community. The efforts of the Human Genome Project combined with the development of new sequencing technologies and dedicated bioinformatic approaches created to detect and profile RNA transcripts have served to further our understanding of RNA editing. Investigators have determined that non-coding RNA (ncRNA) A-to-I editing is often deregulated in cancer. This discovery has led to an increased number of published studies in the field. However, the eventual clinical application for these findings remains a work in progress. In this review, we provide an overview of the ncRNA editing phenomenon in cancer. We discuss the bioinformatic strategies for RNA editing detection as well as the potential roles for ncRNA A to I editing in tumor immunity and as clinical biomarkers.

scholarly journals The cell line A-to-I RNA editing catalogue

2020 ◽  
Vol 48 (11) ◽  
pp. 5849-5858 ◽  
Author(s):  
Amos A Schaffer ◽  
Eli Kopel ◽  
Ayal Hendel ◽  
Ernesto Picardi ◽  
Erez Y Levanon ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cell Line ◽  
Rna Editing ◽  
Cell Lines ◽  
Normal Tissue ◽  
Critical Role ◽  
Human Cell Lines ◽  
Over Expression ◽  
Regulatory Processes ◽  
Future Work

Abstract Adenosine-to-inosine (A-to-I) RNA editing is a common post transcriptional modification. It has a critical role in protecting against false activation of innate immunity by endogenous double stranded RNAs and has been associated with various regulatory processes and diseases such as autoimmune and cardiovascular diseases as well as cancer. In addition, the endogenous A-to-I editing machinery has been recently harnessed for RNA engineering. The study of RNA editing in humans relies heavily on the usage of cell lines as an important and commonly-used research tool. In particular, manipulations of the editing enzymes and their targets are often developed using cell line platforms. However, RNA editing in cell lines behaves very differently than in normal and diseased tissues, and most cell lines exhibit low editing levels, requiring over-expression of the enzymes. Here, we explore the A-to-I RNA editing landscape across over 1000 human cell lines types and show that for almost every editing target of interest a suitable cell line that mimics normal tissue condition may be found. We provide CLAIRE, a searchable catalogue of RNA editing levels across cell lines available at http://srv00.recas.ba.infn.it/atlas/claire.html, to facilitate rational choice of appropriate cell lines for future work on A-to-I RNA editing.

scholarly journals 4478 Not just GLUT1: genome sequencing reveals genetic heterogeneity in Doose syndrome

2020 ◽  
Vol 4 (s1) ◽  
pp. 13-13
Author(s):  
Jeffrey Dennis Calhoun ◽  
Jonathan Gunti ◽  
Katie Angione ◽  
Elizabeth Geiger ◽  
Krista Eschbach ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Genetic Heterogeneity ◽  
Subject Matter ◽  
De Novo ◽  
Structural Abnormality ◽  
Short Read ◽  
Coding Regions ◽  
Initial Analysis ◽  
Pathogenic Variants ◽  
Unrelated Subject

OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligibility for the cohort included a potential diagnosis of EMAS by child neurology faculty at Children’s Hospital Colorado. Exclusion criteria included lack of drop seizures upon chart review or structural abnormality on MRI. Some individuals had prior genetic testing and priority for genome sequencing was given to individuals without clear genetic diagnosis based on previous testing. We analyzed single nucleotide variants (SNVs), small insertions and deletions (INDELs), and larger structural variants (SVs) from trio genomes and determined those that were likely contributory based on standardized American College of Medical Genetics (ACMG) criteria. RESULTS/ANTICIPATED RESULTS: Our initial analysis focused on variants in coding regions of known epilepsy-associated genes. We identified pathogenic or likely pathogenic variants in 6 different individuals involving 6 unique genes. Of these, 5 are de novo SNVs or INDELs and 1 is a de novo SV. One of these involve a de novo heterozygous variant in an X-linked gene (ARHGEF9) in a female individual. We hypothesize the skewed X-inactivation may result in primarily expression of the pathogenic variant. We anticipate identifying additional candidate variants in coding regions of genes previously not associated with EMAS or pediatric epilepsies as well as in noncoding regions of the genome. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite the genetic heterogeneity of EMAS, our initial analysis identified de novo pathogenic or likely pathogenic variants in 15% (6/40) of our cohort. As the cost continues to decline, short read genome sequencing represents a promising diagnostic tool for EMAS and other pediatric onset epilepsy syndromes. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose. SD has consulted for Upsher-Smith, Biomarin and Neurogene on an unrelated subject matter. GLC holds a research collaborative grant with Stoke therapeutics on unrelated subject matter.

Sign in / Sign up

Export Citation Format

Share Document