Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32569800.fastq.gz | Fastqsanger.gz | |||
| SRR32569800_1.fastq.gz | Fastqsanger.gz | |||
| SRR32569800_2.fastq.gz | Fastqsanger.gz | |||
| SRR32569801.fastq.gz | Fastqsanger.gz | |||
| SRR32569801_1.fastq.gz | Fastqsanger.gz |
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Project description:Intratumoral genetic heterogeneity and mutational burden have been suggested to be the fuel and the source of resistance for many molecularly targeted therapies throughout a multitude of cancers. Emerging evidence indicates that tumor cells could hijack the powerful mutagenesis machinery mediated by the DNA deaminase APOBEC family proteins to intensify mutagenesis, promote intratumoral heterogeneity, and foster therapy resistance through a cell-autonomous mechanism. However, this mechanism has yet to be characterized. Utilizing prostate cancer (PCa) as a relevant model, we have identified the Synaptotagmin Binding Cytoplasmic RNA Interacting Protein (SYNCRIP) as a molecular brake for APOBEC-driven mutagenesis, intratumoral heterogeneity, and resistance to Androgen Receptor (AR) targeted therapies. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified eight mutated resistance driver genes and revealed unparalleled details of how these heterogeneously aberrant subclones fuel the evolution of AR therapy resistance. For the first time, these findings exposed a cell-autonomous mechanism activating APOBEC-driven mutagenesis, consequently fueling mutational burden, genetic heterogeneity, and therapy resistance, and suggested that APOBEC proteins could be the potential therapeutic targets for preventing or overcoming resistance in PCa.
2023-07-20 | GSE202321 | GEO
Project description:<p><b>Reprinted from Roberts et al. "An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers", Nature Genetics, 45:970-976, 2013, with permission of Nature Publishing Group:</b></p> <p>Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.</p>
| phs000677 | dbGaP
Project description:Intratumor mutational heterogeneity has been documented in primary non-small cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC-mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk germline APOBEC3 variant, strongly correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN- induced expression of APOBEC3B in lung adenocarcinoma cells in culture suggesting a role for the immune microenvironment in the generation of mutational heterogeneity. CNA occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.
2019-05-07 | PXD012845 | Pride
Project description:<p>Integrated proteo-genomics studies to characterize tumor heterogeneity of metastatic lung adenocarcinoma and thymic carcinoma are lacking. We carried out whole exome sequencing, RNA sequencing, copy number estimation and mass spectrometry-based proteomics of 40 tumors from five rapid/warm autopsy patients. We found highly variable mutational heterogeneity that was largely driven by APOBEC-mutagenesis with the expression of APOBEC3B (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=APOBEC3B">Gene ID: 9582</a>) and APOBEC3A_B (<a href="https://www.ncbi.nlm.nih.gov/gene/100913187">Gene ID: 100913187</a>) due to underlying APOBEC3 region germline variants as the likely mediating mechanism. APOBEC3A_B expression was associated with increased immune tumor microenvironment and CD274 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CD274">Gene ID: 29126</a>) expression while smoking was associated with increased APOBEC-mutagenesis in TP53 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=TP53">Gene ID: 7157</a>) mutant tumors with high APOBEC3B expression. Heterogeneity at the level of the transcriptome and proteome occurred in association with copy number heterogeneity, not APOBEC-induced mutational heterogeneity. Arm and focal copy number alterations (CNAs) occurred as an evolutionarily late event in a subset of patients, with corresponding changes in the transcriptome and proteome, implicating CNAs as a driving force of heterogeneity in the evolution of metastatic disease.</p>
| phs001432 | dbGaP
Project description:APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
| PRJNA226256 | ENA
Project description:APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
| PRJNA226257 | ENA
Project description:The genome-wide identification, tissue-specificity and functional implications of Apobec-1 mediated C-to-U RNA editing remains incomplete. Deep sequencing, data filtering and validation from wild-type and Apobec-1 deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs (74-81% true-positive), all within 3' untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites were unique to liver. Changes in RNA editing led to corresponding changes in intestinal mRNA and protein levels in 11 genes. We found distinctive polysome profiles for several editing targets and demonstrated nuclear but not cytoplasmic editing of novel exonic sites in intestinal (but not hepatic) apoB RNA. RNA editing was validated using cell-free extracts from wild-type but not Apobec-1 deficient mice. These studies define selective, tissue-specific targets of Apobec-1 dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific. Examination of C-to-U RNA editing in mouse liver and intestine
2014-05-23 | E-GEOD-57910 | biostudies-arrayexpress
Project description:The utility of RADseq in an experimental setting is also demonstrated, based on our chasacterisation of an APOBEC mutation signature in an APOBEC3A transfected mouse cell line. 0D5 cells, derived from SSM3 cells, were co-transfected with a mixture containing pcDNA3.1 vectors expressing either APOBEC3A or APOBEC3B (kindly donated by Vincent Caval), pcDNA3.1 construct expressing deaminase null APOBEC3A linked to a uracil deglycosylase construct and a plasmid encoding mutant GFP and WT mCherry that is a reporter for APOBEC mutagenesis. Cells were grown, and gDNA extracted, prior to preparation of RADseq libraries using a PstI- MspI double-digest. Libraries underwent a Pippin Prep to select fragments in the size range of 220-520 bp (genomic sequence plus 148 bp of adapters). Single-end sequencing (1x101bp) was performed on an Illumina NovaSeq6000 utilizing v1.5 chemistry. Reads were aligned to mm10 using bwa mem and variants called using the GATK4 pipeline.
2023-06-30 | GSE234146 | GEO
Project description:Background: RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoproteinB (apoB) mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1 mediated C-to-U RNA editing remains incomplete. Results: Deep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1 deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs (74-81% Sanger sequenced validated), all within 3’ untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites were unique to liver. Changes in RNA editing led to corresponding changes in intestinal mRNA and protein levels in 11 genes. RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression revealed that a subset of targets identified in wild-type mice were restored in Apobec-1 deficient mouse intestine and liver following Apobec-1 rescue. We found distinctive polysome profiles for several RNA editing targets and demonstrated novel exonic editing sites in nuclear preparations from intestine (but not hepatic) apoB RNA. RNA editing was validated using cell-free extracts from wild-type but not Apobec-1 deficient mice, demonstrating that Apobec-1 is required. Conclusions: These studies define selective, tissue-specific targets of Apobec-1 dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific.
2014-06-02 | PXD001007 | Pride