APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA226256 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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.
| S-EPMC3789062 | biostudies-literature
Project description:Interventions: Blood samples(10 points) are collected after the first administration of capecitabine for pharmacokinetic analysis and cytidine deaminase activity measurement.
Primary outcome(s): To evaluate the correlation AUC of 5-DFUR/AUC of 5-DFCR ratio and cytidine deaminase activity.
Study Design: Single arm Non-randomized
| 2634538 | ecrin-mdr-crc
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:This study evaluates the similarity of adaptive immune mechanisms between jawless and jawed vertebrates using lamprey cytidine deaminase (CDA). We identified the ancestral gene Lr-CDAs of the AID/APOBEC deaminase family and evaluated its biological function in vivo. Lr-CDA1 deletion affected the assembly of three types of variable lymphocyte receptors (VLRs). We identified a switch-like region in lamprey gVLRs bound to Lr-CDAs, which upon repression, downregulated VLRB expression. Overall, we propose that lampreys have an early form of class switch recombination (CSR) that is mediated by Lr-CDAs and acts on gVLRs, affecting the assembly, maturation, and diversity regulation of VLR genes in Lethenteron reissneri. This CSR process in lampreys is linked to tumorigenesis and chromosomal translocation markers via Lr-CDAs.
2024-04-16 | GSE252201 | GEO
Project description:Retroviruses cause lifelong infections resulting from their ability to thwart innate immunity. The Apobec family of cytidine deaminases are part of the innate immune response that recognizes and mutates foreign nucleic acids, including those from multiple viruses. Multiple retroviral antagonists of Apobecs have been identified, including mouse mammary tumor virus (MMTV)-encoded Rem protein. Previous experiments have shown that Rem-null MMTV or closely related TBLV proviruses from BALB/c tumors accumulate G-to-A and C-to-T mutations typical of Apobecs compared to wild-type proviruses expressing Rem. The difference in mutations between Rem-expressing and non-expressing MMTV strains largely disappeared in mice lacking the Apobec family member, activation-induced cytidine deaminase (AID). These results suggested that Rem is an AID antagonist. In this study, we attempted to study AID-mediated mutations of TBLV proviruses lacking Rem expression obtained from tumors in C57BL/6 (B6) wild-type and AID-knockout backgrounds. Surprisingly, no differences in G-to-A mutations were observed in TBLV proviruses regardless of Rem expression, yet such mutations were significantly reduced in proviruses obtained from mA3/AID-double knockout mice relative to those from wild-type B6 or AID-knockout mice. Many cellular mRNAs involving the innate immune response, but not Apobecs, were elevated in the absence relative to the presence of Rem expression on the B6 AID-knockout background. These results revealed that Apobec-mediated mutagenesis is dependent on mouse strain and suggested a second means of Rem-dependent immune evasion.
2024-04-16 | GSE263741 | GEO
Project description:Base editing with a Cpf1–cytidine deaminase fusion
| PRJNA432936 | ENA
Project description:Retroviruses cause lifelong infections resulting from their ability to thwart innate immunity. The Apobec family of cytidine deaminases are part of the innate immune response that recognizes and mutates foreign nucleic acids, including those from multiple viruses. Multiple retroviral antagonists of Apobecs have been identified, including mouse mammary tumor virus (MMTV)-encoded Rem protein. Previous experiments have shown that Rem-null MMTV or closely related TBLV proviruses from BALB/c tumors accumulate G-to-A and C-to-T mutations typical of Apobecs compared to wild-type proviruses expressing Rem. The difference in mutations between Rem-expressing and non-expressing MMTV strains largely disappeared in mice lacking the Apobec family member, activation-induced cytidine deaminase (AID). These results suggested that Rem is an AID antagonist. In this study, we attempted to study AID-mediated mutations of TBLV proviruses lacking Rem expression obtained from tumors in C57BL/6 (B6) wild-type and AID-knockout backgrounds. Surprisingly, no differences in G-to-A mutations were observed in TBLV proviruses regardless of Rem expression, yet such mutations were significantly reduced in proviruses obtained from mA3/AID-double knockout mice relative to those from wild-type B6 or AID-knockout mice. Many cellular mRNAs involving the innate immune response, but not Apobecs, were elevated in the absence relative to the presence of Rem expression on the B6 AID-knockout background. These results revealed that Apobec-mediated mutagenesis is dependent on mouse strain and suggested a second means of Rem-dependent immune evasion.
2024-04-15 | GSE263655 | GEO
Project description:APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
| PRJNA226257 | ENA
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